Patent Application
20220181131
The present disclosure generally relates to the field of mass spectrometry including an improved device control to maximize system utilization.
Quadrupole mass analyzers are one type of mass analyzer used in mass spectrometry. As the name implies, a quadrupole consists of four rods, usually cylindrical or hyperbolic, set in parallel pairs to each other, as for example, a vertical pair and a horizontal pair. These four rods are responsible for selecting sample ions based on their mass-to-charge ratio (m/z) as ions are passed down the path created by the four rods. Ions are separated in a quadrupole mass filter based on the stability of their trajectories in the oscillating electric fields that are applied to the rods. Each opposing rod pair is connected together electrically, and a radio frequency (RF) voltage with a DC offset voltage is applied between one pair of rods and the other. Ions travel down the quadrupole between the rods. Only ions of a certain mass-to-charge ratio will be able to pass through the rods and reach the detector for a given ratio of voltages applied to the rods. Other ions have unstable trajectories and will collide with the rods. This permits selection of an ion with a particular m/z or allows the operator to scan for a range of m/z-values by continuously varying the applied DC and RF voltages.
By setting stability limits via applied RF and DC potentials that are capable of being ramped as a function of time, such instruments can be operated as a mass filter, such that ions with a specific range of mass-to-charge ratios have stable trajectories throughout the device. In particular, by applying fixed and/or ramped AC and DC voltages to configured cylindrical but more often hyperbolic electrode rod pairs in a manner known to those skilled in the art, desired electrical fields are set-up to stabilize the motion of predetermined ions in the x and y dimensions. As a result, the applied electrical field in the x-axis stabilizes the trajectory of heavier ions, whereas the lighter ions have unstable trajectories. By contrast, the electrical field in the y-axis stabilizes the trajectories of lighter ions, whereas the heavier ions have unstable trajectories. The range of masses that have stable trajectories in the quadrupole and thus arrive at a detector placed at the exit cross section of the quadrupole rod set is defined by the mass stability limits.
It is desirable to make the best measurements on selected reaction monitoring (SRM) and selected ion monitoring (SIM) methods possible, and it can be desirable to do many of them really fast. To get the best measurements you need to have the quadrupole at the specified settings for a given duration to allow the ions of interest time to pass through and be measured. However, there is a trade-off between the number of monitored mass-to-charge ratios and the quality of the data given there is a finite time to obtain the measurements. Additionally, there are time delays when changing between quadrupole states that cause periods of time where nothing can be measured. From the foregoing it will be appreciated that a reduction in the time delays could increase the number and quality of measurements.
In a first aspect, a method can include obtaining an impulse response curve for an electrical component; performing a constrained convex optimization to determine an DC filter input to achieve a required voltage on a set of quadrupole rods; utilizing the results of the constrained convex optimization to cause a DC rod drive to produce the DC filter input; selecting ions passing through the set of quadrupole rods based on the mass-to-charge ratio; measuring the intensity of the ions.
In a second aspect, a method can include supplying a first set of voltages to a multipole to select a first target mass-to-charge ratio; maintaining the first set of voltages while collecting intensity data for ions having the first target mass-to-charge ratio; scanning from the first set of voltages to a second set of voltages while collecting intensity data for ions within the range of mass-to-charge ratios between the first target mass-to-charge ratio and a second target mass-to-charge ratio, wherein the second set of voltages select the second target mass-to-charge ratio; maintaining the second set of voltages while collecting intensity data for ions having the second mass-to-charge ratio; and generating a mass spectrum using the intensity data for ions within the range of mass-to-charge ratios.
In a third aspect, a mass spectrometer can include an ion source configured to produce ions from a sample; a set of quadrupole rods configured to select ions based on a mass-to-charge ratio; a DC rod driver configured to produce a voltage; a DC rod driver filter configured to filter RF frequency interference; and a controller. The controller can be configured to utilize the results of the constrained convex optimization to cause a DC rod drive to produce the DC filter input and provide a required voltage to the set of quadrupole rods, the constrained convex utilizing a impulse response curve of the DC rod driver filter to determine a DC filter input to achieve the required voltage on the set of quadrupole rods; select ions passing through the set of quadrupole rods based on the mass-to-charge ratio; and measure the intensity of the ions.
In a fourth aspect, a mass spectrometer can include an ion source configured to produce ions from a sample; a set of quadrupole rods configured to select ions based on a mass-to-charge ratio; DC rod driver configured to produce a voltage and supply the voltage to the set of quadrupole rods; a DC rod driver filter configured to filter RF frequency interference; and a controller. The controller can be configured to supply a first set of voltages to the set of quadrupole rods to select a first target mass-to-charge ratio; maintain the first set of voltages while collecting intensity data for ions having the first target mass-to-charge ratio; scan from the first set of voltages to a second set of voltages on the quadrupole rods while collecting intensity data for ions within the range of mass-to-charge ratios between the first target mass-to-charge ratio and a second target mass-to-charge ratio, wherein the second set of voltages select the second target mass-to-charge ratio; maintain the second set of voltages on the quadrupole rods while collecting intensity data for ions having the second mass-to-charge ratio; and generate a mass spectrum using the intensity data for ions within the range of mass-to-charge ratios, intensity data for ions having the first target mass-to-charge ratio, and intensity data for ions having the second mass-to-charge ratio.
For a more complete understanding of the principles disclosed herein, and the advantages thereof, reference is now made to the following descriptions taken in conjunction with the accompanying drawings, in which:
It is to be understood that the figures are not necessarily drawn to scale, nor are the objects in the figures necessarily drawn to scale in relationship to one another. The figures are depictions that are intended to bring clarity and understanding to various embodiments of apparatuses, systems, and methods disclosed herein. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts. Moreover, it should be appreciated that the drawings are not intended to limit the scope of the present teachings in any way.
Embodiments of systems and methods to dynamically exclude product ions that may be present in the master scan are described herein.
The section headings used herein are for organizational purposes only and are not to be construed as limiting the described subject matter in any way.
In this detailed description of the various embodiments, for purposes of explanation, numerous specific details are set forth to provide a thorough understanding of the embodiments disclosed. One skilled in the art will appreciate, however, that these various embodiments may be practiced with or without these specific details. In other instances, structures and devices are shown in block diagram form. Furthermore, one skilled in the art can readily appreciate that the specific sequences in which methods are presented and performed are illustrative and it is contemplated that the sequences can be varied and still remain within the spirit and scope of the various embodiments disclosed herein.
All literature and similar materials cited in this application, including but not limited to, patents, patent applications, articles, books, treatises, and internet web pages are expressly incorporated by reference in their entirety for any purpose. Unless described otherwise, all technical and scientific terms used herein have a meaning as is commonly understood by one of ordinary skill in the art to which the various embodiments described herein belongs.
It will be appreciated that there is an implied “about” prior to the temperatures, concentrations, times, pressures, flow rates, cross-sectional areas, etc. discussed in the present teachings, such that slight and insubstantial deviations are within the scope of the present teachings. In this application, the use of the singular includes the plural unless specifically stated otherwise. Also, the use of “comprise”, “comprises”, “comprising”, “contain”, “contains”, “containing”, “include”, “includes”, and “including” are not intended to be limiting. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the present teachings.
As used herein, “a” or “an” also may refer to “at least one” or “one or more.” Also, the use of “or” is inclusive, such that the phrase “A or B” is true when “A” is true, “B” is true, or both “A” and “B” are true. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.
A “system” sets forth a set of components, real or abstract, comprising a whole where each component interacts with or is related to at least one other component within the whole.
Various embodiments of mass spectrometