Mass spectrometer and method

Abstract

To recognize a noise.SOLUTION: A method includes steps of: acquiring a time region signal expressing an electric charge that is executed by a computer containing a processor and a memory, and is induced into an induction electric charge detector by an ion moved in an electric charge detection mass spectrometer, that is, a CDMS; converting the time region signal into a frequency region spectrum containing a continuous pair frequency fluctuation; and excluding a specific frequency pair fluctuation without having their harmonic frequency pair fluctuation to the continuous pair frequency fluctuation from the continuous pair frequency fluctuation.SELECTED DRAWING: Figure 4A

Description

[Technical field]

[0001] The present invention relates to a charge detection mass spectrometer (CDMS). [Background technology]

[0002] Charge Detection Mass Spectrometry (CDMS) is a technique that allows the deconvolution of complex spectra of macromolecules. As the size of a molecule increases, so does the number of different charge states that the molecule can acquire. At the limit, the charge states of molecules with different masses overlap, resulting in a smeared continuum on the mass-to-charge m / z scale of a conventional mass spectrometer (MS). Such mass spectra provide little or no analytically useful information, as individual species no longer stand out as distinct peaks. This is particularly problematic for electrospray of macromolecules, because this ionization technique results in many different charge states as molecular mass increases. In contrast to MS, which determines the mass-to-charge m / z of an ion, CDMS determines the mass (i.e., not just the mass-to-charge m / z) by determining both the mass-to-charge m / z and charge z of the ion. In conventional CDMS, individual ions are injected into an ion trap and oscillated back and forth through an induced charge detector. A particular ion induces a small measurable voltage upon entering the induced charge detector tube, the amplitude of which is proportional to its charge. The measured period time of the oscillation gives the mass-to-charge ratio m / z of the particular ion, and the product of these two measurements gives the true mass of the particular ion. By allowing many oscillations in the ion trap and analyzing the resulting signal by Fourier Transform (FT), the accuracy of both the charge measurement and the mass-to-charge ratio m / z measurement is improved. The measurement of true mass is in contrast to conventional MS such as orthogonal-acceleration time-of-flight (oa-TOF) MS, which only determines the mass-to-charge ratio m / z. In general, the accuracy of CDMS is determined by two limiting factors: electronic noise in the detection electronics, which gives the charge measurement uncertainty, and the energy spread of the incident ions, which gives the oscillation period variation.

[0003] In 2012, Contino and Jarrold [1] presented a charge detection mass spectrometer (CDMS, as the context would suggest, also known as a CDMS analyzer) with a detection limit of 30 elementary electrons for a single ion. This paper gives a comprehensive review of CDMS to date and is incorporated herein by reference in its entirety. This CDMS included a cone trap incorporating an electrospray source coupled to a dual hemispherical deflection analyzer (HDA), followed by a mirror image charge detector. Ions were energy selected by the dual HDA before entering the trap. The fundamental oscillation frequency of the trapped ions was extracted by fast Fourier transform (FFT). The oscillation frequency and kinetic energy gave the mass-to-charge ratio m / z of the trapped ion. The magnitude of the FFT at the fundamental frequency was proportional to the charge. In particular, this CDMS required the use of dual HDAs as energy filters to limit the spread of ion energies entering the electrostatic cone trap, thereby reducing the variation in oscillation frequency, to achieve a detection limit of 30 elementary electrons for single ions. However, limiting the spread of ion energies entering the electrostatic cone trap reduced the throughput of the CDMS. Lower noise electronics led by 2015 to Keifer, Shinholt, and Jarrold [2] to demonstrate improved charge accuracy, better than the integer level, sufficient for true mass determination.

[0004] In 2018, Hogan and Jarrold [3] employed a segmented electrostatic linear ion trap (ELIT) that has a lower dependence on the oscillation period with respect to ion energy than the cone trap of their predecessor CDMS. This CDMS also required the use of a dual HDA energy filter, but significant dependence on the oscillation frequency with ion energy spread and radial position remained. Notably, for this CDMS, the kinetic energy dependence of the ion oscillation frequency was reduced by an order of magnitude, which should have resulted in an order of magnitude reduction in the uncertainty of the mass-to-charge ratio m / z ratio determination. However, due to the orbital dependence of the ion oscillation frequency, only a four-fold improvement was achieved. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Charge detection mass spectrometry for single ions with a limit of detection of 30 charges - International Journal of Mass Spectrometry 345-347 (2013) 153-159 [Non-Patent Document 2] Charge Detection Mass Spectrometry with Almost Perfect Charge Accuracy - Anal. Chem. 2015, 87, 10330-10337 [Non-Patent Document 3] Optimized Electrostatic Linear Ion Trap for Charge Detection Mass Spectrometry - J. Am. Soc. Mass Spectrom. (2018) Oct; 29(10):2086-2095 Summary of the Invention [Problem to be solved by the invention]

[0006] One object of the present invention is, inter alia, to provide a method, computer, computer program, instructions and / or CDMS that at least partially obviates or mitigates at least some of the disadvantages of the prior art, whether specified herein or elsewhere. For example, it is an object of embodiments of the present invention to provide a method that allows for improved detection limits. For example, it is an object of embodiments of the present invention to provide a method that allows for increased dynamic range. For example, it is an object of embodiments of the present invention to improve the accuracy and / or resolution of mass-to-charge, charge and / or mass of ions. [Means for solving the problem]

[0007] A first aspect is a method for identifying noise, the method being implemented by a computer including a processor and a memory, the method comprising: acquiring a time domain signal representative of charge induced in an induced charge detector by ions traveling in a charge detection mass spectrometer or CDMS; converting the time domain signal into a frequency domain spectrum comprising a series of frequency-amplitude pairs; and eliminating from the series of frequency-amplitude pairs any particular frequency-amplitude pair that does not have a harmonic frequency-amplitude pair in the series of frequency-amplitude pairs.

[0008] A second aspect provides at least one of: a computer including a processor and a memory configured to perform a method according to the first aspect; a computer program including instructions that, when executed by a computer including a processor and a memory, cause the computer to perform the method according to the first aspect; and a non-transitory computer-readable storage medium including instructions that, when executed by a computer including a processor and a memory, cause the computer to perform the method according to the first aspect.

[0009] A third embodiment is a charge detection mass spectrometer, or CDMS, comprising: an electrostatic field ion trap including a set of electrostatic electrodes including a first electrostatic electrode and a second electrostatic electrode, and an induced charge detector, the electrostatic field ion trap configured to at least partially define an ion path through the induced charge detector; a computer including a processor and a memory configured to carry out the method according to the first aspect; Provides CDMS including

[0010] According to the invention there is provided a method as set out in the accompanying claims. Also provided is a computer, a computer program, instructions and / or a CDMS. Further features of the invention will become apparent from the dependent claims and the following description.

[0011] method A first aspect is a method for identifying noise, the method being implemented by a computer including a processor and a memory, the method comprising: acquiring a time domain signal representative of charge induced in an induced charge detector by ions traveling in a charge detection mass spectrometer or CDMS; converting the time domain signal into a frequency domain spectrum comprising a series of frequency-amplitude pairs; and eliminating from the series of frequency-amplitude pairs any particular frequency-amplitude pair that does not have a harmonic frequency-amplitude pair in the series of frequency-amplitude pairs.

[0012] In this manner, noise in the frequency domain spectrum is attenuated because certain frequency-amplitude pairs that do not have their harmonic frequency-amplitude pairs in the set of frequency-amplitude pairs are filtered out therefrom (referred to herein as harmonic filtering). That is, certain frequency-amplitude pairs that do not have their harmonic frequency-amplitude pairs in the set of frequency-amplitude pairs are identified (i.e., distinguished, discriminated) as noise (i.e., false positives) from other frequency-amplitude pairs that do have their harmonic frequency-amplitude pairs in the set of frequency-amplitude pairs, which correspond to charges induced in the induced charge detector by ions moving in the CDMS (i.e., positives such as true positives). In particular, the inventors have determined that charges induced in the induced charge detector due to noise, such as electronic noise, are typically described by a single frequency-amplitude pair (i.e., fundamental or first harmonic) that does not have higher harmonics. In contrast, the inventors have determined that the charge induced in the induced charge detector due to an ion is typically described by more than one frequency-amplitude pair (i.e., the fundamental or first harmonic and at least one higher harmonic). Furthermore, the inventors have determined that the harmonic signature of the ion (i.e., the specific harmonic frequency-amplitude pairs contained in the frequency domain spectrum) can be predetermined by the design, e.g., geometry, of the CDMS and / or the induced charge detector. In other words, the noise components in the time domain signal are removed from the time domain signal by excluding the corresponding noise frequency-amplitude pairs from the frequency domain spectrum. In this way, the detection limit of the CDMS is improved and / or the dynamic range of the CDMS is expanded since the noise is attenuated. In particular, since the noise is removed by excluding certain frequency-amplitude pairs as noise from the set of frequency-amplitude pairs, the accuracy and / or resolution of the mass-to-charge, charge and / or mass of the ion calculated using the retained (i.e., not excluded) frequency-amplitude pairs of the set of frequency-amplitude pairs can be improved.

[0013] In particular, the inventors have determined that noise, e.g., electronic noise, such as that resulting from the application of a trapping potential and / or arising in the induced charge detector, its amplifiers and / or associated electronics, significantly limits the detection limit and / or dynamic range of conventional CDMS. Without proper noise reduction, the tiny charge induced from ions as they move through the induced charge detector can be overridden (i.e., masked, dominated, hidden) by noise, thus significantly limiting the detection limit and / or dynamic range of a CDMS.

[0014] Typically, an ion or a population of ions is introduced into a CDMS, typically grounded, electrostatic field ion trap, and trapped there by potentials applied to a set of electrodes of the electrostatic field ion trap. The ion or population of ions moves through (i.e., passes) an induced charge detector along an ion path at least partially defined by the electrostatic field ion trap, e.g., oscillating along or around the ion path, such that a charge (typically a signal) is induced thereon. The respective amplitude of the induced signal is proportional to the charge of the ion or the respective charge of the population of ions, and the periodic time of the respective movement results in the mass-to-charge ratio m / z of the ion or the mass-to-charge ratio m / z of each ion of the population of ions. In conventional CDMS, noise, e.g., electronic noise, can alter the measured amplitude of the induced charge, change the measured periodic time of the movement, and / or interfere with the measurement of the ion or population of ions, thereby adversely affecting the measurement accuracy and thus significantly limiting the detection limit and / or dynamic range of conventional CDMS.

[0015] More specifically, the inventors have identified at least two different noise sources, eg, electronic noise sources, that are preferably reduced or eliminated, as follows. I. A relatively large pick-up pulse can occur due to the rising edge of the switching of a set of power supplies (ie, the high voltage power supplies) at the trapping initiation event (ie, the potentials applied to the electrostatic ion trap at time t0).

[0016] II. During the acquisition time after the set of power supplies has settled to its required voltage level, voltage ripple and / or electronic noise may be injected from the set of power supplies. In particular, the inventors have recognized that both of these noise sources result from capacitive pick-up, for example from the electric field region between the electrostatic electrodes of the CDMS, leaking into the induced charge detector itself, thereby inducing a noise signal that is received by the amplifier. That is, the noise signal is induced in the induced charge detector as a result of changes in the electric field of the set of electrostatic electrodes. Examples of changes that cause an induced noise signal include the rising edge of the switching of the set of power supplies at the trapping start event (i.e. the potentials applied to the electrostatic field ion trap at time t0), voltage ripple and / or electronic noise from the set of power supplies during the collection time, and the falling edge of the switching of the set of power supplies at the trapping end event.

[0017] Additionally and / or alternatively, the inventors have realized that the method according to the first aspect is agnostic to noise sources and is therefore suitable for identifying noise originating from any noise source, such as from ion fragmentation when the ion decays during acquisition of the time-varying signal. In this way, the method according to the first aspect generally handles noise attenuation without requiring special processing for noise originating from a given noise source. In this way, noise attenuation is simplified compared to conventional methods, since the method for identifying noise is generally applicable independent of the noise source. Additionally and / or alternatively, the method according to the first aspect requires relatively low computational resources compared to conventional methods, since the method for identifying noise is generally applicable independent of the noise source. For example, the method according to the first aspect can be performed in real time, as described in more detail below, and is suitable for, for example, data directed acquisition (DDA).

[0018] Identifying Noise A first aspect provides a method of identifying noise. It should be understood that noise, e.g. electronic noise, includes and / or is an unwanted component (also known as an undesired component) in the time domain signal (i.e., a false positive). It should be understood that noise is identified (i.e., distinguished, discriminated) from a wanted component (also known as a desired component) in the time domain signal (i.e., a true positive) resulting from a charge induced in an induced charge detector by an ion moving in the CDMS. Thus, in one example, the method includes and / or is a method of identifying an unwanted component, e.g., noise, in the time domain signal from a wanted component in the time domain signal resulting from a charge induced in an induced charge detector by an ion moving in the CDMS. Additionally and / or alternatively, in one example, the method includes and / or is a method of eliminating noise.

[0019] Identifying the noise More generally, a first aspect is a method for identifying noise, implemented by a computer including a processor and a memory, comprising: acquiring a time domain signal representative of charge induced in an induced charge detector by ions traveling in a charge detection mass spectrometer or CDMS; converting the time domain signal into a frequency domain spectrum comprising a series of frequency-amplitude pairs; and identifying as noise certain frequency-amplitude pairs from the set of frequency-amplitude pairs that do not have harmonic frequency-amplitude pairs in the set of frequency-amplitude pairs.

[0020] In this manner, certain frequency-amplitude pairs of a series of frequency-amplitude pairs may be identified as noise, thereby enabling, for example, the elimination of the noise and / or investigation of its source. computer The method is implemented by a computer including a processor and a memory. Suitable computers are known. In one example, the method is implemented by a computer offline, at-line, online and / or in real-time (i.e., with respect to using CDMS to collect a time domain signal representative of charge induced in an induced charge detector by ions moving in the CDMS). For example, the time domain signal can be collected using CDMS, stored in a storage device, and subsequently (i.e., thereafter) post-processed offline using the method. For example, the time domain signal can be collected using CDMS, stored in a storage device, and processed and / or post-processed in parallel (i.e., simultaneously) and / or subsequently at-line using the method. For example, the time domain signal can be collected using CDMS and processed in parallel (i.e., simultaneously) online using the method. For example, the time domain signal can be collected using CDMS and processed in parallel (i.e., simultaneously) in real-time (i.e., fast enough to control the collection of the same sample or subsequent samples using CDMS) using the method.

[0021] Time Domain Signal The method includes acquiring a time domain signal representative of charge induced in an induced charge detector by ions traveling in a charge detection mass spectrometer, or CDMS.

[0022] It should be understood that the time domain signal includes and / or is a time varying signal (also known as a transient signal). It should be understood that the induced charge (i.e. the charge induced in the induced charge detector) is caused by the presence of an ion in its vicinity. It should be understood that the induced charge has a polarity opposite to that of the ion. It should be understood that the magnitude of the induced charge is proportional to the charge of the ion. It should be understood that the frequency (also known as frequency content) of the time domain signal is equal to the frequency of the periodic motion, e.g., oscillation around the ion path continuously or along the ion path at a constant speed or back and forth motion along the ion path, from which the mass to charge of the ion can be calculated. It should be understood that the amplitude of the time domain signal represents the charge of the ion. It should be understood that noise contributes to the frequency and / or amplitude of the time domain signal and therefore noise degrades the detection limit, dynamic range, mass to charge accuracy and / or resolution, charge accuracy and / or resolution and / or mass accuracy and / or resolution.

[0023] Inductive charge detectors suitable for CDMS are known. In one example, the ions include and / or are a single ion, and acquiring a time domain signal representative of a charge induced in an induced charge detector by an ion moving through the CDMS comprises acquiring a time domain signal representative of a charge induced in an induced charge detector by a single ion moving through the CDMS. As such, the method is suitable for analysis of mass-to-charge, charge and / or mass of a single ion.

[0024] In one example, obtaining a time domain signal representative of the charge induced in the induction detector by the ions moving in the CDMS includes obtaining a time domain signal representative of the charge induced in the induction detector by a plurality of ions moving in the CDMS, including the ions described above, optionally with mutually different mass-to-charge ratios. In other words, the plurality of ions includes the ions described above. In this manner, the method is suitable for analyzing the mass-to-charge, charge and / or mass of a plurality of ions, for example, analyzing the mass-to-charge, charge and / or mass of each of the plurality of ions (i.e., individually). It should be understood that the plurality of ions may include ions that are similar or different (i.e., have the same or different mass-to-charge, charge and / or mass). Thus, it should be understood that the time domain signal is contributed by the respective charges induced by the plurality of ions, and the respective mass-to-charge, charge and / or mass of each ion can be determined therefrom individually.

[0025] In one example, obtaining a time domain signal representative of charges induced in an induced charge detector by ions moving in the CDMS includes obtaining a time domain signal representative of respective charges induced in an induced charge detector by a population of ions including ions moving in the CDMS. In this manner, the method is suitable for mass-to-charge, charge and / or mass analysis of a population of ions, such as respective mass-to-charge, charge and / or mass analysis of a population of ions (i.e., individually). It should be understood that a population of ions may include ions that are similar or different (i.e., have the same or different mass-to-charge, charge and / or mass). Thus, it should be understood that the time domain signal is contributed by respective charges induced by the population of ions, and the respective mass-to-charge, charge and / or mass of each ion can be determined therefrom individually.

[0026] In one example, acquiring a time domain signal representative of charge induced in an induced charge detector by ions moving in the CDMS includes acquiring a time domain signal representative of charge induced in an induced charge detector by ions moving in the CDMS via (i.e., passing and / or through) the induced charge detector N times, where N is a natural number equal to or greater than 1, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, 100, 200, 500 or more. Generally, ions move around an ion path defined by the CDMS through at least one revolution (also known as an orbit), and preferably through at least N revolutions, where N is a natural number equal to or greater than 1, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, 100, 200, 500 or more. Thus, a CDMS may be known as a multi-turn CDMS. In general, increasing the number of revolutions that an ion travels, and therefore the measurement time, reduces the uncertainty of the mass determined therefrom. However, increasing the number of revolutions also increases the analysis time, while increasing the possibility of loss of a particular ion due to collisions with residual gas, other ions, and / or the walls of the CDMS. The vacuum level is, for example, at most 2.7×10 -7 Pa(2×10 -9 By improving the pressure to 300 MPa (100 psi) or higher, the probability of loss of a particular ion due to collisions with residual gas can be reduced, thereby allowing the number of revolutions to be increased. Thus, the number of revolutions an ion travels can be balanced accordingly.

[0027] Suitable CDMS are known, as described in more detail in relation to the third aspect. In one example, acquiring a time domain signal representative of charge induced in the inductive detector by ions moving in the CDMS includes acquiring a time domain signal representative of charge induced in the inductive detector by ions moving in one direction and / or at a constant velocity in the CDMS. Thus, the method is suitable for an orbital electrostatic field sector ion trap, e.g., as described in more detail with respect to the third aspect. For example, ions typically orbit around the electrostatic field sector ion trap in one direction and / or at a constant velocity.

[0028] In one example, acquiring a time domain signal representative of charge induced in an inductive detector by ions moving in the CDMS includes acquiring a time domain signal representative of charge induced in an inductive detector by ions moving harmonically and / or bidirectionally in the CDMS. In this manner, the method is suitable for ELIT and / or Orbitrap, e.g., as described in more detail with respect to the third aspect. For example, ions typically oscillate bidirectionally in an ELIT with axial harmonic motion. For example, ions typically oscillate radially and axially in an Orbitrap with simple axial harmonic motion.

[0029] conversion The method includes transforming the time domain signal into a frequency domain spectrum comprising a series of frequency-amplitude pairs. It should be understood that the series of frequency-amplitude pairs describes the frequencies present in the time domain signal. It should be understood that the series of frequency-amplitude pairs may comprise one or more frequency-amplitude pairs, for example, depending on the number of frequencies present in the time domain signal. It should be understood that the amplitudes of more frequency-amplitude pairs may represent the peak area or peak height of a peak in the frequency domain spectrum.

[0030] In one example, the set of frequency-amplitude pairs includes S frequency-amplitude pairs (where S is a natural number equal to or greater than 1), for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 20000, 30000, 40000, 50000, 60000, 70000, 80000, 90000, 100000, or more frequency-amplitude pairs. It should be understood that in general, the number of frequency-amplitude pairs S increases with the number of ions and / or noise.

[0031] In one example, converting the time domain signal into a frequency domain spectrum including a series of frequency-amplitude pairs includes converting the time domain signal into a frequency domain spectrum including a series of frequency-amplitude pairs using a Fourier transform, such as a fast Fourier transform, an FT, i.e., an FFT, and / or a two-sided Laplace transform, a Mellin transform, a Laplace transform, a Fourier series transform, a sine and / or a cosine transform, a Hartley transform, a short-time Fourier transform (STFT), a rectangular mask short-time Fourier transform, a Chirplet transform, a fractional Fourier transform (FRFT), a Hankel transform, a Fourier-Bros-Iagolnitzer transform, and / or a linear canonical transform, and / or a Fourier-related transform. Other suitable transforms are also known. In one preferred example, the FT includes and / or is an FFT. In this way, converting the time domain signal into a frequency domain spectrum including a series of frequency-amplitude pairs can be performed efficiently and requires relatively low computational resources.

[0032] In one example, converting the time domain signal into a frequency domain spectrum comprising a series of frequency-amplitude pairs includes converting the time domain signal into a frequency domain spectrum comprising a series of frequency-amplitude pairs using a maximum entropy method. Suitable maximum entropy methods are known.

[0033] In one example, converting the time domain signal into a frequency domain spectrum comprising a series of frequency-amplitude pairs includes converting the time domain signal into a frequency domain spectrum comprising a series of frequency-amplitude pairs using a Fourier transform, or FT, and a maximum entropy method, as described above.

[0034] Time-Domain Signal Preprocessing In one example, the method includes pre-processing the time domain signal before converting the time domain signal into a frequency domain spectrum including a series of frequency-amplitude pairs, e.g., pre-processing the time domain signal includes windowing (e.g., excluding certain time ranges such as the beginning or end, and / or including only certain time ranges of interest such as when ions are moving, and / or excluding certain time ranges of no interest such as when ions break up during collection of the time-varying signal), data cleaning (e.g., finding, removing, and / or replacing bad and / or missing data), smoothing (e.g., eliminating high variance data), detrending (e.g., removing trends), scaling or normalizing (e.g., changing boundaries), and / or filtering (e.g., band-pass, high-pass, and / or low-pass filtering), etc. In this way, for example, artifacts in the time domain signal can be removed.

[0035] Inspecting signals in the time domain In one example, the method includes examining the time domain signal for consistency of the frequency domain spectrum as a function of time, for example, by subdividing the time domain signal into a plurality of time domain signal segments (e.g., as successive or moving time windows), converting the plurality of time domain signal segments into a plurality of corresponding frequency domain spectra, comparing the plurality of frequency domain spectra to one another, and discarding one or more of the corresponding time domain signal segments based on the results of the comparison. In this way, for example, ion fragmentation can be identified and one or more of the corresponding time domain signal segments can be discarded.

[0036] Thresholding a series of frequency-amplitude pairs In one example, the method includes removing one or more frequency-amplitude pairs from the set of frequency-amplitude pairs that have a frequency equal to or greater than a threshold frequency, e.g., a predetermined absolute or relative threshold frequency (such as the top 30%, 20%, or 10%). Thus, for example, prior to the elimination step, frequency-amplitude pairs having relatively high frequencies can be removed from the set of frequency-amplitude pairs, thereby reducing the number of frequency-amplitude pairs that may be eliminated (i.e., reducing calculations).

[0037] In one example, the method includes removing one or more frequency-amplitude pairs from the set of frequency-amplitude pairs that have an amplitude below a threshold frequency, e.g., a predetermined absolute or relative threshold amplitude (such as the bottom 30%, 20%, or 10%). Thus, for example, prior to the elimination step, frequency-amplitude pairs having relatively low amplitudes can be removed from the set of frequency-amplitude pairs, thereby reducing the number of frequency-amplitude pairs that may be eliminated (i.e., reducing calculations).

[0038] exclusion The method includes eliminating from the set of frequency-amplitude pairs certain frequency-amplitude pairs that do not have harmonic frequency-amplitude pairs in the set of frequency-amplitude pairs. The harmonics of a particular frequency-amplitude pair are conventionally determined, and it should be understood that each harmonic frequency-amplitude pair has a frequency (within a tolerance as described below) that is an integer multiple of the frequency of the frequency-amplitude pair (typically the fundamental or first harmonic).

[0039] In particular, the inventors have determined that charge induced in an induced charge detector due to noise, such as electronic noise, is typically described by a single frequency-amplitude pair (i.e., the fundamental or first harmonic) with no higher order harmonics. In contrast, the inventors have determined that charge induced in an induced charge detector due to an ion is typically described by more than one frequency-amplitude pair (i.e., the fundamental or first harmonic and at least one higher order harmonic). Furthermore, the inventors have determined that the harmonic signature of an ion (i.e., the particular harmonic frequency-amplitude pairs contained in the frequency domain spectrum) can be predetermined by the design, e.g., geometry, of the CDMS and / or the induced charge detector.

[0040] In one example, eliminating particular frequency-amplitude pairs from the series of frequency-amplitude pairs that do not have their harmonic frequency-amplitude pairs in the series of frequency-amplitude pairs includes iterating through the series of frequency-amplitude pairs and eliminating each particular frequency-amplitude pair from the series of frequency-amplitude pairs that does not have its harmonic frequency-amplitude pair in the series of frequency-amplitude pairs.

[0041] In one example, eliminating a particular frequency-amplitude pair from the set of frequency-amplitude pairs that does not have its harmonic frequency-amplitude pair in the set of frequency-amplitude pairs includes eliminating a particular frequency-amplitude pair from the set of frequency-amplitude pairs that does not have its harmonic frequency-amplitude pair in the set of frequency-amplitude pairs within a predetermined frequency tolerance range, for example, the predetermined frequency tolerance range is absolute (i.e., constant) or relative (i.e., proportional to frequency). In this manner, frequency-amplitude pairs having respective frequencies that are close to the harmonic frequencies of the particular frequency-amplitude pair can be identified. In contrast, if no frequency-amplitude pair is identified that is close to the harmonic frequencies of the particular frequency-amplitude pair, the particular frequency-amplitude pair can be eliminated.

[0042] In one example, eliminating certain frequency-amplitude pairs from the set of frequency-amplitude pairs that do not have their harmonic frequency-amplitude pairs in the set of frequency-amplitude pairs includes eliminating certain frequency-amplitude pairs from the set of frequency-amplitude pairs that do not have their harmonic frequency-amplitude pairs in the set of frequency-amplitude pairs within a predetermined amplitude tolerance range, e.g., the predetermined amplitude tolerance range is absolute (i.e., constant) or relative (i.e., proportional to the amplitude of the particular frequency-amplitude pair). In this manner, frequency-amplitude pairs having respective amplitudes relative to the amplitude of the particular frequency-amplitude pair can be identified. In contrast, certain frequency-amplitude pairs can be eliminated if they do not have an amplitude relative to the amplitude of the particular frequency-amplitude pair. In particular, the inventors have determined that the relative amplitude of a harmonic signature (i.e., a particular harmonic frequency-amplitude pair in the frequency domain spectrum) can be characteristic of ions traveling in a CDMS and can be calculated, e.g., by modeling.

[0043] In one example, eliminating a particular frequency-amplitude pair from the set of frequency-amplitude pairs that does not have its harmonic frequency-amplitude pair in the set of frequency-amplitude pairs includes eliminating a particular frequency-amplitude pair from the set of frequency-amplitude pairs that does not have a predetermined harmonic signature (i.e., a particular harmonic frequency-amplitude pair contained in the frequency domain spectrum). In particular, the inventors have determined that the harmonic signature (i.e., a particular harmonic frequency-amplitude pair contained in the frequency domain spectrum) of an ion can be predetermined by the design, e.g., geometry, of the CDMS and / or induced charge detector. For example, the harmonic signature may include only the fundamental or the first and second harmonics. For example, the harmonic signature may include only the fundamental or the first, second and third harmonics. For example, the harmonic signature may include only the fundamental or the first and third harmonics. For example, the harmonic signature may include only the fundamental or the first and odd harmonics. For example, the harmonic signature may include only the fundamental or the first and even harmonics.

[0044] In one example, eliminating from the series of frequency-amplitude pairs certain frequency-amplitude pairs that do not have a harmonic frequency-amplitude pair in the series of frequency-amplitude pairs includes eliminating from the series of frequency-amplitude pairs certain frequency-amplitude pairs that have a predetermined harmonic frequency-amplitude pair in the series of frequency-amplitude pairs, preferably a predetermined third and / or higher harmonic frequency-amplitude pair.

[0045] In one example, eliminating certain frequency-amplitude pairs from the set of frequency-amplitude pairs that do not have their harmonic frequency-amplitude pairs in the set of frequency-amplitude pairs includes eliminating certain frequency-amplitude pairs from the set of frequency-amplitude pairs that do not have a predetermined harmonic frequency-amplitude pair signature in the set of frequency-amplitude pairs.

[0046] In one example, eliminating a particular frequency-amplitude pair from the set of frequency-amplitude pairs that does not have its harmonic frequency-amplitude pair in the set of frequency-amplitude pairs includes eliminating one particular frequency-amplitude pair, all particular frequency-amplitude pairs, and / or only the particular frequency-amplitude pair from the set of frequency-amplitude pairs that does not have its harmonic frequency-amplitude pair in the set of frequency-amplitude pairs. In this way, all unwanted frequency-amplitude pairs, such as those resulting from noise, can be removed.

[0047] retention In one example, the method includes retaining a particular frequency-amplitude pair from the series of frequency-amplitude pairs that has a harmonic frequency-amplitude pair in the series of frequency-amplitude pairs, such that a desired frequency-amplitude pair, e.g., resulting from one or more ions, can be retained.

[0048] In one example, the method includes retaining all particular frequency-amplitude pairs from the set of frequency-amplitude pairs that have harmonic frequency-amplitude pairs in the set of frequency-amplitude pairs, such that all desired frequency-amplitude pairs resulting from one or more ions, for example, can be retained.

[0049] Additionally and / or alternatively, the first aspect provides a method of identifying noise, the method being implemented by a computer including a processor and a memory, the method comprising: acquiring a time domain signal representative of charge induced in an induced charge detector by ions traveling in a charge detection mass spectrometer or CDMS; converting the time domain signal into a frequency domain spectrum comprising a series of frequency-amplitude pairs; and retaining, from the set of frequency-amplitude pairs, one particular frequency-amplitude pair, all the particular frequency-amplitude pairs, and / or only the particular frequency-amplitude pairs that have harmonic frequency-amplitude pairs in the set of frequency-amplitude pairs.

[0050] In one example, retaining a particular frequency-amplitude pair having its harmonic frequency-amplitude pair in the set of frequency-amplitude pairs includes retaining a particular frequency-amplitude pair having its harmonic frequency-amplitude pair in the set of frequency-amplitude pairs within a predetermined frequency tolerance, e.g., the predetermined frequency tolerance is absolute (i.e., constant) or relative (i.e., proportional to frequency). In this manner, a frequency-amplitude pair having a frequency close to a harmonic frequency of the particular frequency-amplitude pair can be identified and retained. In contrast, if no frequency-amplitude pair is identified close to a harmonic frequency of the particular frequency-amplitude pair, the particular frequency-amplitude pair can be excluded.

[0051] In one example, retaining a particular frequency-amplitude pair having its harmonic frequency-amplitude pair in the set of frequency-amplitude pairs includes retaining a particular frequency-amplitude pair having its harmonic frequency-amplitude pair in the set of frequency-amplitude pairs within a predetermined amplitude tolerance, e.g., the predetermined amplitude tolerance may be absolute (i.e., constant) or relative (i.e., proportional to the amplitude of the particular frequency-amplitude pair). In this manner, a frequency-amplitude pair having its amplitude relative to the amplitude of the particular frequency-amplitude pair may be identified. In contrast, a particular frequency-amplitude may be rejected if the frequency-amplitude pair does not have an amplitude relative to the amplitude of the particular frequency-amplitude pair. In particular, the inventors have determined that the relative amplitude of a harmonic signature (i.e., a particular harmonic frequency-amplitude pair in the frequency domain spectrum) may be characteristic of ions traveling in a CDMS and may be calculated, e.g., by modeling.

[0052] In one example, retaining, from the series of frequency-amplitude pairs, a particular frequency-amplitude pair having its harmonic frequency-amplitude pair in the series of frequency-amplitude pairs includes retaining, from the series of frequency-amplitude pairs, a particular frequency-amplitude pair having its predetermined harmonic frequency-amplitude pair, preferably only a predetermined second harmonic frequency-amplitude pair, in the series of frequency-amplitude pairs.

[0053] In one example, retaining, from the series of frequency-amplitude pairs, particular frequency-amplitude pairs having their harmonic frequency-amplitude pairs in the series of frequency-amplitude pairs includes retaining, from the series of frequency-amplitude pairs, particular frequency-amplitude pairs having a predetermined harmonic frequency-amplitude pair signature in the series of frequency-amplitude pairs.

[0054] In one example, retaining a particular frequency-amplitude pair in the series of frequency-amplitude pairs that has its harmonic frequency-amplitude pair in the series of frequency-amplitude pairs includes retaining a particular frequency-amplitude pair in the series of frequency-amplitude pairs that has a predetermined harmonic signature (i.e., a particular harmonic frequency-amplitude pair in the frequency domain spectrum). In particular, the inventors have determined that the harmonic signature (i.e., a particular harmonic frequency-amplitude pair in the frequency domain spectrum) of an ion can be predetermined by the design, e.g., geometry, of the CDMS and / or induced charge detector. For example, the harmonic signature may include only the fundamental or the first and second harmonics. For example, the harmonic signature may include only the fundamental or the first, second and third harmonics. For example, the harmonic signature may include only the fundamental or the first and third harmonics. For example, the harmonic signature may include only the fundamental or the first and odd harmonics. For example, the harmonic signature may include only the fundamental or the first and even harmonics.

[0055] calculation In one example, the method includes calculating the mass to charge ratio of the ions using the frequencies of the retained frequency-amplitude pairs, and optionally using the frequencies of each harmonic frequency-amplitude pair.

[0056] In one example, the method includes calculating the charge of the ion using the amplitudes of the retained frequency-amplitude pairs, and optionally using the amplitudes of each harmonic frequency-amplitude pair.

[0057] In one example, the method includes calculating a mass of the ion using the calculated mass to charge ratio of the ion and the calculated charge of the ion. collection In one example, obtaining a time domain signal representative of charge induced in an induced charge detector by ions moving in the CDMS includes using the CDMS to collect a time domain signal representative of charge induced in the induced charge detector by ions moving in the CDMS.

[0058] control In one example, the method includes using the calculated mass to charge ratio of the ions and / or the charges of the ions to control the CDMS, for example in real time.

[0059] Computer, computer program, and non-transitory computer-readable storage medium A second aspect provides a computer including a processor and a memory configured to perform a method according to the first aspect; a computer program including instructions that, when executed by a computer including a processor and a memory, cause the computer to perform the method according to the first aspect; and / or a non-transitory computer-readable storage medium including instructions that, when executed by a computer including a processor and a memory, cause the computer to perform the method according to the first aspect.

[0060] CDMS A third embodiment is a charge detection mass spectrometer, or CDMS, comprising: an electrostatic field ion trap including a set of electrostatic electrodes including a first electrostatic electrode and a second electrostatic electrode, and an induced charge detector, the electrostatic field ion trap configured to at least partially define an ion path through the induced charge detector; and a computer including a processor and a memory, configured to perform the method according to the first aspect.

[0061] In one example, the CDMS is generally as described in WO 2022 / 049388 A1 and / or WO 2022 / 214815 A1, the subject matter of which is incorporated by reference herein.

[0062] Electrostatic ion trap The CDMS includes an electrostatic field ion trap including a set of electrostatic electrodes including a first electrostatic electrode and a second electrostatic electrode. As described below, the electrostatic field ion trap may include and / or may be, for example, an electrostatic sector field ion trap and / or an electrostatic linear field ion trap. It should be understood that the set of electrostatic electrodes includes a first electrostatic electrode and a second electrostatic electrode (i.e., a plurality of electrostatic electrodes). In one example, the set of electrostatic electrodes includes E electrostatic electrodes, where E is a natural number equal to or greater than 2, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, 100, 200, 500, or more. In one example, the first electrostatic electrode includes a stack of two or more electrostatic electrodes, for example, inner and outer electrodes of an electrostatic sector electrode or a cone trap electrode or a segmented electrode, as described below. The second electrostatic electrode may be as described mutatis mutandis with respect to the first electrostatic electrode.

[0063] Electrostatic sector ion trap In one example, the electrostatic field ion trap includes and / or is an electrostatic sector field ion trap, e.g., the first electrostatic electrode includes and / or is a first electrostatic sector electrode and the second electrostatic electrode includes and / or is a second electrostatic sector electrode. In one example, in a cylindrical, toroidal or spherical electrostatic sector, the first electrostatic sector electrode is an inner electrode and the second electrostatic sector electrode is an outer electrode, or the second electrostatic sector electrode is an inner electrode and the first electrostatic sector electrode is an outer electrode. It should be understood that an electrostatic sector field ion trap is a periodic structure and at least partially defines a closed ion path (also known as an orbit) such that ions can move (also known as oscillate) repeatedly around the closed ion path, e.g., an integer or non-integer number of revolutions. Typically, ions travel through at least one revolution around the ion path, preferably at least N revolutions, where N is a natural number equal to or greater than 1, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, 100, 200, 500, or more. Thus, electrostatic field sector ion traps may be known as multi-turn (also known as multi-pass) electrostatic field sector ion traps, and CDMSs may be known as multi-turn CDMSs. In general, increasing the number of revolutions that ions travel, and thus the measurement time, reduces the uncertainty of the mass determined therefor. However, increasing the number of revolutions also increases the analysis time, while increasing the possibility of loss of certain ions due to collisions with residual gas, other ions and / or the walls of the CDMS, etc. By increasing the vacuum, for example to a maximum of 2.7×10 -7 Pa(2×10 -9By improving the pressure to or above 100 MPa (Torr), the possibility of loss of a particular ion due to collisions with residual gas can be reduced, thereby increasing the number of revolutions. The number of revolutions an ion travels through can therefore be balanced accordingly. The fundamental frequency f (and / or its harmonics) of an ion travelling around the ion path depends on the mass-to-charge ratio m / z and is measured using an induced charge detector as described below. If the electrostatic field sector ion trap is isochronous to the first order, the mass uncertainty is reduced as described in more detail below, e.g. compared to the ELIT of ref. [3].

[0064] It should be understood that the electrostatic field sector ion trap is configured to at least partially define an ion path through the induced charge detector. That is, in use, the electrostatic field sector ion trap at least partially defines an ion path through the induced charge detector. By at least partially, it should be understood that the ion path may be completely defined by the electrostatic field sector ion trap, or alternatively may be partially defined by the electrostatic field sector ion trap and partially defined by one or more ion optical elements, such as lenses and / or magnets. In one example, the electrostatic field sector ion trap is configured to define (i.e. entirely define) an ion path through the induced charge detector. It should be understood that the ion path is the ion optical axis of a hypothetical perfect ion, and that the ion optical axis is an arcuate closed line that defines a plane. In contrast, energy spread means that the respective ion trajectories deviate in and out of plane from the ion optical axis, such that the ion path volumetrically sweeps around the ion optical axis, together with the angular and spatial deviations of the ion population. It should be understood that the orthogonal cross-section of the ion path, e.g. its shape and / or dimensions, may vary around the ion path. In particular, as described in more detail below, ions may be caused to, e.g. alternately, be point-focused and parallel-focused around the ion path, while a spherical electrostatic sector may, e.g., give rise to an at least partially spherical ion path. Additionally and / or alternatively, the ion path may be described and / or defined as an ion beam.

[0065] Ions are understood to move in a constant orientation around the ion path in that the trajectory direction is constant, even though the instantaneous direction of the ion's motion is constantly changing, which may be conveniently called unidirectional. In contrast, ions move back and forth in alternately opposite directions in ELITs such as the ELITs of Non-Patent Documents 2 and 3, which may be conveniently called bidirectional or reciprocating motion, resulting in mutual interactions between ions moving in opposite directions, which precludes the introduction of multiple ions therein. More specifically, depending on the heterogeneity of the sample, typically several thousand ions are measured to generate a mass spectrum. According to the sequential (or random) trapping mode of Non-Patent Document 3, the probability that the ELIT contains zero ions, one ion, or more than two ions is given by a Poisson distribution such that the maximum number of single-ion ELIT trapping events that can be realized is just 37% (i.e., a 37% duty cycle). For a 100 ms long trapping period, the optimal rate of single ion trapping events is equal to a maximum of about 13,300 single ion events per hour for ELIT, so that a spectrum of a homogeneous sample can be collected in less than half an hour under optimal conditions (i.e. when the signal is stable and the number of single ion trapping events is close to the maximum that can be achieved). In contrast, a unidirectional closed ion path defined at least in part by an electrostatic field sector ion trap can be used to simultaneously determine the mass of each of multiple ions, for example as described in more detail below, thereby reducing collection times compared to ELIT. In particular, as discussed above, the space charge capacity of an electrostatic field sector ion trap is increased compared to a reflection-based ion trap, and the unidirectional ion path reduces or eliminates mutual interactions between multiple ions, so that ions must slow down to low speeds as they orbit within the mirror section.Furthermore, for a given ion path length, the effective average cross-sectional area of ​​the ion path, and therefore its volume, is larger for an electrostatic field sector ion trap than for an ELIT, for example, because the ion path for an electrostatic field sector ion trap generally allows ions to fan out transversely to the ion optical axis, for example in an arc. Thus, an electrostatic field sector ion trap can be filled with a relatively large number of ions, for example, an order of magnitude more than an ELIT, while the kinetic energy of the ions is relatively constant. Furthermore, the bidirectional or reciprocating ion path of the ELIT of Non-Patent Documents 2 and 3, for example, induces overlapping signals in the charge tube when two or more ions are trapped, thereby interfering with mass determination. In contrast, the unidirectional ion path means that the possibility of overlapping signals being induced by two or more ions in the induced charge detector is reduced. In general, it should be understood that while partially overlapping induced signals can be separated in the frequency domain, completely overlapping induced signals, for example due to phase coherent ions, overtaking ions, or ions moving in opposite directions, may interfere with mass determination. Thus, to avoid phase coherent ions, it is preferable to avoid ion packets or clouds, while unidirectional paths preclude traveling in opposite directions. In particular, as described in more detail below, multiple ions can be introduced such that they are spatially and / or temporally separated from one another, thereby reducing or eliminating the possibility of inducing overlapping signals at the induced charge detector. Thus, by further increasing the number of ions in the electrostatic field sector ion trap to just 10, and because the duty cycle is not limited to only 37%, the same mass spectrum can instead be collected in less than a minute for ELIT.

[0066] In general, an ion optical description of the transfer of ions between the entrance and exit of an analyzer can be represented as a transfer matrix or via ray tracing. A curvilinear coordinate system (x,y,z) can be defined with its origin on the optical axis, with z along the optical axis. For ions of equal mass, such a transfer matrix, if time is of interest, can be written as

[0067]

number

[0068] where X and A describe the position (typically resolved into lateral deviations x, y) and tilt angle (typically resolved into angular deviations α, β) of a particular ion relative to the z-axis, respectively, and δK=(K / K0-1) and δT=(T / T0-1) are the relative energy and time deviations, respectively, with indexes i and i+1 indicating these quantities at the inlet and outlet, respectively. K and K0 are the energies of the reference ion and the particular ion, respectively, and T and T0 are the times at which the reference ion and the particular ion enter or leave the analyzer, respectively. (X|X) and (A|A) represent the magnification terms, and (X|A) and (A|X) represent the convergence terms. By making these terms equal to zero, respectively, parallel-to-point, point-to-parallel, point-to-point and parallel-to-parallel ion optics are provided. (X|δK), (A|δK) and (δT|δK) represent the dispersion terms for the energy deviations. Alternatively, the transfer matrix may be expressed in terms of, for example, lateral deflections x, y, angular deflections α, β and / or mass deflections γ.

[0069] For applications of interest, the ions originate from a low intensity source having relatively low energy (ie, low energy ions), but have a relatively large energy spread δK. Ions with the same mass-to-charge ratio m / z but different energies travel through the analyzer at the same time when (δT|δK)=0. Such analyzers are energy isochronous. In one example, |(δT|δK)|≦0.1, preferably |(δT|δK)|≦0.05, and more preferably |(δT|δK)|≦0.01. That is, the analyzer may be quasi-energy isochronous, which relaxes the tolerances of the geometry while still allowing a relatively large number of orbits. Ranges for (δT|X), (δT|A), (X|δK) and / or (A|δK) may be defined similarly.

[0070] It should be understood that the focal plane is the location where ions transmitted from the optical axis with their angular distribution are brought to a focus after passing through the analyzer. In one dimension x, this is mathematically expressed in aberration theory notation as (x│a)=0. An analyzer behaves aerti cally (i.e. is aberration-free) if (x│a)=(y│b)=0 at the focal plane.

[0071] More generally, ions with the same mass-to-charge ratio m / z but different energies and different tilt angles at the inlet will move through the outlet independent of the energy and the inlet tilt angle, where (X|A)=(A|X)=(A|δK)=0. Such analyzers are astigmatic and achromatic focusing, and the trajectories are mirror symmetric. In one example, |(X|A)|, |(A|X)|, and / or |(A|δK)|≦0.1, preferably |(X|A)|, |(A|X)|, and / or |(A|δK)|≦0.05, and more preferably |(X|A)|, |(A|X)|, and / or |(A|δK)|≦0.01. That is, the analyzer may be quasi-astigmatic and / or quasi-achromatic, which relaxes the tolerances of the geometry while still allowing a relatively large number of revolutions.

[0072] In general, an achromatic system is one in which the transfer matrix elements of the abscissas do not depend on momentum. In general, an isochronous system is one in which the transit time of a trajectory through the system does not depend on the initial coordinates. It is well known that first-order achromatic systems are also isochronous except for pure momentum dependence. The converse is also true. This result extends to higher orders: in a system in which the color terms all vanish up to a certain order, conditions can be found such that the transit time is independent of the abscissas up to the same order. Under the same conditions, the converse is also true.

[0073] However, the spatial focusing requirement of (X | A) = (A | X) = 0 requires identical ion trajectories for a particular ion for each revolution. For the application of interest, the spatial focusing requirement can be relaxed by only assuming that a particular ion moves steadily in phase space, thus -2≦(X│X)+(A│A)≦2 It is necessary that:

[0074] In this way, a particular ion may travel on different trajectories during different revolutions. This mitigation can, for example, allow for increased design freedom and / or tolerance to structural errors, alternatively and / or in addition to accommodating spatial and / or angular deviations resulting from, for example, ion implantation.

[0075] Conversely, perfect spatial and temporal focusing eliminates ion beam divergence and mass resolution degradation by returning a particular ion to the same position and at the same tilt angle with each revolution as the number of revolutions increases. TOF MS analyzer geometries with such perfect spatial and temporal focusing have been proposed (MULTUM, MULTUM II and planar figure-8), some of which are constructed as described in more detail below with reference to

[15] , which is incorporated herein by reference in its entirety.

[0076] In one example, the electrostatic field sector ion trap includes a set of electrostatic sectors including a first electrostatic sector and a second electrostatic sector. It should be understood that the first electrostatic sector and the second electrostatic sector are separated from each other by, for example, a field-free region (also known as a drift space) that the ion path traverses. It should be understood that the induced charge detector is disposed in the field-free region. The induced charge detector can be disposed in the electric field, but direct capacitive coupling of noise from the power supply limits detection. In one example, the electrostatic field sector ion trap includes a set of electrostatic sectors including a first electrostatic sector and a second electrostatic sector, and a set of electric quadrupole lenses including Q quadrupole lenses, where Q is a natural number equal to or greater than 1, for example, Q is four or six times the number of electrostatic sectors. In general, quadrupole lenses focus in one coordinate direction and defocus in mutually orthogonal coordinate directions. Therefore, a single quadrupole lens cannot be used to, for example, focus an ion beam to a point or generate a two-dimensional image. However, a combination of quadrupole lenses, such as two quadrupole lenses (doublets) and three quadrupole lenses (triplets), may be used to perform two-dimensional focusing. For example, two quadrupole lens doublets may be placed corresponding to the entrance and exit of the electrostatic sector, respectively. In one example, the electrostatic field sector ion trap does not include a set of electric quadrupole lenses and / or RF electric lenses, thereby reducing complexity. It should be understood that the electrostatic sector includes two corresponding electrodes, radially spaced apart from one another, having corresponding radii of curvature in two mutually orthogonal dimensions, to which corresponding opposing DC potentials are applied to provide a toroidal electric field defining an ion optical axis therethrough, the potential on the ion optical axis (i.e., the central orbit) being preferably the same as the potential at a field-free region, e.g., ground. It should be understood that the electrostatic field sector ion trap includes a power source, e.g., a set of DC power sources, electrically coupled thereto.

[0077] Additionally and / or alternatively, the electrostatic field sector ion trap may be defined by a set of cells (also known as units or elements) including a first cell and a second cell, the first cell including a set of drift spaces, a set of electrostatic sectors including the first electrostatic sector, and optionally a set of quadrupole lenses. It should be understood that the second cell may be as described with respect to the first cell. Symmetric geometries of cells are more easily understood, but the principle extends to asymmetrically shaped cells. An electrostatic field sector ion trap defined by four cells can be considered to be a doubly symmetric geometry of two cells, such as MULTUM and MULTUM II of reference

[15] . Although the planar figure-of-eight geometry of reference

[15] at first glance appears to be defined by two cells, complete focusing is achieved after two revolutions, and therefore this planar figure-of-eight geometry is also defined by four cells.

[0078] In one example, the first electrostatic sector includes and / or is a cylindrical, toroidal or spherical electrostatic sector. A cylindrical electrostatic sector offers the simplest geometry, having effectively a single radius of curvature in only one dimension (the second radius of curvature in the mutually orthogonal dimension is infinite), but does not confine ions in that orthogonal dimension, e.g., the y-direction, and therefore generally requires confining the electric field in said y-direction (curvilinear coordinate). A cylindrical electrostatic sector is generally used together with an electric quadrupole lens. The planar figure-of-eight geometries of MULTUM and reference

[15] include four and two cylindrical electrostatic sectors, respectively, each of which has eight electric quadrupole lenses together. A toroidal electrostatic sector has two different radii of curvature in two mutually orthogonal dimensions, the ratio of which must be defined for validity, and can confine ions in both dimensions such that an electric quadrupole lens may not be required. The toroidal electrostatic sector has two different radii of curvature, so its construction is relatively complex. The MULTUM II geometry of

[15] and the rhomboid geometry of

[16] each contain four toroidal electrostatic sectors and do not require an electric quadrupole lens. The spherical electrostatic sector is a special case of the toroidal electrostatic sector, which has the same two radii of curvature and can confine ions in both dimensions so that an electric quadrupole lens is not required. The figure-of-eight geometry of [4] contains two spherical electrostatic sectors and does not require an electric quadrupole lens. Therefore, by basing the cell on a spherical electrostatic sector, the number of ion optics can be reduced compared to cells based on a cylindrical electrostatic sector or a toroidal sector.

[0079] In one example, the first electrostatic sector has a deflection angle ψ0 greater than 45.0°, preferably at least 60.0°, for example in the range of greater than 60.0° to 270.0°, preferably in the range of 90.0° to 240.0°. In one example, the second electrostatic sector is as described with respect to the first electrostatic sector, for example having the same or a different deflection angle ψ0. In one example, each electrostatic sector of the set of electrostatic sectors has the same deflection angle ψ0. In this way, complexity is reduced and / or symmetry is increased. In one example, alternating electrostatic sectors of the set of electrostatic sectors have the same respective deflection angle ψ0.

[0080] In one example, the set of electrostatic sectors has a total deflection angle ψ0 greater than 360.0°, preferably at least 390.0°, for example in the range of greater than 360.0° to 720.0°, preferably in the range of 390.0° to 660.0°, i.e. the ion path includes a crossover.

[0081] In one example, the set of electrostatic sectors does not include or consist of a ring of eight 45° toroidal electrostatic sectors. In one example, the first and second electrostatic sectors are, for example, directly, diagonally and / or diametrically opposed to one another, and the ion path and / or ion optical axis is linear between the exit of the first electrostatic sector and the entrance of the second electrostatic sector. In one example, the ion path and / or ion optical axis between the exit of the first electrostatic sector and the entrance of the second electrostatic sector is in a field-free region, i.e., the ion path and / or ion optical axis between the exit of the first electrostatic sector and the entrance of the second electrostatic sector does not include, for example, a quadrupole lens.

[0082] In one example, the set of electrostatic sectors includes only the first and second electrostatic sectors, and preferably the first and second electrostatic sectors are spherical electrostatic sectors of radius r with a deflection angle ψ of nominally 199.2°, e.g., in the range of 198.2°-200.2°, preferably in the range of 198.7°-199.7°, more preferably in the range of 199.0°-199.4°, e.g., 199.2°, and the electrostatic field sector ion trap has a length g of nominally 5.9r (e.g., within 2%, preferably within 1%). r , thereby providing the three-dimensional figure-of-eight geometry according to [4].

[0083] In one example, the electrostatic field sector ion trap includes a set of field-free regions (also known as drift regions) including a first field-free region and a second field-free region. In one example, the length of the ion path through the set of field-free regions is at least 50%, preferably at least 55%, more preferably at least 60%, and most preferably at least 65% of the total length of the ion path. Thus, an inductive charger detector can be positioned in the set of field-free regions to extend along approximately 50% of the ion path, thereby increasing the measurement duty cycle.

[0084] In one example, the first electrostatic sector includes a set of shunts including a first shunt arranged to define the boundaries of the field due to the first electrostatic sector. In this way, the edge fields due to the first electrostatic sector can be controlled and / or the induced charge detector can be shielded from the electric field due to the first electrostatic sector. For example, the shunts can attenuate the noise coupled to the induced charge detector by several orders of magnitude. For example, a 100V power supply electrically coupled to the first electrostatic sector can exhibit an RMS noise of less than 1 mV. By using the shunts, this noise can be attenuated to about 1 μV RMS and therefore can be compatible with a suitable charge-sensitive amplifier, which typically has a sensitivity of 0.6 μV / charge.

[0085] In one example, the electrostatic field sector ion trap (i.e. its behavior) is isochronous to first order, e.g. with respect to energy, e.g. after one revolution and / or an integer number of revolutions, as discussed above (i.e. energy isochronous). In this way, the uncertainty of the mass to charge ratio m / z is reduced compared to an ELIT, e.g. the ELIT of [3]. Exemplary geometries of such electrostatic field sector ion traps include the figure of eight of reference [4], the MULTUM, MULTUM II and planar figure of eight of reference

[15] and the rhomboid of reference

[16] . Other geometries are also known. In one example, the electrostatic field sector ion trap is isochronous to first order with respect to energy and has a residual to second order, e.g. a parabolic residual to second order. In this way, the uncertainty of the mass to charge ratio m / z due to the small energy dispersion ΔE of the ions is further reduced. Second order spatial aberrations result in precession of ions during orbit, which can be controlled using constraining electric fields to prevent ion losses resulting from precession in electrostatic field sector ion traps based, for example, on cylindrical and / or toroidal electrostatic sectors, or can enable electrostatic field sector ion traps based, for example, on spherical electrostatic sectors.

[0086] In one example, the electrostatic field sector ion trap is configured to at least partially define an ion path in two or three mutually orthogonal dimensions. For example, the electrostatic field sector ion trap may be configured to at least partially define an ion path in two mutually orthogonal dimensions, such as the x and z dimensions, and may be referred to as a planar electrostatic field sector ion trap, with the ion optical axis defining a plane. It should be understood that deviations in position, tilt angle and / or energy may cause ions to deviate from the ion optical axis, such that the ion beam may be represented by a distribution across it, for example in phase space. Examples of planar electrostatic field sector ion traps include the MULTUM, MULTUM II and planar figure-of-eight of reference

[15] and the rhomboid of reference

[16] . The structure of such planar electrostatic field sector ion traps may be simplified and may be based on cylindrical, toroidal and / or spherical electrostatic sectors including quadrupole lenses, as appropriate.

[0087] In one example, the ion path defined by the electrostatic field sector ion trap includes a crossover or point focus, e.g., the MULTUM, MULTUM II and planar figure of eight of reference

[15] and the figure of eight of reference [4]. Thus, the electrostatic field sector ion trap can be isochronous with respect to energy, but the length of the ion path is increased for a given circumference or area of ​​the electrostatic field sector ion trap, e.g., compared to a ring.

[0088] Electrostatic linear field ion trap In one example, the electrostatic field ion trap includes and / or is an electrostatic linear field ion trap, also known as an electrostatic linear field ion trap (ELIT), where the first electrostatic electrode includes and / or is a first reflecting or mirror electrode and the second electrostatic electrode includes and / or is a second reflecting or mirror electrode, for example as described in [2], [3],

[17] and

[18] , the subject matter of which is incorporated herein by reference. ELITs are known and typically include a pair of reflecting or mirror electrodes facing each other, such as cone traps or segmented electrodes. In 2012, Contino and Jarrold [1] (Non-Patent Document 1) presented a charge detection mass spectrometer (CDMS, which is clear from the context, also known as a CDMS analyzer) with a detection limit of 30 elementary electrons for a single ion. The CDMS included a cone trap incorporating an electrospray source coupled to a dual hemispherical deflection analyzer (HDA), followed by a mirror image charge detector. Ions were energy selected by the dual HDAs before entering the trap. The fundamental oscillation frequency of the trapped ions was extracted by fast Fourier transform (FFT). The oscillation frequency and kinetic energy gave the mass-to-charge ratio m / z of the trapped ion. The magnitude of the FFT at the fundamental frequency was proportional to the charge. In particular, this CDMS required the use of the dual HDAs as an energy filter to limit the spread of ion energies entering the electrostatic cone trap, thereby reducing the variation in oscillation frequency, so as to achieve a detection limit of 30 elementary electrons for a single ion. However, limiting the spread of ion energies entering the electrostatic cone trap reduced the throughput of the CDMS. Lower noise electronics led, by 2015, Keifer, Shinholt and Jarrold [2] to demonstrate improved charge accuracy, better than the integer level, sufficient for true mass determination.

[0089] In 2018, Hogan and Jarrold [3] employed a segmented electrostatic linear ion trap (ELIT) that has a lower dependence on the oscillation period with respect to ion energy than the cone trap of their previous CDMS. This CDMS also required the use of a dual HDA energy filter, but significant dependence on the oscillation frequency with ion energy spread and radial position remained. Notably, for this CDMS, the kinetic energy dependence of the ion oscillation frequency was reduced by an order of magnitude, which should have resulted in an order of magnitude reduction in the uncertainty of the mass-to-charge ratio m / z ratio determination. However, due to the orbital dependence of the ion oscillation frequency, only a four-fold improvement was achieved.

[0090] It should be understood that an electrostatic linear field ion trap is a periodic structure, at least partially defining a closed ion path, whereby ions can travel (also known as reciprocating or oscillating) repeatedly along the closed ion path, e.g., an integer or non-integer number of revolutions. In general, ions travel through at least one pass, and preferably at least N passes, along the ion path, where N is a natural number equal to or greater than 1, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, 100, 200, 500, or more. Thus, an electrostatic linear field ion trap may be known as a multi-pass) electrostatic linear field ion trap, and a CDMS may be known as a multi-pass CDMS. In general, increasing the number of passes traveled by ions, and thus the measurement time, reduces the uncertainty of the mass determined therefor. However, increasing the number of passes also increases the analysis time, while increasing the possibility of loss of certain ions, e.g., due to collisions with residual gas, other ions and / or the walls of the CDMS, etc. For example, the maximum vacuum level is 2.7×10 -7 Pa(2×10 -9By improving the pressure to 1000 MPa (1000 MPa) or higher, the probability of loss of a particular ion due to collisions with residual gas can be reduced, thereby allowing the number of passes to be increased. The number of passes travelled by an ion can therefore be balanced accordingly. The fundamental frequency f (and / or its harmonics) of an ion travelling along the ion path depends on its mass to charge ratio m / z and is measured using an induced charge detector, as described below.

[0091] It should be understood that the electrostatic linear field ion trap is configured to at least partially define an ion path through the induced charge detector. That is, in use, the electrostatic linear field ion trap at least partially defines an ion path through the induced charge detector. By at least partially, it should be understood that the ion path may be completely defined by the electrostatic linear field ion trap, or alternatively, may be partially defined by the electrostatic linear field ion trap and partially defined by one or more ion optical elements, e.g., lenses and / or magnets. In one example, the electrostatic linear field ion trap is configured to define (i.e., entirely define) an ion path through the induced charge detector. It should be understood that a cross section of the ion path orthogonal thereto, e.g., its shape and / or dimensions, may vary along the ion path. Additionally and / or alternatively, the ion path may be described and / or defined as an ion beam.

[0092] It should be understood that ions move back and forth in alternating opposite directions along the ion path of an ELIT such as the ELITs of Non-Patent Documents 2 and 3, which for convenience may be referred to as bidirectional or reciprocating motion, resulting in mutual interactions between ions moving in opposite directions, which precludes the introduction of multiple ions therein.

[0093] Curved Trap In one example, the electrostatic ion trap includes and / or is a curved trap (commonly referred to as a "c-trap") of the type utilized in the Orbitrap mass spectrometer sold by Thermo Fisher Scientific, e.g., as described in U.S. Patent Application Publication No. 2022 / 0246414. The curved trap is composed of a set of generally parallel rod electrodes that are concavely curved toward the ion exit. Radial confinement of ions within the ion storage can be achieved by applying oscillating voltages in a specified phase relationship to opposing pairs of rod electrodes, and axial confinement can be implemented by applying electrostatic voltages to end lenses positioned axially outward of the rod electrodes.

[0094] Inductive Charge Detector The CDMS includes an induced charge detector, and the electrostatic field ion trap is configured to at least partially define an ion path through (i.e., via) the induced charge detector, in other words, the induced charge detector at least partially surrounds or encircles the ion path.

[0095] Generally, ions induce a charge as they move through an induced charge detector, which is detected by a charge-sensitive amplifier that outputs a signal. It should be understood that an induced charge detector includes a charge-sensitive amplifier and optionally a digitizer communicatively connectable or coupled to a computer including a processor and memory. The mass of the ion can be determined using the signal, for example, by Fourier analysis using a Fourier transform (FT) or a fast Fourier transform (FFT), least squares method, filter diagonalization method (FDM) and / or maximum likelihood method, etc. In one example, the signal includes and / or is a time domain signal that can be amplified and / or digitized for analysis. The use of an FFT allows for detection of charges that do not rise above noise, for example in the time domain, reducing the LOD to less than 7e (elementary charge). The mass-to-charge ratio m / z is given by the relationship:

[0096]

number

[0097] Therefore, it is inversely proportional to the square of the fundamental frequency f, where C is a constant that is a function of the ion energy and the dimensions of the electrostatic field sector ion trap. Typically, C is determined from ion trajectory simulations or by device calibration using known species. The charge z of an ion is proportional to the magnitude of the FFT (when the number of ion cycles or trapping time is taken into account). Thus, by determining the mass-to-charge ratio m / z and charge z of an ion, the mass m of the ion can be trivially calculated by multiplication.

[0098] In one example, the induced charge detector includes a first set of charge detector tubes including a first charge detector tube. For example, the charge detector tubes can be located in one or more of the field-free regions, e.g., all of the field-free regions. For example, the first set of charge detector tubes can include and / or be segmented charge detector tubes including a plurality of charge detector tubes. In one example, the induced charge detector includes C sets of charge detector tubes including the first set of charge detector tubes, where C is a natural number equal to or greater than 1, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more, e.g., C is equal to the number of field-free regions. In this way, the duty cycle of induced charge detection can be increased. In one example, the first set of charge detector tubes can include and / or be segmented charge detector tubes, e.g., axially and / or radially segmented charge detector tubes. By axially segmenting the charge detector tubes such that the segments are in series or tandem, a signal can be sequentially induced in each of the segments by ions moving therethrough. For example, as described below, increasing the length of a segment beyond about twice its width does not substantially increase the magnitude of the induced signal, but multiple segments, and therefore induced signals, improve measurement statistics. By radially segmenting the charge detector tube such that the segments are parallel, two ions that are substantially coincident in the z dimension (curvilinear coordinate) but separated from each other in the x and / or y dimensions can induce signals in different radial segments, thereby reducing the possibility of signal overlap that would otherwise result from two ions traveling together through the charge detector tube. In this way, the ion capacity of the CDMS can be increased. In one example, the internal cross-section, e.g., shape, of the induced charge detector corresponds to, e.g., is similar to, the cross-section, e.g., shape, of the ion path through it.For example, a charge detector tube having a cylindrical bore is suitable for a generally cylindrical ion path, but the first charge detector tube may have a tapered bore, for example corresponding to a frusto-conical ion path entering and / or exiting an electric quadrupole lens, or may be adapted to provide an annulus or tapered annulus for an ion path entering and / or exiting a spherical electrostatic sector. In one example, the first charge detector tube includes an outer electrode and an inner electrode, thereby providing an annulus or tapered annulus for an ion path therethrough, and optionally includes one or more supports therebetween, for example positioned and / or having a cross-section configured to reduce the likelihood of ion collisions therewith.

[0099] In one example, the first charge detector tube having a length L and width W has a ratio of length L to width W in the range of 3:2 to 8:2, preferably in the range of 3:2 to 5:2, such as a ratio of length L to width W of 2:1 and / or a ratio of length L to width W that is at least 2:1. In particular, the magnitude of the induced signal is not substantially increased by making the first charge detector tube longer relative to its width.

[0100] In one example, the portion of the ion path through the induced charge detector is in the range of 30% to 70%, preferably in the range of 40% to 60%, e.g., 50%, of the ion path defined by the electrostatic field sector ion trap. In this way, artifacts, such as signal processing artifacts, in the time domain signal of the ion as analyzed by FT are reduced. In particular, if the portion of the ion path through the induced charge detector is about 50% of the ion path defined by the electrostatic field sector ion trap, even harmonics when analyzing the time domain signal by FT can be reduced or eliminated. An ideal 50% duty cycle square wave has no even harmonics in its FFT, and the fewer the harmonics, the larger the magnitude of the fundamental peak. The magnitude of the fundamental peak is proportional to the charge of the ion, so the increased magnitude can reduce the charge uncertainty by increasing the signal-to-noise ratio of the fundamental peak.

[0101] In one example, the CDMS includes a set of electrostatic focusing lenses, including a first electrostatic focusing lens, arranged to constrain the ion path, at least partially, for example, in a first dimension transverse to the ion path. In other words, the ion path can be compressed, for example, in one axial direction. In one example, the set of electrostatic focusing lenses is arranged to constrain the ion path, at least partially, for example, in a second dimension transverse to the ion path, the first and second dimensions being mutually orthogonal. In other words, the ion path can be compressed, for example, in two axial directions. In this way, the structure of the CDMS can be simplified while spatial aberrations (if any) caused by the set of electrostatic focusing lenses are insignificant. Additionally and / or alternatively, the internal dimensions, for example, inner diameter, of the induced charge detector can be reduced, thereby improving its rise time, since the cross-sectional area of ​​the ion path is reduced by constraining the ion path. In one example, the first dimension is orthogonal to the direction of the ion path through the induced charge detector. In one example, the first focusing lens includes and / or is, for example, a cylindrical lens, an Einzel lens, and / or a plate lens disposed across a crossover of the ion path. In this way, symmetry about the crossover can be maintained while simplifying the geometry. For example, an Einzel lens can maintain at least rotational symmetry. In one example, the set of electrostatic focusing lenses is positioned to constrain the ion path at least partially in a second dimension, for example across the ion path, the first and second dimensions being mutually orthogonal. It should be understood that the set of electrostatic focusing lenses including the first focusing lens is positioned to constrain the ion path at least partially in a first dimension, for example, not by an RF field and / or a magnetic field.

[0102] In one example, the cross section of the ion path through the induced charge detector is arcuate and has a central angle in the range of -3° to +3°, preferably in the range of -2° to +2°, more preferably in the range of -1° to +1°. In this way, the ion beam is confined to a relatively narrow arc, thereby reducing the cross sectional area of ​​the ion path, allowing the internal dimensions, e.g., inner diameter, of the induced charge detector to be reduced, thereby improving its rise time.

[0103] In one example, the induced charge detector is configured to operate at ground potential, thus reducing its noise level and allowing detection of very low induced signals. controller The CDMS includes a controller, e.g., a computer including a processor and memory, configured to determine the mass of each of an ion population (single ion or multiple ions) moving in a defined ion path using the frequency and magnitude of a respective signal induced by the ion population in the induced charge detector. When a particular ion enters the induced charge detector, it induces a small measurable voltage (i.e., an induced signal), the amplitude of which is proportional to its charge. To improve the measurement accuracy, this induced signal is amplified by an amplifier. The measured period time of the oscillation gives the mass-to-charge ratio m / z of the particular ion, and the product of these two measurements gives the true mass of the particular ion. By allowing many oscillations in the ion trap and analyzing the resulting signal with a Fourier transform (FT), the accuracy of both the charge measurement and the mass-to-charge ratio measurement is improved.

[0104] Set the power supply The CDMS includes a power supply set including a first power supply electrically coupled to the electrostatic field ion trap and configured to apply a potential to the electrostatic field ion trap at time t0. It should be understood that the power supplies in the power supply set are high voltage (HV) power supplies. Suitable power supplies are known.

[0105] In one example, the set of power sources includes a first power source and a second power source electrically coupled to a first electrostatic electrode, e.g., an inner electrode and an outer electrode of a set of electrostatic sectors, respectively, and configured to apply thereto a potential and a mutually inverted (i.e., opposite or anti-phase) potential at time t0. Typically, the potentials applied to the inner and outer electrodes of an electrostatic sector are opposite to each other, but similar in magnitude (e.g., within 95%), but not necessarily equal.

[0106] In one example, the CDMS includes a set of electrostatic focusing lenses including a first focusing lens, and the set of power sources includes a third power source electrically coupled to the set of electrostatic focusing lenses, e.g., the first focusing lens.

[0107] amplifier The CDMS includes an amplifier electrically coupled to the induced charge detector and configured to amplify a signal received thereby. It should be understood that the amplifier has an input for receiving a signal and an output for outputting an amplified signal therefrom. Suitable amplifiers are known.

[0108] Iontophoresis In one example, the CDMS includes a means for introducing ions into the ion path. In one example, the introduction of ions is through a field-free region, for example by switching ion displacement in the x and / or y directions (curvilinear coordinates), such as by using deflection electrodes as described in

[14] . In one example, the introduction of ions is through an electrostatic field sector ion trap, for example by switching a first electrostatic sector, for example only the first electrostatic sector, or by switching a set of electrostatic sectors, for example two or more or all of the electrostatic sectors, mutatis mutandis, as described in

[13] . By switching only the first electrostatic sector, thereby operating the remaining electrostatic sectors at their respective operating potentials, ions can be introduced successively into the ion path to fill the ion path until the first introduced ion arrives in proximity to the first electrostatic sector, at which point the first electrostatic sector is switched back to its respective operating potential. For example, for a figure-of-eight geometry, ions may be introduced to fill approximately 3 / 4 of the top of the figure-of-eight. Conversely, switching all electrostatic sectors of a set of electrostatic sectors simplifies control while reducing the number of power supplies required. In one example, the electrostatic field sector ion trap, e.g., the first electrostatic sector, includes an ion inlet for introducing ions into the ion path. In one example, the ion inlet includes and / or is a passage through an outer electrode of the first electrostatic sector.

[0109] Energy Filter In one example, the CDMS does not include an energy filter, such as a dual HDA as described above, to limit the spread of ion energy entering the electrostatic field sector ion trap. In contrast to the cone trap and ELIT of Non-Patent Documents 2 and 3, the electrostatic field sector ion trap CDMS has a relatively wide tolerance for ion energy spread and / or deviations in radial and / or angular position for ions, while ions outside this relatively wide tolerance, such as high energy or off-axis ions, are unstable and therefore collide rapidly with the walls of the electrostatic field sector ion trap without adversely affecting the mass determination of other ions. In one example, the CDMS has an energy acceptance of more than 0.40%, preferably at least 0.5%, more preferably at least 1%, and most preferably at least 2%, 3%, or 4%. In one example, the CDMS has an energy acceptance of up to 20%, preferably at most 15%, and more preferably at most 10%.

[0110] Lift Device In one example, the CDMS includes a lift device configured to increase the ion energy of ions introduced into the ion path. In one example, the lift device is configured to trap ions introduced into the ion path. In this manner, ions can be gated for introduction into the electrostatic field sector ion trap, for example, such that multiple ions introduced therein are spatially and / or temporally separated from one another, such that multiple ions can generally move simultaneously around the ion path in a spatially and / or temporally separated manner from one another. In one example, the lift device is configured to collimate ions introduced into the ion path, thereby providing a pencil of ions that are spatially separated from one another. In one example, the lift device is configured to introduce a plurality P of ions (i.e., a population of ions), where P is a natural number greater than 1, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, 100 or more ions, preferably P is at least 4, and more preferably P is at least 10, 10, 20, 50, 100 or more ions. P is the average number of ions introduced, the number of ions typically having a Poisson distribution, the ions being randomly separated in space from one another, thereby adopting substantially random discrete initial positions along a portion of the ion path, i.e., separated in space and / or time from one another, whereby it should be understood that a plurality of ions generally move simultaneously separated in space and / or time around one another. At the high intensity limit, as in the case of a magnetic sector, the ion beam contains many ions per linear distance along the beam. At the other end of the scale, the ions are injected individually according to a Poisson distribution (although, except for space charge considerations, the ions are still beams in their behavior). In one example, the lift device is configured to introduce ions into the ion path by pulsing the ions into the ion path. More generally, in one example, the CDMS includes means for introducing ions into the ion path, generally as described with respect to the lift device, but optionally increasing the ion energy.In one example, the means for introducing ions into the ion path includes means for introducing a plurality P of ions (i.e., a population) into the ion path, where P is a natural number greater than one, each of the plurality of ions adopting substantially random, discrete initial positions along a portion of the ion path, such that the plurality of ions generally move simultaneously separated in space and / or time around one another. That is, the ions, e.g., the plurality of ions, are not typically focused in space and / or time as they would be focused for introduction into a conventional mass-to-charge analyzer, such as a quadrupole analyzer, time-of-flight analyzer, or an ion trap analyzer, such as a three-dimensional quadrupole ion trap, cylindrical ion trap, linear quadrupole ion trap, or Orbitrap. In other words, no effort is made to focus the ions. Rather, a disordered population of ions is introduced into the ion path, such as provided by thermalizing the ions in a gas cell, which reduces the energy distribution of the ions without focusing. If the ions are trapped and / or their respective energies increased (e.g., using a lift device) prior to being introduced into the ion path, the ions may be introduced into the ion path by applying a potential gradient that substantially maintains the spatial and / or temporal disorder and / or decorrelation of the ions upon introduction into the ion path.

[0111] Ion source In one example, the CDMS includes an ionization source, for example an atmospheric pressure ionization (API) source, such as an electrospray ionization (ESI) source or a nanospray ionization source; other ionization sources are known.

[0112] magnet In one example, the CDMS does not include magnetic deflectors or sectors, i.e., the CDMS may include only electrostatic electrodes and / or sectors, optionally electric quadrupole lenses and / or electric lenses as described herein.

[0113] Ion Treatment In one example, a CDMS includes one or more devices upstream and / or downstream of the electrostatic field sector ion trap for ion processing, such as activation of ions using externally injected particles, such as reagent ions or reagent ions trapped together with precursor ions, interaction with (e.g., externally injected) electrons, electron detachment, preferably using energetic charged particles including fast electrons, manipulation of the mass-to-charge ratio of ions by proton attachment or charge reduction processes, interaction between ions in ground or excited states and neutral molecules (e.g., externally injected), interaction with photons, excitation of ion motion using auxiliary AC waveforms or duty cycle variation of RF trapping waveforms, ion isolation using AC waveforms or duty cycle control, collisionally activated dissociation, ion storage and transfer. Processing may involve one or more of the above functions performed simultaneously or sequentially.

[0114] Vacuum System In one example, the CDMS includes a vacuum system including, for example, a chamber housing an electrostatic sector field ion trap and an induced charge detector therein, a vacuum pump, and a controller. -6 Pa(1×10 -8 Torr), preferably up to 6.7×10 -7 Pa(5×10 -9 Torr), more preferably up to 2.7×10 -7 Pa(2×10 -9 The chamber is differentially pumped with a vacuum of 100 MPa (100 MPa) or better.

[0115] mass spectrometer In one example, the CDMS includes and / or is a stand-alone CDMS, or conversely, in one example, the CDMS is included in a mass spectrometer, e.g., included therein integrally (i.e., originally) or as an upgrade or retrofit.

[0116] Fragmentation Device In one example, the CDMS includes a fragmentation device.

[0117] Tandem mass spectrometry is a well-established technique that provides structural information and increased specificity (also known as selectivity) for selected precursor ions. In general, ions (i.e. precursor ions) with a targeted (i.e. selected) mass-to-charge ratio m / z are isolated and subsequently fragmented to provide information about the structure of the ion in full spectrum mode. In triple quadrupole (also known as tandem quadrupole) experiments, targeted fragment ions are monitored to increase the specificity of the experiment and to obtain highly quantitative information about the target molecule. Tandem mass spectrometry experiments are performed using a combination of various mass analyzers including quadrupole, ion trap, time-of-flight, FTICR, magnetic sector and Orbitrap (RTM) instruments. For all of these experiments, knowledge of the mass-to-charge ratio m / z (and therefore mass) of the selected precursor ion is required to perform the desired isolation step. In the particular case of very high mass ions, utilizing electrospray ionization knowledge of the mass-to-charge ratio m / z of the precursor ion alone is insufficient to determine the true mass of the selected ion, since this ionization technique, as discussed above, results in many different charge states as the molecular mass increases. It is therefore necessary to be able to select high molecular weight species of target mass for subsequent fragmentation to obtain structural and / or quantitative information. As described herein, CDMS is a proven technique for measuring the mass of these very large electrospray generated ions. Fragmentation studies have been performed using CDMS instruments that utilize the cone trap geometry originally described by Benner

[17] as well as the ELIT

[18] . In these studies, photofragmentation occurs in the cone trap and the ELIT, respectively. However, this approach results in the sharing of ion kinetic energy between the generated photofragments (i.e., product ions), which causes some of these photofragments to become unstable in the trap (thus resulting in the loss of these photofragments) and reduces the mass resolution of the remaining photofragments due to deviations from the optimal design energy of the trap itself.Furthermore, this technique does not allow for the selection of one or more precursor ions to be photofragmented, although these CDMS are essentially limited to the determination of the mass of a single ion.

[0118] In contrast, a CDMS including a fragmentation device allows product ions (generally product ions, i.e. one or more product ions or multiple product ions) to be reintroduced into the ion path to allow determination of the respective masses of a mixture of ions (i.e. a mixture of ions having different masses), isolation of a single selected species (i.e. a single precursor ion or multiple precursor ions having the same mass) for fragmentation inside or outside the electrostatic sector field ion trap device, thereby providing true tandem mass spectrometry experiments spanning the entire mass range of product ions.

[0119] In one example, the fragmentation device includes and / or is an RF ion trap that includes one or more of the following fragmentation techniques: Collision Induced Dissociation (CID), light-based photofragmentation (lamp or laser based, UV, visible or infrared), Electron Capture Dissociation (ECD), Electron Transfer Dissociation (ETD), Electron Induced Dissociation (EID), Surface Induced Dissociation (SID), Resonance Induced Dissociation. Other fragmentation techniques are also known. In one example, the fragmentation device is configured to trap precursor ions and / or their product ions, for example, by including one or more regions for trapping precursor ions and / or their product ions. Thus, precursor ions may be introduced (directly or indirectly from the ion path), trapped, for example, in a first region, and subsequently transferred, for example, by application of a potential gradient to a second region for fragmentation therein, after which product ions are similarly returned to the first or third region, optionally having their respective energies increased before being transferred into the ion path.

[0120] In one example, the fragmentation device is configured to increase (or more generally control) the ion energy of the product ions introduced into the ion path, for example by accelerating the product ions through a predetermined potential difference. In this manner, the ion energy of the product ions can be controlled to correspond to the design, e.g., optimum conditions, of the electrostatic field sector trap, thereby overcoming the shortcomings of conventional CDMS involving photofragmentation as discussed above.

[0121] In one example, the fragmentation device is configured to thermalize the product ions, for example by collisional cooling with a buffer gas, and accelerate the product ions to a desired kinetic energy (i.e., increase the ion energy of the product ions) into an electrostatic sector field trap for mass determination.

[0122] In one example, the fragmentation device includes and / or is an RF ion trap, e.g., a multipole linear ion trap, e.g., a quadrupole, hexapole, or octapole, as described in U.S. Pat. No. 5,847,386, the entirety of which is incorporated herein by reference. In one example, the fragmentation device includes and / or is a stacked electrode device, e.g., as described in U.S. Pat. No. 5,206,506, the entirety of which is incorporated herein by reference. In one example, the fragmentation device includes and / or is a 3D quadrupole ion trap. In one example, the fragmentation device includes and / or is a linear ion trap, e.g., as described in U.S. Pat. No. 7,312,442, U.S. Pat. No. 7,755,034, U.S. Pat. No. 6,995,366, EP 1,706,890, or WO 2017 / 134436, the entirety of which is incorporated herein by reference.

[0123] Internal Fragmentation Device In one example, the electrostatic field sector ion trap is configured to at least partially define an ion path through the fragmentation device (as compared to through an induced charge detector where the fragmentation device and the induced charge detector are in series along the ion path). That is, the fragmentation device is between, for example, a first and a second electrostatic sector of a set of electrostatic sectors such that the ion path passes through the fragmentation device. In other words, the fragmentation device may be described as being internal or in-line with respect to the electrostatic field sector ion trap such that the ion path is continuous through the fragmentation device. That is, ions entering and exiting the fragmentation device are respectively direct exit from and direct entry into the ion path. For example, the masses of each of the one or more precursor ions are determined while the fragmentation device is stopped (i.e. configured in a first state such that the one or more precursor ions can travel through the ion path without being fragmented), for example as described with respect to the first embodiment. The fragmentation device is then activated (i.e. configured in a second state to fragment the one or more precursor ions), whereupon the one or more precursor ions are fragmented therein into respective product ions as they travel through the ion path as the ion path passes through the fragmentation device. The fragmentation device is then stopped and the respective masses of the one or more product ions are determined, for example as described with respect to the first aspect. In one example, the fragmentation device is configured to trap the precursor ion upon entering the fragmentation device, fragment the precursor ion thereby providing a plurality of product ions therefrom, as described below, and optionally trap the plurality of product ions and increase the ion energy of each of the plurality of product ions, whereupon the plurality of product ions with increased respective ion energies exit the fragmentation device for determining the respective masses of the plurality of product ions.That is, precursor ions are trapped, fragmented, and the ion energy of the resulting product ions is increased to determine the mass of each of the product ions in-line.

[0124] External Fragmentation Device In one example, the CDMS includes a means for ejecting ions from the ion path into a fragmentation device. That is, the fragmentation device is outside the electrostatic field sector ion trap such that the ion path does not pass through the fragmentation device. In other words, the fragmentation device may be described as being external or off-line to the electrostatic field sector ion trap. That is, ions entering and exiting the fragmentation device are indirectly exiting and indirectly entering the ion path, respectively. For example, the masses of each of the one or more precursor ions are determined, for example, as described with respect to the first aspect. Because the ion path does not pass through the fragmentation device, the fragmentation device can be deactivated or activated. The precursor ions are then ejected from the ion path into a fragmentation device that is activated (i.e. configured in a second state to fragment the one or more precursor ions), whereupon the one or more precursor ions are fragmented into respective product ions therein. The product ions are then injected (i.e. introduced) into the ion path from the fragmentation device and the mass of each of the one or more product ions is determined, for example as described in relation to the first aspect. In one example, the means for ejecting ions is configured to eject the precursor from the ion path into the fragmentation device, which is configured to trap the ejected precursor ion as it enters the fragmentation device, as described below, fragment the precursor ion thereby providing a plurality of product ions therefrom, and optionally trap the plurality of product ions as described below, increase the ion energy of each of the plurality of product ions, and inject (i.e. introduce) the plurality of product ions having increased respective ion energies into the ion path to determine the mass of each of the plurality of product ions.That is, precursor ions are ejected, the precursor ions are trapped and fragmented, the ion energy of the resulting product ions is increased offline, and the product ions are injected into the ion path to determine their respective masses. In one example, the means for ejecting ions from the ion path to the fragmentation device includes and / or is one or more deflection electrodes and / or a deflection / focusing field applied in an orthogonal Y direction, e.g. as described below. In one example, the electrostatic field sector ion trap includes an ion outlet for ejected ions to exit the ion path. The ion outlet may be as described with respect to the ion inlet. In one example, the ion inlet provides an ion outlet, i.e. a combined ion inlet / outlet.

[0125] In one example, the fragmentation device is configured to introduce product ions into the ion path, for example by pulsing the product ions into the ion path as described with respect to introducing precursor ions into the electrostatic field sector ion trap In this manner, the product ions enter the electrostatic field sector ion trap as a pencil of spatially separated ions, thereby improving their mass determination.

[0126] In one example, the fragmentation device is combined with a lift device configured to increase the ion energy of ions introduced into the ion path, as described above, i.e., the fragmentation device and lift device may be combined as a single device, whose functions may be performed independently or dependently, for example only lift without fragmentation for precursor ions, or fragmentation and lift for product ions.

[0127] Ion isolation optical device In one example, the CDMS includes ion isolation optics configured to isolate precursor ions for fragmentation by the fragmentation device. In this manner, among a plurality of precursor ions, e.g., a pencil of spatially separated precursor ions, a particular precursor ion having a mass or mass-to-charge m / z determined by the CDMS is selected for fragmentation by the fragmentation device such that structural information can be obtained for the particular precursor ion, thereby overcoming the drawbacks of conventional CDMS including photofragmentation as described above. In one example, the ion isolation optics is configured to isolate a precursor ion species (i.e., a single precursor ion or a plurality of precursor ions having a particular mass or a particular mass-to-charge m / z) for fragmentation by the fragmentation device. In one example, the ion isolation optics is configured to isolate precursor ions by causing loss of ions other than the precursor ion to be isolated, e.g., by destabilizing these other ions in the ion isolation optics and / or the electrostatic sector field trap.

[0128] In one example, the ion isolation optics includes and / or is a quadrupole lens, an Einzel lens, a deflection plate, and / or is provided by an electrostatic field sector ion trap, or a combination thereof. In one example, the quadrupole lens is configured to isolate precursor ions by selectively focusing precursor ions to be isolated, selectively diverging ions other than the precursor ions to be isolated, and / or selectively deflecting precursor ions to be isolated or ions other than the precursor ions to be isolated, respectively, using a focusing voltage, a diverging voltage, and / or a deflecting voltage. In one example, the Einzel lens is configured to isolate precursor ions by selectively focusing precursor ions to be isolated, using a focusing voltage. In one example, the deflection plate is configured to selectively deflect precursor ions to be isolated or selectively deflect ions other than the precursor ions to be isolated. In one example, the electrostatic field sector ion trap is configured to isolate the precursor ion by an oscillating voltage applied thereto according to its mass-to-charge m / z, in which ions other than the precursor ion are selected to be unstable. In this way, a single precursor ion or multiple precursor ions having the mass-to-charge m / z or all its harmonics are isolated, respectively. In one example, the ion isolation optics are configured to isolate the precursor ion by applying an electric field according to the oscillation frequency, e.g., its harmonics, of the precursor ion in the electrostatic field sector ion trap and according to its mass-to-charge m / z, as described, for example, by Verenchikov in

[19] , which is incorporated herein by reference in its entirety. More specifically, Verenchikov

[19] proposed a device called a resonant mass spectrometer, in which ions are passed through an isochronous open trap. Open trap means that the ions undergo multiple oscillations in a first direction in the trap. While the device utilizes a two-dimensional electric field to trap ions in these two dimensions, ions can all travel into the third dimension and exit the device to a destructive detector - no ion paths are closed, hence the term open trap.A set of n ions of different mass-to-charge ratios m / z have unique vibrational frequencies {f1, f2, …, f. n}, where each frequency is the inverse of the isochronous transit time through the analyzer. By applying a radio frequency deflection field of a selected frequency F, only ions having higher harmonics of that frequency F are allowed (i.e., selected) to pass through the open trap and reach the detector. That is, ions having a unique frequency f i Ions having the following conditions: F = N × f i Or F = (N + 0.5) × f i where N is an integer and f i is the frequency of oscillation of the selected ion.

[0129] Verenchikov's patent utilizes the substantially two-dimensional fields necessary for an open trap to allow ions to be conditioned as they travel orthogonally through the device before being detected by a destructive detector such as an Electron Multiplier (EMT) or Micro Channel Plate (MCP). In contrast, CDMS according to the first and third aspects are closed traps, in particular closed three-dimensional ion traps with inductive detection. Ions can be conditioned by deflection fields placed in the field-free region of the electrostatic field sector trap, allowing the selection of a specific species (i.e. precursor ion) in the same principle as

[19] . After isolation, the selected species can be moved out of the electrostatic field sector trap for subsequent fragmentation in a fragmentation device, as previously described. The resulting population of fragment or product ions can then be reaccelerated back into the electrostatic field sector trap for tandem mass analysis. As explained with respect to the first aspect, the electrostatic field sector ion trap has a relatively high space charge capacity, allowing accurate simultaneous mass determination of the fragment population without distortion.

[0130] MS n In one example, CDMS allows for the MS analysis of ions by repeatedly isolating and fragmenting nth generation product ions for further structural elucidation. n Configured to run an experiment.

[0131] real time In one example, the determination of the mass involves real-time Fourier transform processing. In this way, an early indication of the resonant frequency required for isolation can be determined from inspection of the signal, and isolation can be performed more quickly. By efficiently isolating the selected species, the experimental cycle time can be accelerated, thus reducing the possibility of loss of the desired species due to collisions with residual gas molecules in the CDMS chamber.

[0132] definition At least some of the example embodiments described herein may be constructed in part or in whole using dedicated hardware. As used herein, the terms "computer", "component", "module" or "unit" may include, but are not limited to, hardware devices such as circuits in the form of discrete or integrated components, Field Programmable Gate Arrays (FPGAs) or Application Specific Integrated Circuits (ASICs) that perform some task or provide related functionality. In some embodiments, the described elements may be configured to reside on tangible, permanent, addressable storage media and configured to execute on one or more processors. These functional elements may include, in some embodiments, components such as software components, object-oriented software components, class components and task components, processes, functions, attributes, procedures, subroutines, segments of program code, drivers, firmware, microcode, circuits, data, databases, data structures, tables, arrays and variables, by way of example. Although example embodiments are described in terms of computers, components, modules and units discussed herein, such functional elements may be combined into fewer elements or separated into additional elements. Although various combinations of any feature have been described herein, it will be understood that the described features may be combined in any suitable combination. In particular, features of any example embodiment may be combined with features of any other embodiment, where appropriate, except where such combinations are mutually exclusive. Throughout this specification, the terms "comprising" or "including" mean the inclusion of the specified elements but do not exclude the presence of other elements.

[0133] For a better understanding of the present invention, and to show how exemplary embodiments thereof may be carried out, reference will now be made, by way of example only, to the accompanying schematic drawings in which: [Brief description of the drawings]

[0134] [Figure 1A] 1 illustrates a schematic diagram of a CDMS according to an exemplary embodiment; [Figure 1B] 1B illustrates a schematic diagram of a CDMS according to an exemplary embodiment based on the CDMS according to the exemplary embodiment of FIG. 1A. [Figure 2A] 1 shows a schematic of a conventional electrostatic sector employing a toroidal field sector; [Figure 2B] 1 shows a schematic of a conventional electrostatic sector employing a toroidal field sector; [Diagram 3] 2A illustrates a schematic of an exemplary embodiment electrostatic field sector ion trap further including shunts to control edge fields; [Figure 4A] 1 illustrates a schematic diagram of a CDMS according to an exemplary embodiment; [Figure 4B] 1 shows schematic top, side and end elevation views of ion trajectory trajectories for a CDMS. [Figure 5A] 1 illustrates a schematic of a CDMS according to an example embodiment, including a lens at the origin to confine ions in the axial (z) dimension. [Figure 5B] 1 shows schematic top, side and end elevation views of ion trajectory trajectories for a CDMS. [Figure 5C] FIG. 13 is a perspective view of a SIMION simulation of ions for CDMS. [Figure 5D] FIG. 2 is a more detailed axial cross-sectional view of the CDMS. [Figure 5E] 1 is a cutaway perspective CAD image of a portion of the CDMS in greater detail. [Figure 5F] This is an exploded perspective CAD image of a portion of the CDMS in greater detail. [Figure 5G] FIG. 2 is a more detailed axial cross-sectional view of the CDMS. [Figure 6] 6 is a graph of the % change in frequency as a function of % ion energy deviation from ideal for the CDMS of FIGS. 5A-5C compared to a conventional CDMS. [Figure 7] 13A and 13B illustrate diagrammatically the advantage of a relatively narrow charge detector tube for enhancing the intensity of higher harmonics in the Fourier transform for a CDMS according to an exemplary embodiment; [Figure 8] 1 illustrates a schematic of a segmented charge detector tube for increasing the number of transient signals per analyzer path for a CDMS according to an exemplary embodiment. [Figure 9] 1 illustrates a schematic diagram of a CDMS according to an exemplary embodiment including a lift device. [Figure 10] 1 illustrates a schematic diagram of a CDMS according to an exemplary embodiment; [Figure 11] 1 illustrates a schematic diagram of a CDMS according to an exemplary embodiment; [Figure 12] 1 illustrates a schematic diagram of a CDMS according to an exemplary embodiment; [Figure 13] 1 illustrates a schematic diagram of a CDMS according to an exemplary embodiment; [Figure 14] 1 illustrates a schematic diagram of a CDMS according to an exemplary embodiment; [Figure 15] 1 illustrates a schematic diagram of a method according to an exemplary embodiment; [Figure 16] 1 illustrates a schematic diagram of a resonant mass separator in accordance with an illustrative embodiment; [Figure 17A] FIG. 13 shows schematic side and end elevation views of ion trajectory trajectories of an exemplary embodiment of a CDMS including ion separation optics at the origin when voltages are applied to its lenses to confine ions in the axial (z) dimension. [Figure 17B] 1 shows schematic side and end elevation views of ion trajectory trajectories upon application of a separation voltage to the lenses. [Figure 17C] 1 shows schematic side and end elevation views of ion trajectory trajectories when a voltage is applied following the lens to further confine the ions in the axial (z) dimension. [Figure 18] 1 illustrates a schematic diagram of a CDMS 18 according to an exemplary embodiment. [Figure 19] 1 illustrates a schematic diagram of a CDMS 19 according to an exemplary embodiment. [Figure 20]1 illustrates a schematic diagram of a CDMS 100 according to an exemplary embodiment. [Figure 21] 1 shows a schematic of a CDMS according to an exemplary embodiment, including a Fasmatech custom electrospray interface for ion transfer to the CDMS analyzer. [Figure 22] 22 shows a schematic diagram of the CDMS analyzer of FIG. 21 in more detail. [Figure 23] 22 shows a schematic longitudinal cross-sectional view of the CDMS of FIG. 21 in more detail. [Figure 24] FIG. 22 is an ion simulation of the CDMS analyzer of FIG. 21 using MSCUBE's SIMAX software, showing the segmented charge tube design. [Diagram 25] Using the ion simulation in FIG. 24, we simulated the FFT signal (frequency domain spectrum) for a single ion of 7000 m / z, showing the first, second and third harmonics with a resolution of approximately 3000 FWHM (1 second transient). [Figure 26] FIG. 21 is a typical single FFT spectrum collected using the CDMS, showing the residual ions and their harmonic content collected on a Spectroswiss X2 Booster system using “Peak by Peak” data collection software. [Figure 27] FIG. 21 shows an FFT spectrum of myoglobin ions collected using CDMS using an oscilloscope for proof of principle of m / z manipulation and a 3 ms transient signal. [Figure 28] FIG. 21 is a transient signal collected using a CDMS, showing how ions outside the analyzer's tolerance range are rapidly rejected, leaving residual ions that contribute to the CDMS spectrum. [Figure 29] 4 illustrates the operation of a harmonic filter to remove spurious noise peaks, according to an example embodiment. [Diagram 30]Shown are two technical replicates (red, blue) of polystyrene beads collected using CDMS in Figure 21, taken on different days and demonstrating the reproducibility of the measurements. [Diagram 31] FIG. 22 is a mass histogram of a 30 nm polystyrene bead sample (8.2 MDa) collected using the CDMS of FIG. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0135] Detailed Description of the Drawings The CDMS described herein, according to an exemplary embodiment, an electrostatic field ion trap including a set of electrostatic electrodes including a first electrostatic electrode and a second electrostatic electrode, and an induced charge detector, the electrostatic field ion trap configured to at least partially define an ion path through the induced charge detector; and a computer including a processor and a memory configured to carry out the method according to the first aspect.

[0136] FIG. 1A illustrates a schematic diagram of a CDMS 10 according to an exemplary embodiment, and FIG. 1B illustrates a schematic diagram of a CDMS 20 according to an exemplary embodiment that is based on the CDMS 10 of FIG. 1A. FIG. 1A shows, in more detail, a schematic of a CDMS 10 by Contino and Jarrold [1]. The CDMS 10 contains an electrospray source 1 and is divided into four differentially pumped regions (I-IV). The first region I contains an ion funnel 2, the second region II and the third region III each contain a hexapole ion guide 3, and the fourth region IV provides two alternative paths for ions via a focusing lens 4 and either an orthogonal reflectron time-of-flight mass spectrometer (TOF-MS) 5 or a dual hemispherical deflection analyzer (HDA) 6 followed by a cone trap 7 incorporating an image charge detector tube. The oscillation frequency of ions in the cone trap 7 is related to the m / z of the ion, but also depends on the kinetic energy of the ion. To reduce the uncertainty in the m / z determination, the dual HDAs 6 were employed to select a narrow window of ion kinetic energies for introduction into the cone trap 7. The HDA6 consists of two concentric hemispherical electrodes, each with a deflection angle ψ of 180° and held at different potentials, which allows the 1 / r 2As shown in Figure 1A, the two hemispherical electrodes are placed in an S-shaped tandem arrangement, thus defining an open (compared to closed) ion path, allowing the ion beam to maintain its original direction as it exits. The electrode potentials applied to the two hemispherical electrodes determine which kinetic energy is passed and therefore which ions are filtered. Careful selection of these electrode potentials, as well as the position and diameter of the entrance and exit apertures, improves the energy resolution of the dual HDA 6. The cone trap 7 consists of two conical end caps located 95.25 mm apart with an aperture of 6.35 mm diameter, thereby providing an electrostatic linear ion trap. The number of ions entering the cone trap 7 was kept low enough so that the probability of trapping more than one ion was small. The charge detector tube (25.4 mm long, 6.35 mm inner diameter) was held along the central axis by an insulator mounted within a shielded cylinder. As the ions pass through the detector tube, a mirror image charge of equal magnitude but opposite sign is induced.

[0137] FIG. 1B shows in more detail the prior art geometry of the cylindrical ELIT trap (i.e., CDMS20) of Non-Patent Document 3. The ELIT includes two mutually opposed equally spaced three-electrode mirrors (E1, E2, E3) with a grounded shield ring electrode (GS) at their respective entrances to create a field-free region between the end caps where the charge detector tubes (C) are located. The potentials V1, V2, V3 applied to the ring electrodes V1, V2, V3, respectively, were optimized to generate a minimum oscillation frequency width for 100 axial ions with a Gaussian energy distribution with a mean of 130 eV / z and a FWHM of 1 eV / z. The ELIT has a substantially improved energy dependence when compared to and replaces the cone trap 7 of CDMS10. That is, CDMS20 also requires an upstream energy filtering device (i.e., dual HDA6) consisting of a dual hemispherical electrostatic energy selector so that oscillation frequency variations due to ion energy spread are kept to a minimum. The choice of a low energy spread of ions reduces the overall transmission of the CDMS 20. As with the CDMS 10, the number of ions entering the ELIT was kept low enough so that the probability of trapping more than one ion was small.

[0138] 2A and 2B show schematic diagrams of a conventional electrostatic electric sector employing a toroidal electric sector. The inventors of the present invention have realized that better energy focusing properties can be achieved by adopting the geometry originally proposed by Poschenrieder [4], which considered time-of-flight energy focusing by electrostatic fields. In particular, Poschenrieder considered linear drift space and field configurations in which the time-of-flight is no longer a function of initial energy to first order, but only of the mass-to-charge ratio m / z. Such configurations are also known as isochronous. For ions of approximately equal energy, electrostatic fields should be used since the trajectories should be identical for all masses. Poschenrieder limited his treatment to a toroidal electric sector, but other configurations are possible, as explained below.

[0139] The work of Poschenrieder proposed the use of a toroidal electric sector in a special arrangement to compensate for the initial ion conditions in time-of-flight mass analysis. Figures 2A and 2B show the general form of such an arrangement. The devices are considered from both a radial (Figure 2A) and an axial (Figure 2B) perspective, each with a different radius of curvature for the electric field, and therefore they are known as toroidal electric sector analyzers. A DC potential V1 is applied to the inner electrode with a radius R1 in the radial plane, and a DC potential V2 is applied to the outer electrode with a radius R2 in the radial plane. The ion optical axis has a radius R0 in the radial plane. The device has a deflection angle ψ0 in the radial direction, an acceptance angle 2α0 in the axial direction, and an acceptance angle 2ω in the axial direction, effectively bounded by a slit with a width u0 in the radial direction and a width w0 in the axial direction, respectively. The isochronous planes are spaced at a distance g from the entrance and exit of the device. rThe electric sector TOF analyzers are arranged at an angle η to the ion optical axis at , providing a point focusing of the ions there. This paper presents several geometries intended to be operated as time-of-flight (TOF) analyzers, whereby packets (also known as clouds) of ions are injected through an entrance aperture and detected at the exit plane using an electron multiplier or similar destructive detector. Electric sector TOF analyzers have found use in imaging applications such as TOF-SIMS instruments due to their aberration-free properties [5]. However, they are less suitable for mainstream applications of orthogonal acceleration (oa) TOF analyzers, since their energy focusing properties are limited to first order. This is because orthogonal acceleration leads to a very large energy spread in the ion beam that is better compensated for by reflectron-based TOF analyzers [6]. Since there is no need for orthogonal acceleration in the specific case of CDMS instruments, the variation of the ion energy is given only by the longitudinal variation of the beam energy, which is determined by upstream beam adjustments. Typical energy fluctuations of a few percent can be easily accommodated by the primary energy focusing properties of the electrostatic field sector ion trap, which are superior to those demonstrated in [3]. The electrostatic field sector ion trap has the additional advantage that ions move with a substantially constant velocity determined by the acceleration energy. This improves the space charge capacity of the sector when compared to reflection-based devices where ions must decelerate slowly as they turn in the mirror sections.

[0140] The particular geometry proposed by Poschenrieder for TOF MS (although TOF MS injection and detection remains problematic) and improvements thereon, as first understood by the inventors, provides an electrostatic field sector ion trap for CDMS according to an exemplary embodiment.

[0141] After entering the electrostatic sector, the ion energy

[0142]

number

[0143] The ion velocity ν of an ideal ion with mass m at θ is given to first order by equation (7) of Poschenrieder [4]:

[0144]

number

[0145] During the ceremony, β is the ion energy E a is the fractional ion energy spread for an ion accelerated to <E a If β = ΔE / E a where u is the deviation of the ion from the central path u0, h and k are

[0146]

number

[0147] where r0 is the radial radius of the central equipotential surface, ρ0 is the axial radius, ψ0 is the deflection angle of the sector in the limit 180°≦ψ0h≦360°, and α0 is the angle of incidence.

[0148] Then, the flight time through the electrostatic sector t e teeth, dt e =r0(1+u)ds / v and its first order form gives the following equation (8) by Poschenrieder [4]:

[0149]

number

[0150] t for incident angle α0 e Eliminating the dependency of

[0151]

number

[0152] This formula is expressed as the distance g of the source point from the field edge. r Define g r When is positive, equation (9) of Poschenrieder [4] describes an electrostatic sector with a deflection angle (also known as the sector angle) ψ0 in the limit 180° ≤ ψ0h ≤ 360°. This electrostatic sector configuration is i The intermediate image at =ψ0 / 2 and the distance g from the exit field edge r '=g r and a second image symmetric with respect to the source point at

[0153] An electrostatic sector according to equation (9) of Poschenrieder [4] is simultaneously free of primary chromatic aberration in the second image. However, a large transverse energy dispersion can be found in the intermediate image, but the transmitted energy spread can be limited here by an appropriate aperture.

[0154] Partial ion energy spread in an electrostatic sector β=ΔE / E a Flight time Δt e The variance of is given by equation (10) of Poschenrieder [4]:

[0155]

number

[0156] Dispersion Δt along a linear drift tube of length DD is simply given by the following equation (11) by Poschenrieder [4]:

[0157]

number

[0158] For the electrostatic sector to escape this constraint, Δt e +Δt D = 0, which leads to the convergence condition given by Equation 12 of Poschenrieder [4]:

[0159]

number

[0160] The actual linear drift length D is the inlet g r And g at the exit r ' and some additional drift range d. Therefore, an electrostatic sector that follows equation 12 of Poschenrieder [4] does not have any energy-dependent dispersion of the flight time (isochronism) for any two points that contain a linear drift range of total length D. In addition, this electrostatic sector is r provides achromatic radiation imaging to a point G at

[0161] The radial intermediate image and the axial intermediate image are ψ i Consider the electrostatic sector with aberration-free imaging coincident with =ψ0 / 2. a If represents the entrance distance from the field slit for axial focusing due to the directional focusing characteristics of the toroidal sector field, the distance of the source point from the field edge g r is given by the following equation 20 of Poschenrieder [4]:

[0162]

number

[0163] Therefore, h = k and c = 1, which corresponds to a spherical capacitor field. r =2g a From this setting, we obtain the following Poschenrieder [4] equation 21:

[0164]

number

[0165] Graphical solution gives the following values: ψ0=199.2° g r =5.9r For this electrostatic sector, the source and its image are exactly coincident so that the focusing in time and space coincides, as shown diagrammatically in Fig. 3. Poschenrieder [4] noted that this electrostatic sector is not well suited for TOF mass spectrometers, but conversely, the inventors have realised that this field is instead suitable for electrostatic ion trapping. In particular, this electrostatic sector is completely isochronous with respect to energy, and the resolution becomes independent of the slit width. With a deflection angle ψ0 = 199.2° and a distance g r Note that these values ​​for =5.9r are obtained graphically and therefore the computational method may provide an elegant solution. Furthermore, the constructed geometry may allow for interactions between these values ​​to some extent and / or to compensate for other electric fields including residual or edge fields. However, the distance g r can be important to achieve true aberration-free performance.

[0166] Poschenrieder's paper [4] focuses on isochronism (time aberration) with respect to the beam initial conditions (all zero to first order), but its treatment of aberration-free (spatial) is much more limited. Poschenrieder [4] does not appear to consider "angle with respect to position" or "angle with respect to energy" spatial aberrations. However, preferably, to enable the use of a relatively narrow charge tube as described herein and to avoid ion losses resulting from ions moving away from the ion path, the aberration-free (imaging) requirement of CDMS is secondary compared to the isochronism requirement of CDMS, i.e., the requirement of aberration-free is a sufficiently stable ion trajectory for induced charge detection.

[0167] Figure 3 shows a schematic of an exemplary embodiment electrostatic field sector ion trap 30 further including shunts for edge field control. A Cartesian coordinate system (x,y,z) is conveniently employed in Figures 3-14.

[0168] In this example, the electrostatic field sector ion trap 30 includes a set of electrostatic sectors 31 including a first electrostatic sector 31A and a second electrostatic sector 31B. In this example, the first electrostatic sector 31A is a spherical electrostatic sector. In this example, the first electrostatic sector 31A and the second electrostatic sector 31B face each other. In this example, the set of electrostatic sectors 31 includes only the first electrostatic sector 31A and the second electrostatic sector 31B. In this example, the first electrostatic sector 31A includes a set of shunts 32 including a first shunt 32A arranged to define a field due to the first electrostatic sector 31A. In this example, the electrostatic field sector ion trap 30 is isochronous. In this example, the electrostatic field sector ion trap 30 is configured to define an ion path IP in three mutually orthogonal dimensions. In this example, the ion path defined by the electrostatic field sector ion trap 30 includes a crossover. In this example, the electrostatic field sector ion trap 30 includes an ion inlet 33 for introducing ions into the ion path, in particular provided at the outer electrode of the first electrostatic sector 31A. In this example, the first electrostatic sector 31A has a deflection angle of ψ0=199.2°. In this example, the field-free region has a length g r = 5.9r. In this example, the electrostatic field sector ion trap 30 has rotational symmetry about the x-axis that passes through the origin. In this example, the electrostatic field sector ion trap 30 is symmetric about the yz-plane that passes through the origin. In this example, the basic unit has two drift spaces (i.e., each g r = 5.9r) and spherical electrostatic sectors 31A, 31B. In this example, the outer electrode of the first electrostatic sector 31A has an inner radius of 23 mm and the inner electrode of the first electrostatic sector 31A has an outer diameter of 17 mm, thereby providing a spherical radial gap of 6 mm between them. The first shunt 32A has a toroidal opening 4 mm wide, thereby presenting a relatively large entrance opening into the first electrostatic sector 31A. The second electrostatic sector 31B is generally as described with respect to the first electrostatic sector 31A, but does not include the ion entrance 33.

[0169] FIG. 3 shows in more detail the special case of two opposing spherical sectors 31A, 31B (same curvature for radial and axial fields), each of which has a deflection angle ψ0=199.2° and a distance to the central crossover point (i.e., the point focus) of 5.9R0 (i.e., g r = 5.9r). Poschenrieder realized that the closed path of this arrangement could prove problematic for injection and detection for conventional TOF analysis and went on to propose a more suitable open geometric solution for the injection and detection means. That is, Poschenrieder did not propose an ion inlet 33 for introducing ions. Furthermore, Poschenrieder did not propose the use of such an analyzer for inductive detection as employed in Fourier transform mass spectrometers. To the best of the inventor's knowledge, the use of a toroidal field for inductive detection of a small cloud of ions in a Fourier transform trap was first proposed by Wollnik [7] in an arrangement using eight 45° toroidal sectors, an originally unknown geometry arranged in a ring configuration for TOF MS analyzers. Also later, Verenchikov proposed the use of a toroidal field with Fourier transform detection [8]. However, neither of these two proposals considered the use of such geometries for CDMS.

[0170] In the arrangement of Figure 3, ions are injected through a hole (i.e. ion inlet 33) in the outer electrode of the first electrostatic sector 31A while the potentials of the electrodes of the first electrostatic sector 31A are held at ground level. Once the trap is filled, these potentials are raised to their operating level and the trapping process begins. Shunts 32A, 32B are added to terminate the electric fields of the electrodes of the first electrostatic sector 31A, which would otherwise leak into the field-free region and disable the operation of the electrostatic field sector ion trap. This particular shunt shape is known in the art and was proposed by Herzog in 1935 (see Yavor p. 230[9]).

[0171] FIG. 4A illustrates a schematic of a CDMS 4 according to an example embodiment, and FIG. 4B illustrates a schematic of top, side and end elevation views of ion trajectory trajectories for the CDMS 4. In this example, the CDMS 4 includes an electrostatic field sector ion trap 40 and an induced charge detector 400 , where the electrostatic field sector ion trap 40 is configured to at least partially define an ion path through the induced charge detector 400 .

[0172] The electrostatic field sector trap 40 is as described for the electrostatic field ion trap 30 as described with respect to Figure 3, and the description thereof is omitted for the sake of brevity, with like reference numerals indicating like integers.

[0173] In this example, the electrostatic field sector ion trap 40 includes a set of electrostatic sectors 41 including a first electrostatic sector 41A and a second electrostatic sector 41B. In this example, the first electrostatic sector 41A is a spherical electrostatic sector. In this example, the basic unit includes two drift spaces and a spherical electrostatic sector. In this example, the first electrostatic sector 41A and the second electrostatic sector 41B are opposite each other. In this example, the set of electrostatic sectors 41 includes only the first electrostatic sector 41A and the second electrostatic sector 41B. In this example, the first electrostatic sector 41A includes a set of shunts 42 including a first shunt 42A arranged to define a field due to the first electrostatic sector 41A. In this example, the electrostatic field sector ion trap 40 is isochronous to a first order with respect to energy. In this example, the electrostatic field sector ion trap 40 is configured to define an ion path in three mutually orthogonal dimensions. In this example, the ion path defined by the electrostatic field sector ion trap 40 includes a crossover. In this example, the electrostatic field sector ion trap 40 includes an ion entrance 43 for admitting ions into the ion path. In this example, the first electrostatic sector 41A has a deflection angle of ψ0=199.2°. In this example, the field-free region has a length g r = 5.9r. In this example, the second electrostatic sector 41B is as described with respect to the first electrostatic sector 41A. In this example, the electrostatic field sector ion trap 40 has rotational symmetry about the x-axis passing through the origin. In this example, the electrostatic field sector ion trap 40 is symmetric in the yz-plane passing through the origin. In this example, the induced charge detector 400 includes a first set 410 of charge detector tubes including a first charge detector tube 410A and a second charge detector tube 410B. In this example, the first charge detector tube has a length L and a width W and has a length L to width W ratio in the range of 3:2 to 5:2, for example 2:1. In this example, the portion of the ion path through the induced charge detector 400 is about 50% of the ion path defined by the electrostatic field sector ion trap 40.

[0174] SIMION

[10] simulations were performed with the geometry shown in Figure 4A, where ions could be trapped indefinitely depending on their initial conditions, as shown diagrammatically in Figure 4B. If the ions are confined to a narrow axial range (small Δα), the resulting trajectories fill a finite arc in the yz plane. Referring again to Figure 4A, and noting that the input ion conditions take the form of a beam of ions along a trajectory T, it can be seen that the radial restoring force is stronger than the axial restoring force. The device is rotationally symmetric about the x-axis through the origin, so that ions with a large angular component β or axial spread Δα will cause the ion trajectory to fill the entire electrostatic sector after many have passed around the periphery of the ion path forming a hollow cone shape in the field-free region and a sphere in the sector. In other words, the ions are trapped within a thin wall (ideally of infinitesimal thickness) that can be described as a pair of intersecting, mutually opposed cones or lobes with approximately hemispherical end caps (corresponding to the gap between the spherical electrodes of the electrostatic sector with a nominal deflection angle ψ0 of 199.2°). A geometric projection of the ion beam IP (shown in grey) adopted after multiple passes through the analyzer (required by CDMS) is shown in Figure 4B.

[0175] FIG. 5A shows a schematic of a CDMS5 according to an exemplary embodiment including a lens at the origin to confine ions in the axial z dimension; FIG. 5B shows schematic elevational views from above, side and end of ion trajectory trajectories for CDMS5; FIG. 5C is a perspective view of a SIMION simulation of ions for CDMS5; FIG. 5D is a more detailed axial cross-section of CDMS5; FIG. 5E is a broken perspective CAD image of a portion of CDMS5 in more detail; FIG. 5F is an exploded perspective CAD image of a portion of CDMS5 in more detail; and FIG. 5G is a more detailed axial cross-section of CDMS5.

[0176] The CDMS 5 is generally as described with respect to the CDMS 4 as described with respect to Figures 4A and 4B, and the description thereof is omitted for the sake of brevity, with like reference numerals indicating like integers.

[0177] In this example, the electrostatic field sector ion trap 50 includes a set of electrostatic sectors 51 including a first electrostatic sector 51A and a second electrostatic sector 51B. In this example, the first electrostatic sector 51A is a spherical electrostatic sector. In this example, the first electrostatic sector 51A and the second electrostatic sector 51B are mutually opposed. In this example, the set of electrostatic sectors 51 includes only the first electrostatic sector 51A and the second electrostatic sector 51B. In this example, the first electrostatic sector 51A includes a set of shunts 52 including a first shunt 52A arranged to define a field due to the first electrostatic sector 51A. In this example, the electrostatic field sector ion trap 50 is isochronous to first order with respect to energy. In this example, the electrostatic field sector ion trap 50 is configured to define an ion path in three mutually orthogonal dimensions. In this example, the ion path defined by the electrostatic field sector ion trap 50 includes a crossover. In this example, the electrostatic field sector ion trap 50 includes an ion inlet 53 for admitting ions into the ion path. In this example, the first electrostatic sector 51A has a deflection angle of ψ0=199.2°. In this example, the field-free region has a length g r = 5.9r. In this example, the second electrostatic sector 51B is as described with respect to the first electrostatic sector 51A. In this example, the electrostatic field sector ion trap 50 has rotational symmetry about the x-axis passing through the origin. In this example, the electrostatic field sector ion trap 50 is symmetric in the yz-plane passing through the origin. In this example, the induced charge detector 500 includes a first set 510 of charge detector tubes including a first charge detector tube 510A and a second charge detector tube 510B. In this example, the first set 510 of charge detector tubes includes axially segmented charge detector tubes including 10 segments. In this example, the first charge detector tube having a length L and a width W has a ratio of length L to width W in the range of 3:2 to 5:2, for example 2:1. In this example, the portion of the ion path through the induced charge detector 500 is about 50% of the ion path defined by the electrostatic field sector ion trap 50.

[0178] Referring again to FIG. 4B, the rotating surface poses a potential topological problem when it comes to the structure of some CDMS. If the ions were allowed to rotate around the entire central axis (i.e., the x-axis), the supports of the central or inner electrode of the induced charge detector 500 and / or the inner electrodes of the first electrostatic sector 51A and / or the second electrostatic sector 51B could be problematic because the ion trajectory completely surrounds these inner electrodes in three dimensions. In general, the addition of supports reduces the number of possible oscillations in the analyzer due to ion collisions with the supports. One or more supports, such as support 52AS, can, for example, bridge between the inner and outer electrodes and reduce the cross-sectional area thereof in the ion path, thereby reducing the loss of ions due to collisions with the supports. Additionally and / or alternatively, the ion path can be constrained to avoid the supports. Thus, a solution to this problem of collisions with supports is to include a set of electrostatic focusing lenses, including a first focusing lens, positioned to constrain the ion path at least partially in the first dimension. In this example, in Figure 5A, a planar Einzel lens 54 containing three electrodes is shown in the center of the device at the crossover point, providing additional focusing in the z-direction (Cartesian coordinates). The geometric projection of the ions after this first focusing lens has been added is shown in Figure 5B(A)-(C). A cross section through the spherical electrode is shown in Figure 5B(D) along with the support 52AS. As a result, now the ions are confined to a finite angle, and the support 52AS can be placed away from the ion beam, thereby facilitating the construction of a CDMS.

[0179] FIG. 5A shows a schematic of a preferred embodiment with some typical values ​​for the device structure. An ion energy of 130 eV / z has been chosen to allow a direct comparison with the prior art ELIT trap of Non-Patent Document 3. It should be understood that higher frequencies and resulting improvements in signal-to-noise and resolution can be obtained by increasing the operating voltage (ion energy) of these devices. Such an approach has not yet been used due to the need to operate the field-free region at high potentials and the possibility of noise injection from the power supply. In the embodiment shown in FIG. 5A, two charge tubes 510A, 510B are employed on either side of a central z-lens 54. Referring again to FIG. 3, g r It can be seen that = 5.9r gives relatively long field free regions on either side of the central lens, making it possible to employ charge tubes 510A, 510B with lengths of about 100 mm. A cross section of the charge tubes 510A, 510B is shown. These charge tubes 510A, 510B present no topological problems for construction and can be easily fabricated using techniques known for example as wire erosion or Electrical Discharge Machining (EDM). A suitable segmented charge tube is described in connection with FIG.

[0180] 5D-5G show the CDMS 5 in more detail. In this example, the first electrostatic sector 51A has a deflection angle of ψ0=199.2°. In this example, the first electrostatic sector 51A comprises an outer spherical electrode 51AO with an inner radius of 23 mm and an outer radius of 28 mm, and an inner spherical electrode 51AI with an outer radius of 17 mm and concentric with the outer spherical electrode 51AO, so that there is a spherical radial gap of 6 mm between them. In this example, the outer spherical electrode 51AO and the inner spherical electrode 51AI are each mounted in the center of a similarly square substantially planar frame, machined and optionally electropolished from a UHV compatible electrical conductor such as 304L or 316L stainless steel (alternatively, for example, gold-coated glass). In this example, the shunt 52A is also mounted within such a frame. Each frame includes four circular openings formed in its proximal corners for mounting on four corresponding insulator (e.g., ceramic such as alumina or Macor (RTM) or polymer such as PTFE) rods 55A-55D (55C and 55D not shown) for lateral alignment of the outer spherical electrode 51AO, the inner spherical electrode 51AI and the shunt 52A. Insulator spacers 56A axially separate the outer and inner spherical electrodes 51AO and 51AI from each other. The outer spherical electrodes 51AO, having a wall thickness of 5 mm, bulge semi-hemispherically from their respective frames. The solid inner spherical electrode 51AI protrudes semi-hemispherically from their respective frames and is supported by two diametrically opposed supports 51AS positioned such that the figure-of-eight ion path IP is clear when flattened by the Einzel lens 54. The inner electrodes of the dish-shaped shunts 52A protrude from their respective frames and are supported by two diametrically opposed supports 52AS generally as described for the supports 51AS for the inner spherical electrode 51AI, thereby providing two quasi-semicircular openings 521A, 521B (i.e., inlets and outlets respectively) of radial width 4 mm.

[0181] The performance advantages of the present invention over the prior art ELIT of Non-Patent Document 3 are shown in Table 1. CDMS5 has comparable angular and spatial acceptance when compared to the ELIT of Non-Patent Document 3, but has more transient signals per unit time and better energy acceptance. This higher energy acceptance can lead to better resolution / sensitivity characteristics. With careful upstream beam collimation and an energy spread of 0.5 eV / z, a single pass mass resolution of several thousand is expected in this embodiment.

[0182] [Table 1]

[0183] Table 1: Performance advantages of CDMS5 according to an exemplary embodiment compared to the prior art ELIT of Non-Patent Document 3. 23.26 transients per ms based on 10 segments of each charge tube. Without segmentation, the number of transients per ms is reduced to 2.326. Even without segmentation, CDMS5 is competitive and simpler, and does not require upstream dual HADs, for example, to select a narrow window of ion kinetic energies for introduction into the electrostatic sector field ion trap 50. Conversely, a larger number of transients can also be achieved using a lift device, as described in connection with FIG. 9.

[0184] Figure 5C is a SIMION simulation of the ions in CDMS5 after several hundred orbits with no ion loss. The Einzel lens constrains the ion trajectory compared to the SIMION simulation of the ions in CDMS4, as shown in Figure 4B.

[0185] FIG. 6 is a graph of the change in frequency (%) as a function of ion energy deviation from ideal (%) for the CDMS5 of FIGS. 5A-5C compared to known CDMSs, specifically the CDMS of FIG. 1B. More specifically, SIMION simulations were performed to calculate the energy focusing characteristics of the CDMS5. It was found that the addition of the z-lens 54 does not result in significant degradation of the device resolution. The first order focusing of this geometry is expected to result in an essentially parabolic residual aberration, which is shown in FIG. 6. In other words, the electrostatic field sector ion trap 50 of the CDMS5 is isochronous to the first order with a parabolic residual in the second order, giving a change in frequency of about 0.05% for an ion energy deviation of ±3%. In comparison, the ELIT trap of Non-Patent Document 3 is not isochronous to the first order, but instead has a linear residual in the first order, giving a change in frequency of about 0.275% for an ion energy deviation of +3% and a change in frequency of about -0.275% for an ion energy deviation of -3%. Thus, the CDMS5 electrostatic field sector ion trap 50 exhibits superior resistance to energy spread compared to the ELIT trap of Non-Patent Document 3, which is one of the main advantages of the present invention.

[0186] 7A and 7B illustrate generally the advantage of a relatively narrow charge detector tube for enhancing the strength of higher harmonics in the Fourier transform for a CDMS according to an example embodiment. More specifically, a further advantage of the present invention is provided by the astigmatic or quasi-astigmatic focusing properties of the electrostatic field sector ion trap. These properties mean that the ion beam is confined to a narrow arc as it traverses the analyzer. The narrow ion beam means that it is possible to use an equally narrow charge tube for detection of the ions. Figures 7A and 7B show how narrower charge tubes give rise to sharper transient signals. This signal has increased harmonic content at higher frequencies as a result of Fourier theory. It is well known that the signal to noise ratio of the processed waveform increases with frequency and that the use of higher harmonics in the Fourier transform improves the resolution of mass spectrometry.

[0187] 8 shows a schematic of an induced charge detector 800 as generally described with respect to induced charge detectors 400 and 500, including a first set of segmented charge detector tubes 810 including a first segmented charge detector tube 810A and a second segmented charge detector tube 810B to increase the number of transient signals per analyzer path for a CDMS according to an exemplary embodiment such as CDMS4 and / or CDMS5. In this example, the first segmented charge detector tube 810A and the second segmented charge detector tube 810B are axially segmented and each include ten segments.

[0188] The relatively long charge tubes provided by the geometry of CDMS4 and CDMS5 allow, for example, axial charge tube segmentation. In principle, the signal induced by a moving ion is negligible after it has passed into the tube for twice the tube width, and an excessively long tube wastes useful signals. Figure 8 shows how segmentation can be employed to increase the number of transient signals per pass. Such segmentation has been proposed before by the use of multiple amplifiers

[11] . It is known that such segmentation still offers advantages by the use of a single amplifier as connected in Figure 8. This principle has been demonstrated in Fourier transform ion cyclotron resonance instruments, see for example the work of Nikolaev

[12] .

[0189] Furthermore, the three-dimensional figure-of-eight path of the electrostatic field sector ion trap 40, and further the constrained three-dimensional figure-of-eight path of the electrostatic field sector ion trap 40, may additionally and / or alternatively allow for radial charge tube segmentation as previously described.

[0190] FIG. 9 shows a schematic of a CDMS 9 according to an exemplary embodiment, including a lift device 99. The CDMS 9 has been generally described with respect to the CDMS 5. The electrostatic sector field ion trap 90 and the induced charge detector 900 are shown schematic as a box, which may represent, for example, the electrostatic sector field ion trap 50 and the induced charge detector 500 of the CDMS 5. To improve the throughput of the electrostatic sector field ion trap of the CDMS according to an exemplary embodiment, it is desirable to operate at a relatively high ion beam kinetic energy, for example in the range of 100 eV to 1,000 eV. The advantage of operating at high energy is faster acquisition and lower aberrations in terms of energy and angle. A first way to increase the kinetic energy is to float the induced charge detector 900 at a high accelerating potential (negative voltage for positive ions), as is commonly done for TOF analyzers. However, in the case of the CDMS, any noise present in the power supply will mask the very low induced signal of the CDMS analyzer. Therefore, an induced charge detector operated at ground potential is highly preferred since it can be effectively shielded from noise by an adjacent ground plate and directly coupled to the amplifier stage (which is a virtual ground). A second method of increasing the kinetic energy is to float the upstream ion optics with an elevated potential. This is known to be technically problematic and can lead to discharge of the components due to field breakdown resulting from Paschen's law. This effect is particularly problematic in the few millibar (mBar) regime where RF ion guides are often used, which limits the applied voltage to about 200V, further limiting the kinetic energy of the ions. A solution to this problem is to pulse the tube (collimator, etc.) (i.e., lift device 99) with a high potential during the fill portion of the CDMS cycle. In this way, the collimator (or other ion optics) operates in high vacuum where no voltage breakdown occurs, thus avoiding problematic discharges. Figure 9 shows how such an upstream collimator 99 can be operated in a pulsed manner to increase the kinetic energy of the ions in the electrostatic field sector ion trap 90.An ion has a certain amount of given energy qV. e At time t1, when the collimator tube 99 is filled with ions, an increased potential V lift At time t2, the trap 90 is pulsed with an increased voltage V, which during the trapping cycle is related to the ion energy by the following equation: i Note that the metric must have the following properties:

[0191]

number

[0192] where i=1,2 and the kinetic energy is T in electron volts. o This means that (V e +V lift ). 10 illustrates a schematic of a CDMS 10 according to an exemplary embodiment. In this example, the CDMS 10 includes an electrostatic field sector ion trap 100 and an induced charge detector 1000, where the electrostatic field sector ion trap 100 is configured to at least partially define an ion path through the induced charge detector 1000.

[0193] In this example, the electrostatic field sector ion trap 100 is as described for MULTUM in reference

[15] . In this example, the electrostatic field sector ion trap 100 includes a set of electrostatic sectors 101 including four similar cylindrical electrostatic sectors 101A-101D, each of which has a deflection angle of ψ0=156.87° and a deflection radius of 50 mm. In this example, the electrostatic field sector ion trap 100 includes a set of electric quadrupole lenses 102 including eight electric quadrupole lenses 102A-102H. In this example, the basic unit includes four drift spaces, two electric quadrupole lenses, and a cylindrical electrostatic sector. In this example, the electrostatic field sector ion trap 100 is isochronous to first order with respect to energy. In this example, the ion path defined by the electrostatic field sector ion trap 100 has three-fold planar symmetry including and through the crossover. Ion implantation can be by deflection as described in reference

[14] or via an ion portal.

[0194] In this example, the inductive charge detector 1000 includes a first set 1010 of segmented charge detector tubes including four segmented charge detector tubes 1010A, 1010B, 1010C, 1010D, generally as described with respect to the inductive charge detectors 400, 500 and 800.

[0195] 11 illustrates a schematic of a CDMS 11 according to an exemplary embodiment. In this example, the CDMS 11 includes an electrostatic field sector ion trap 110 and an induced charge detector 1100, where the electrostatic field sector ion trap 110 is configured to at least partially define an ion path through the induced charge detector 1100.

[0196] In this example, the electrostatic field sector ion trap 110 is as described for the MULTUM Linear plus in reference

[15] and generally as described for the electrostatic field sector ion trap 100 with an additional electric quadrupole lens to allow ion injection (and ejection).

[0197] In this example, the inductive charge detector 1100 includes a first set of segmented charge detector tubes 1110 including four segmented charge detector tubes 1110A, 1110B, 1110C, 1110D, generally as described with respect to the inductive charge detector 1000.

[0198] 12 illustrates a schematic of a CDMS 12 according to an exemplary embodiment. In this example, the CDMS 12 includes an electrostatic field sector ion trap 120 and an induced charge detector 1200, where the electrostatic field sector ion trap 120 is configured to at least partially define an ion path through the induced charge detector 1200.

[0199] In this example, the electrostatic field sector ion trap 120 is as described for MULTUM in reference

[15] . In this example, the electrostatic field sector ion trap 120 includes a set of electrostatic sectors 121 including four similar toroidal electrostatic sectors 121A-121D, each having a deflection angle of ψ0=157.10°, a deflection radius of 50 mm and a C1 value of 0.0337. In this example, the electrostatic field sector ion trap 120 does not include an electric quadrupole lens. In this example, the basic unit includes two drift spaces and a toroidal electrostatic sector. In this example, the electrostatic field sector ion trap 120 is isochronous to first order with respect to energy. In this example, the ion path defined by the electrostatic field sector ion trap 120 has three-fold planar symmetry through and including a crossover. Ion injection can be by deflection as described for reference

[14] or via an ion inlet.

[0200] In this example, the inductive charge detector 1200 includes a first set of segmented charge detector tubes 1210 including four segmented charge detector tubes 1210A, 1210B, 1210C, 1210D, generally as described with respect to the inductive charge detector 1000.

[0201] 13 illustrates a schematic of a CDMS 13 according to an exemplary embodiment. In this example, the CDMS 13 includes an electrostatic field sector ion trap 130 and an induced charge detector 1300, where the electrostatic field sector ion trap 130 is configured to at least partially define an ion path through the induced charge detector 1300.

[0202] In this example, the electrostatic field sector ion trap 130 is as described for a planar figure-of-eight in reference

[15] . In this example, the electrostatic field sector ion trap 130 includes a set of electrostatic sectors 131 including two similar cylindrical electrostatic sectors 131A and 131B, each of which has a deflection angle of ψ0=227.95° and a deflection radius of 50 mm. In this example, the electrostatic field sector ion trap 130 includes a set of electric quadrupole lenses 132 including eight electric quadrupole lenses 132A-132H. In this example, the basic unit includes six drift spaces, four electric quadrupole lenses, and a cylindrical electrostatic sector. In this example, the electrostatic field sector ion trap 130 is isochronous to first order with respect to energy. In this example, the ion path defined by the electrostatic field sector ion trap 130 has three-fold planar symmetry including and through the crossover. Ion injection can be by deflection as described in reference

[14] or via an ion portal. The electrostatic field sector ion trap 130 already has a planar figure-eight geometry, as opposed to the three-dimensional figure-eight geometry of the electrostatic field sector ion traps 30, 40 and 50, and thus does not suffer from the topological problems discussed above.

[0203] In this example, the inductive charge detector 1300 includes a first set of segmented charge detector tubes 1310 including four segmented charge detector tubes 1310A, 1310B, 1310C, 1310D, generally as described with respect to the inductive charge detector 1000.

[0204] 14 illustrates a schematic of a CDMS 14 according to an exemplary embodiment. In this example, the CDMS 14 includes an electrostatic field sector ion trap 140 and an induced charge detector 1400, where the electrostatic field sector ion trap 140 is configured to at least partially define an ion path through the induced charge detector 1400.

[0205] In this example, the electrostatic field sector ion trap 140 is as described for the rhomboid in reference

[16] . In this example, the electrostatic field sector ion trap 140 includes a set of electrostatic sectors 141 including two double toroidal electrostatic sectors 142A, 142B, each of which includes a first toroidal electrostatic sector 141A with a deflection angle of ψ0=156.2° and a second toroidal electrostatic sector 141A with a deflection angle of ψ0=23.8°. In this example, the electrostatic field sector ion trap 120 does not include an electric quadrupole lens. In this example, the basic unit includes three drift spaces and two toroidal electrostatic sectors. In this example, the electrostatic field sector ion trap 140 is isochronous to first order with respect to energy. In this example, the ion path defined by the electrostatic field sector ion trap 140 does not include a crossover and has one plane of symmetry. Ion implantation can be by deflection as described in reference

[14] or via an ion portal.

[0206] In this example, the inductive charge detector 1400 includes a first set of segmented charge detector tubes 1410 including four segmented charge detector tubes 1410A, 1410B, 1410C, 1410D, generally as described with respect to the inductive charge detector 1000.

[0207] It should be understood that any of CDMS4-CDMS9 may interface with the hexapole 3 in region III of CDMS10, thereby replacing region IV of CDMS10, or interface with the focusing lens 4 in region IV, thereby replacing the HAD 6 and modified cone trap with the image charge detector 7 in region IV, and the orthogonal TOF-MS 5 may optionally be removed.

[0208] 15 illustrates a schematic of a method according to an exemplary embodiment. In particular, the method is a method of determining the mass of an ion. The method includes moving ions with an electrostatic field sector ion trap around an ion path defined at least in part by the electrostatic field sector ion trap through an induced charge detector (S1501). The method includes inducing a signal at the induced charge detector with the moving ions (S1502). The method includes determining the mass of the ion using the induced signal (S1503). The method may include any of the steps described herein.

[0209] FIG. 16 shows a schematic diagram of a resonance mass separator (RMS) according to an exemplary embodiment, as described in reference

[19] . More specifically, FIG. 16 shows a SIMION model and spiral ion trajectories in a resonance mass separator consisting of a cylindrical sector and a set of periodic Einzel and quadrupole lenses. The model RMS 130 consists of cylindrical sectors 131 and 132 with different radii, similar to Sakurai et al. (Nucl. Instrum. Meth. A427, 1999, pp. 182-186). The cylindrical sectors generate a substantially two-dimensional electrostatic field in the XY plane. The ion path 133 is arranged in a spiral by injecting an ion beam (or gently bunched ion packets) at a small angle to the XY plane and confining the ions to a set of periodic Einzel lenses 134 and a periodic quadrupole lens 135. The ions follow a spiral ion path 133 consisting of a curved elliptical average ion path projection in the XY plane and a relatively slow ion drift in the drift Z direction. The periodic lenses 134 and 135 confine the ion beam along the spiral ion path despite moderate ion packet divergence. The modeled RMS parameters are as follows: the ion trajectory is inscribed in a 170x250mm cell, the ion path per revolution is 700mm, and the Z length is 200mm to fit 40 revolutions, making the total flight path L=28m. The sector is excited to pass a 6 keV ion beam, so that a target mass at m / z=1000 passes through a single rotation in T0=20 μs and through the RMS in 800 μs. The ion beam parameters are 1 mm beam diameter, 4 mrad angular divergence and energy spread (Gaussian distribution) of FWHM=20 eV, which is in excess compared to the ion beam emittance that can be obtained passing through a gaseous RF guide. When no AC excitation is applied, 1000 amu ions pass through the RMS without loss. AC Excitation

[0210]

number

[0211] is then applied to a quadrupole lens 135 with an aperture of 4 mm and an effective length of 4 mm, taking into account the edge fields. When an AC signal is applied, the separator filters multiple m / z bands, the shape of which is determined by the AC amplitude V0 and frequency F=(N+0.5) / T0.

[0212] 17A-17C show a schematic of a CDMS 17 according to an exemplary embodiment. The CDMS 17 is generally as described for the CDMS 4, and further includes a fragmentation device (not shown) and ion isolation optics at the origin. The central element of the focusing lens has been modified to allow the introduction of a high frequency deflection field compared to the corresponding focusing element of the CDMS 4. The Z focusing capability of the lens, required for efficient trapping in this geometry, is still preserved, but an additional deflection / focusing field is introduced in the orthogonal Y direction. To perform tandem mass analysis, it is necessary to first identify the target species of interest to be isolated, which is the usual voltage configuration of the CDMS, as shown in FIG. 17A. This is performed for each fill. To achieve the highest possible mass measurement accuracy for the CDMS, the ions are allowed to perform many round trips of the analyzer to ascertain their frequency (function of m / z) and intensity (function of signal strength). Once the desired precursor mass is identified, as shown in FIG. 17B, the following configuration is performed: V = V0cos[2πFt] A suitable oscillation voltage of 1000 Hz is applied to the central lens plate. The time it takes to perform the isolation step depends on the required resolution of the separation. This resolution can be determined by the closest distance for the m / z dependent oscillation frequencies for the different species contained in the trap. Once the selected mass species is isolated, knowledge of its oscillation frequency and phase allows the trapping electrodes to be switched to steer the ion out of the trap along the optical axis of the ion. The DC voltage on the central lens can be increased to confine the ion more tightly in the "Z" axis (Figure 17C) so that the ion can be precisely steered out of the trap when the sector electrodes are switched. The ion can be sent back upstream or downstream to an external fragmentation device. Mutatis mutandis, fragmentation devices for CDMS 5, 10, 11, 12, 13, 14 and 16 can be provided.

[0213] Figure 18 illustrates diagrammatically a CDMS 18 according to an exemplary embodiment. CDMS 18 is generally as described with respect to CDMS 12 and further includes a fragmentation device 185. In this example, electrostatic field sector ion trap 180 is configured to at least partially define an ion path through fragmentation device 185. Mutatis mutandis, fragmentation devices can be provided for CDMSs 4, 5, 10, 11, 13, 14 and 16.

[0214] 19 shows a schematic of a CDMS 19 according to an exemplary embodiment. The CDMS 19 is generally as described with respect to the CDMS 17, with the fragmentation device 195 further including a lift device as described with respect to the lift device 99 of the CDMS 9. Thus, isolated ions are therefore sent back upstream to the external fragmentation device 195 where they are fragmented and product ions are introduced into the ion pathway in the same manner as the product ions.

[0215] 20 illustrates generally in schematic form a CDMS 100 according to an exemplary embodiment as described with respect to the mass spectrometer 100 of US2022246414. In contrast to the mass spectrometer 100 of US2022246414, the data system (i.e., computer) of the CDMS 100 according to the exemplary embodiment is configured to perform the method according to the first aspect.

[0216] The device 100 includes an ionization source 105 that generates ions from the sample to be analyzed. The term "ion" as used herein refers to any charged molecule or aggregate of molecules, and is specifically intended to encompass high molecular weight entities that may also be referred to in the art as macroions, charged particles, and charged aerosols. Without limiting the scope of the invention, ions that may be analyzed by the device 100 include proteins, protein complexes, antibodies, viral capsids, oligonucleotides, and high molecular weight polymers. The ionization source 105 may take the form of an electrospray ionization (ESI) source, where ions are formed by spraying charged droplets of a sample solution from a capillary to which an electric potential is applied. The sample may be provided to the ionization source 105 as a continuous stream, for example, as the eluate from a chromatography column.

[0217] Ions generated by the ionization source 105 are directed and focused through a series of ion optics disposed within a vacuum chamber at progressively reduced pressure. As shown in Figure 1, the ion optics may include an ion transmission tube, a stacked ring ion guide, a radio-frequency (RF) multipole, and an electrostatic lens. The vacuum chamber in which the ion optics are housed may be evacuated by any suitable pump or combination of pumps operable to maintain the pressure at a desired value.

[0218] The apparatus 100 may further include a quadrupole mass filter (QMF) 110 that transmits only ions within a selected range of m / z values. The operation of quadrupole mass filters is well known in the art and need not be discussed in detail herein. In general, the m / z range of ions that are selectively transmitted is set by appropriately adjusting the amplitudes of RF and resolving direct current (DC) voltages applied to the electrodes of the QMF 110 to establish an electric field that causes ions with m / z outside the selected range to form unstable trajectories. The transmitted ions then traverse additional ion optics (e.g., lenses and RF multipoles) and enter the ion storage 115. As known in the art, the ion storage 115 employs a combination of oscillatory and electrostatic fields to confine ions within it. In a specific implementation, the ion storage 115 may take the form of a curved trap (commonly referred to as a "c-trap") of the type utilized in the Orbitrap mass spectrometer sold by Thermo Fisher Scientific. A curved trap consists of a set of generally parallel rod electrodes that are concavely curved toward the ion exit. Radial confinement of ions within the ion storage 115 may be achieved by applying oscillating voltages in a specified phase relationship to opposing pairs of the rod electrodes, and axial confinement may be implemented by applying static voltages to end lenses positioned axially outward of the rod electrodes.

[0219] Ions entering the ion storage 115 can be confined therein for a specified cooling period to reduce their kinetic energy before the ions are introduced into the electrostatic trap. Confining the ions in the ion storage for a specified period can also aid in desolvation of the ions, i.e., removal of any residual solvent moieties from the analyte ions. As discussed herein above, the presence of residual solvent can result in mass shifts during analysis, which impede the ability to accurately measure m / z and charge. To facilitate kinetic cooling and desolvation of the ions, an inert gas such as argon or helium can be added to the interior space of the ion storage, but the pressure of the cooling gas must be adjusted to avoid unintended fragmentation of the analyte ions and / or excessive leakage of gas into the electrostatic trap 120. The duration of the cooling period depends on many factors, including the kinetic energy of the ions entering the ion storage 115, the inert gas pressure, and the desired kinetic energy profile of the ions injected into the electrostatic trap 120. After the cooling period is complete, ions trapped in the ion storage 115 may be radially ejected from the ion storage towards the entrance lens 125 which acts to focus and direct the ions to the entrance 130 of the electrostatic trap 120. Rapid ejection of ions from the ion storage 115 can be achieved by rapidly collapsing the oscillating field inside the ion storage and applying a DC pulse to a rod electrode positioned away from the ejection direction.

[0220] To reliably measure ion charge using CDMS techniques, only individual ions of a particular ion species may be present in the electrostatic trap 120 during a measurement event. The term "ion species" as used herein refers to ions of a given elemental / isotopic composition and charge state, with ions of different elemental / isotopic composition being considered to be different ion species, as well as ions of the same elemental composition but different charge states. The term "ion species" is used herein synonymously with the terms "analyte ion" and "ion of interest." When multiple ions of the same ion species are present during a measurement event, the measured charge state (determined from the amplitude of the signal generated by the image current detector 132, as described below) will be a multiple of the actual charge state of the individual ions. To avoid this type of erroneous measurement, the ion population in the ion storage 115 should be kept small enough so that the probability of two ions of the same ion species being trapped in the ion storage is kept at an acceptable minimum. This may be accomplished by attenuation of the ion beam generated by the ionization source 105 (more specifically, by "detuning" the ion optics located in the upstream ion path so that a high loss of ions occurs) and / or by adjusting the fill time (the period during which ions are accepted into the ion accumulation 115). To control the fill time, one or more ion optics located upstream in the ion accumulation ion path may be operated as a gate to selectively allow or block the passage of ions into the interior space of the ion accumulation 115.

[0221] The electrostatic trap 120 may take the form of an orbital electrostatic trap of the type commercially available from Thermo Fisher Scientific under the trademark "Orbitrap" and shown in cross section in FIG. 1. Such an orbital electrostatic trap includes an inner spindle-shaped electrode 135 that defines a central longitudinal axis designated as the z-axis in a cylindrical coordinate system. An outer barrel-shaped electrode 140 is positioned coaxially with respect to the inner electrode 135 to define therebetween a generally annular trapping region 145 into which ions are injected. The inner and outer electrodes 135, 140 are each symmetric about a transverse plane (designated as z=0, alternatively referred to as the "equator"), in which the inner electrode 135 has a maximum outer radius of R1 and the outer electrode 140 has a maximum inner radius of R2. As has been widely discussed in the scientific literature (see, e.g., Makarov, "Electrostatic Axially Harmonic Orbital Trapping: A High-Performance Technique of Mass Analysis," Analytical Chemistry, Vol. 72, No. 6, pp. 1156-62 (2000), which is incorporated herein by reference), the inner and outer electrodes can be configured to establish an electrostatic potential U(r,z) within the trapping region 145 (upon application of an electrostatic voltage to one or both of the electrodes) that approximates the following relationship:

[0222]

number

[0223] where r and z are cylindrical coordinates (r=0 is the central longitudinal axis and z=0 is the transverse symmetry plane), C is a constant, k is the field curvature, and R m is the characteristic radius. This electric field can also be called a quadrupole logarithmic field.

[0224] The outer electrode 140 is divided along a transverse plane of symmetry into a first part 150 and a second part 155, which are separated from each other by a narrow insulating gap. This arrangement allows the outer electrode 140 to be used as an image current detector together with a differential amplifier 160. The presence of an ion in close proximity to the outer electrode induces a charge on the electrode having a magnitude proportional to the charge of the ion (and of opposite polarity to the charge of the ion). The oscillatory reciprocating motion of the ion along the z-axis between the first part 150 and the second part 155 of the outer electrode 140 causes the image current detector 132 to output a time-varying signal (referred to as a "transient signal") having a frequency equal to the frequency of the ion's longitudinal oscillation and an amplitude representative of the charge of the ion.

[0225] Ions can be tangentially introduced into the trapping region 145 through the entrance aperture 130 formed in the outer electrode 240. The entrance aperture 130 is axially (along the z-axis) offset from the transverse plane of symmetry such that when the ions are introduced into the trapping region 145, they experience a restoring force in the direction of the plane of symmetry, which causes the ions to begin longitudinal oscillation along the z-axis as they orbit around the inner electrode 135, as shown in FIG. 20. A notable feature of a quadrupole logarithmic field is that its potential distribution does not contain cross terms in r and z, and the potential in the z-dimension is exclusively quadratic. Thus, the motion of the ions along the z-axis can be described as a harmonic oscillator (since the force along the z-dimension that the field exerts on the ions is directly proportional to the displacement of the ions along the z-axis from the transverse plane of symmetry) and is completely independent of the orbital motion. Thus, the frequency ω of the ion oscillation along the z-axis is simply related to the mass-to-charge ratio (m / z) of the ions by the following relationship:

[0226]

number

[0227] Measurement of charge state and m / z, and subsequent calculation of product mass, proceeds by collection and processing of a transient signal. Collection of the transient signal by detector 132 begins immediately after injection of the analyte ion and continues for a predetermined transient signal length. The length of the transient signal required for accurate measurement of m / z and charge state depends on the analyte and the physical and operational parameters of the electrostatic ion trap 120. In general, the transient signal needs to be of adequate duration so that the signal can be reliably distinguished from noise. For typical analyte ions, it is expected that a transient signal length of 500 milliseconds can be used to obtain a sufficient signal-to-noise ratio using a commercially available orbital trap mass spectrometer. It will be appreciated that the maximum transient signal length is limited by the duration that the analyte ion is stably trapped within trapping region 145 without colliding with background gas atoms / molecules or other ions, which is in part a function of the trapping region pressure.

[0228] overview In electrosprays of very large species (>1 MDa), such as virus molecules, the possible charge states change continuously, and conventional mass analyzers that detect only m / z ratios cannot give clear spectral peaks and provide little useful analytical data. CDMS overcomes this limitation by injecting individual (or small populations) of ions and measuring both m / z and z, and the true mass (m) can be measured by the product of these two parameters. Mass resolution depends on both m / z resolution and charge (z) accuracy. Here we present the first CDMS spectrum from a 199.2° dual spherical electric sector ion trap configured for such measurements. This device has the advantage of a simple structure yet a high space charge capacity for higher experimental throughput. The instrument (Figures 21-23) includes a custom API interface, a CDMS analyzer and an amplifier-data acquisition system. The CDMS analyzer was comprehensively simulated using SIMAX software.

[0229] API Interface (Fasmatech) [Reference 20] 21-23, a polydisperse sample of nominal 30 nm diameter polystyrene beads with an average molecular weight of 8.2 MDa was analyzed. The ions were dissolved in 50 / 50 MeOH / water at 2×10 11 The particles were electrosprayed at a concentration of 10 ...

[0230] CDMS analyzer FIG. 22 shows a schematic of the dual sector geometry first proposed by Poschenrieder [Reference 21] as a TOF analyzer adapted and configured for CDMS measurements. The large ion volume leads to a high space charge capacity of this analyzer. In more detail, FIG. 22 shows the injection hole, ion path and central lens of the CDMS analyzer. The segmentation of the charge tube is not shown. Trapping is initiated by raising the sector voltage upon the arrival of an ion packet from the upstream interface. The CDMS analyzer acts as a unique energy filter, eliminating ions outside its phase space tolerance within the first few milliseconds, leaving long-lived residual ions to contribute to the collected spectrum. The charge tube is segmented and configured to give a characteristic harmonic signature useful for subsequent data analysis. A central lens is employed to prevent large bow deviations, preventing ions from colliding with the inner hemispherical support.

[0231] Simulation (SIMAX) [Reference 22] A refined potential array for the entire CDMS analyzer was generated using SIMION [Ref. 4] (Figure 24). This array was imported into SIMAX software to examine ion acceptance and m / z resolution. The SIMAX package allows the specification of individual image charge electrodes (charge tubes) to generate fast Fourier transform mass spectra. Using the hard sphere model in SIMAX, the effect of UHV pressure was understood, which was measured using a 10 -7 Pa(10 -9 For the 8.2 MDa ion at a background pressure of 1000 uV (0.25 mbar), transient signal lengths of approximately 1 s were found to be negligible. SIMAX gave the predicted harmonic signature of the analyzer used for data processing (Figure 25). The simulated m / z resolution was in agreement with the experimental results presented here.

[0232] Data collection and analysis (Spectroswiss) [Reference 24] Data were collected using a charge-sensitive preamplifier and a Spectroswiss FTMS Booster X2 employing a signal conditioning amplifier and a high-performance digitizer with FPGA chip along with Spectroswiss software (Figure 26). The length of the transient signal was set to 1.5 seconds and collection was stopped until the phase-space out-of-tolerance ions were eliminated by the CDMS analyzer. Analysis was performed on long-lived remaining ions. Transient signals were analyzed in chunks of short transient signals to determine ion lifetimes, which are essential for proper FFT quantification. Structured noise signals in this early prototype were evident in the raw data due to the electronic pickup. Using the characterized harmonic signature of the analyzer, these spurious signals were eliminated from the final data set. After charge calibration of the preamplifier and booster combination, a true mass histogram of a polystyrene bead sample was generated (Figure 31).

[0233] CDMS analyzer results Proof of operation of the analyzer was confirmed by analyzing ion packets of myoglobin in conventional m / z mode (Figure 27). The beating of isotopes within individual charge states limits the transient signal time leading to relatively poor resolution in this acquisition mode. Megadalton ions were trapped for a maximum of 1.5 seconds, corresponding to an m / z resolution of about 5,000 FWHM for the 8.2 MDa species. The first harmonic m / z envelope of the sample peaked at about 7000 m / z, indicating a charging nearly close to the Rayleigh limit for these spherical beads. The analyzer acts as its own energy filter, eliminating ions outside its phase space tolerance within the first few milliseconds, leaving the remaining ions to contribute to the collected spectrum (Figure 28). The final mass spectrum was calibrated by injecting a small signal of known amplitude into the preamplifier. The accuracy in this case is limited by the electrical tolerance of the input capacitor, which is currently only 25%.

[0234] Figure 29 (top) shows the frequency domain spectrum before noise rejection and Figure 29 (bottom) shows the frequency domain spectrum after noise rejection according to an exemplary embodiment. Figure 29 (bottom) shows that adding a harmonic filter (frequency ratio) rejects the noise (grey) and makes the true ion signal (red) more apparent. In this example, the predetermined frequency tolerance is ±0.01%.

[0235] FIG. 30 shows two technical replicates (red, blue) of polystyrene beads collected using the CDMS of FIG. 21 taken on different days and showing the reproducibility of the measurements. FIG. 31 is a mass histogram of a 30 nm polystyrene bead sample (8.2 MDa) collected using the CDMS of FIG.

[0236] While preferred embodiments have been shown and described, it will be understood by those skilled in the art that various modifications and changes can be made therein without departing from the scope of the invention as defined in the appended claims and described above.

[0237] Attention is directed to all articles and documents related to this application that have been filed contemporaneously herewith or earlier than this application and that are open to public inspection herewith, and the contents of all such articles and documents are incorporated herein by reference.

[0238] All of the features disclosed in this specification (including any accompanying claims and drawings) and / or all of the steps of any method or process so disclosed may be combined in any combination, except where at most some of such features and / or steps are mutually exclusive.

[0239] Each feature disclosed in this specification (including any accompanying claims and drawings), unless expressly stated otherwise, may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is merely an example of a generic series of equivalent or similar features.

[0240] The invention is not limited to the details of the foregoing embodiments, and extends to any novel or any novel combination of features disclosed herein (including any accompanying claims and drawings), or any novel or any novel combination of steps of any method or process so disclosed.

[0241] References

[0242] [Table 2]

Claims

1. 1. A method for identifying noise, the method being implemented by a computer including a processor and a memory, comprising: acquiring a time domain signal representative of charge induced in an induced charge detector by ions traveling in a charge detection mass spectrometer or CDMS; converting the time domain signal into a frequency domain spectrum comprising a series of frequency-amplitude pairs; eliminating, from said series of frequency-amplitude pairs, certain frequency-amplitude pairs that do not have harmonic frequency-amplitude pairs in said series of frequency-amplitude pairs; The method includes:

2. 2. The method of claim 1 , wherein acquiring the time domain signal representative of the charge induced in the inductive detector by the ions traveling in the CDMS comprises acquiring the time domain signal representative of the charge induced in the inductive detector by a plurality of ions traveling in the CDMS, optionally the plurality of ions having different mass to charge ratios from one another.

3. 2. The method of claim 1 , wherein acquiring the time domain signal representative of the charge induced in the inductive detector by the ions moving in the CDMS comprises acquiring the time domain signal representative of the charge induced in the inductive detector by the ions moving in the CDMS at a constant velocity.

4. 3. The method of claim 1 or 2, wherein acquiring the time domain signal representative of the charge induced in the inductive detector by the ions moving in the CDMS comprises acquiring the time domain signal representative of the charge induced in the inductive detector by the ions moving with harmonic motion in the CDMS.

5. 2. The method of claim 1 , wherein transforming the time domain signal into the frequency domain spectrum comprising the series of frequency-amplitude pairs comprises transforming the time domain signal into the frequency domain spectrum comprising the series of frequency-amplitude pairs using a Fourier transform or FT, such as a Fast Fourier Transform or FFT.

6. 2. The method of claim 1, wherein eliminating the particular frequency-amplitude pairs from the series of frequency-amplitude pairs that do not have harmonic frequency-amplitude pairs in the series of frequency-amplitude pairs comprises eliminating the particular frequency-amplitude pairs from the series of frequency-amplitude pairs that do not have harmonic frequency-amplitude pairs in the series of frequency-amplitude pairs, within a predetermined frequency tolerance.

7. 2. The method of claim 1, wherein eliminating the particular frequency-amplitude pairs from the series of frequency-amplitude pairs that do not have harmonic frequency-amplitude pairs in the series of frequency-amplitude pairs comprises eliminating the particular frequency-amplitude pairs from the series of frequency-amplitude pairs that do not have harmonic frequency-amplitude pairs in the series of frequency-amplitude pairs within a predetermined amplitude tolerance range.

8. 2. The method of claim 1, wherein eliminating from the series of frequency-amplitude pairs certain frequency-amplitude pairs that do not have a harmonic frequency-amplitude pair in the series of frequency-amplitude pairs comprises eliminating from the series of frequency-amplitude pairs certain frequency-amplitude pairs that have a predetermined harmonic frequency-amplitude pair in the series of frequency-amplitude pairs, preferably a predetermined third, higher, or both, of its harmonic frequency-amplitude pairs.

9. 2. The method of claim 1, wherein eliminating from the series of frequency-amplitude pairs that do not have a harmonic frequency-amplitude pair therein comprises eliminating from the series of frequency-amplitude pairs that do not have a predetermined harmonic frequency-amplitude pair signature therein.

10. 2. The method of claim 1, comprising retaining certain frequency-amplitude pairs from said series of frequency-amplitude pairs that have harmonic frequency-amplitude pairs therein.

11. 11. The method of claim 10, wherein retaining the particular frequency-amplitude pair in the series of frequency-amplitude pairs that has its harmonic frequency-amplitude pair in the series of frequency-amplitude pairs comprises retaining the particular frequency-amplitude pair in the series of frequency-amplitude pairs that has its harmonic frequency-amplitude pair in the series of frequency-amplitude pairs within a predetermined frequency tolerance.

12. 12. The method of claim 10 or 11, wherein retaining the particular frequency-amplitude pair in the series of frequency-amplitude pairs that has its harmonic frequency-amplitude pair in the series of frequency-amplitude pairs comprises retaining the particular frequency-amplitude pair in the series of frequency-amplitude pairs that has its harmonic frequency-amplitude pair in the series of frequency-amplitude pairs within a predetermined amplitude tolerance range.

13. 12. The method of claim 10 or 11, wherein retaining the particular frequency-amplitude pair from the series of frequency-amplitude pairs that has its harmonic frequency-amplitude pair in the series of frequency-amplitude pairs comprises retaining the particular frequency-amplitude pair from the series of frequency-amplitude pairs that has only its predetermined harmonic frequency-amplitude pair, preferably a predetermined second harmonic frequency-amplitude pair, in the series of frequency-amplitude pairs.

14. 14. The method of claim 10, wherein retaining the particular frequency-amplitude pair in the series of frequency-amplitude pairs that has a harmonic frequency-amplitude pair therein comprises retaining the particular frequency-amplitude pair in the series of frequency-amplitude pairs that has a predetermined harmonic frequency-amplitude pair signature in the series of frequency-amplitude pairs.

15. 12. A method according to claim 10 or 11, comprising calculating the mass to charge ratio of the ions using the frequencies of the retained frequency-amplitude pairs, and optionally using the frequencies of harmonic frequency-amplitude pairs thereof.

16. 12. A method according to claim 10 or 11, comprising calculating the charge of the ion using the amplitudes of the retained frequency-amplitude pairs, and optionally using the amplitudes of harmonic frequency-amplitude pairs thereof.

17. 2. The method of claim 1 , wherein obtaining the time domain signal representative of the charge induced in the induced charge detector by the ions moving in the CDMS comprises using the CDMS to collect the time domain signal representative of the charge induced in the induced charge detector by the ions moving in the CDMS.

18. 2. The method of claim 1, comprising using the calculated mass to charge ratio of the ions, the charges of the ions, or both to control the CDMS, e.g., in real time.

19. At least one of a computer including a processor and a memory configured to perform the method of claim 1, a computer program including instructions that, when executed by a computer including a processor and a memory, cause the computer to perform the method of any one of claims 1 to 18, and a non-transitory computer-readable storage medium including instructions that, when executed by a computer including a processor and a memory, cause the computer to perform the method of any one of claims 1 to 18.

20. A charge detection mass spectrometer or CDMS, an electrostatic field ion trap including a set of electrostatic electrodes including a first electrostatic electrode and a second electrostatic electrode, and an induced charge detector, the electrostatic field ion trap configured to at least partially define an ion path through the induced charge detector; A computer including a processor and a memory configured to perform the method of claim 1. A charge detection mass spectrometer or CDMS including:

21. 21. The CDMS of claim 20, wherein the electrostatic field ion trap comprises or is an electrostatic field sector ion trap, or both, and the set of electrostatic electrodes comprises or is a set of electrostatic sectors, or both, and optionally the first electrostatic electrode and the second electrostatic electrode are first electrostatic sectors and second electrostatic sectors, respectively.

22. 22. The CDMS of claim 21 including a set of electrostatic focusing lenses including a first focusing lens arranged to at least partially constrain the ion path in a first dimension, preferably the first dimension being orthogonal to a direction of the ion path through the induced charge detector.

23. 23. The CDMS of claim 21 or 22, comprising a lift device configured to increase ion energy of ions introduced into the ion path, such as by pulsing the ions into the ion path, optionally the lift device configured to trap the ions introduced into the ion path.

24. 21. The CDMS of claim 20, wherein the electrostatic field ion trap comprises or is an electrostatic linear field ion trap, or both, and optionally the first electrostatic electrode comprises or is a first reflective or mirror electrode, or both, and optionally the second electrostatic electrode comprises or is a second reflective or mirror electrode, or both.

25. 21. The CDMS of claim 20, wherein the electrostatic field ion trap includes or is a curved trap, or both.

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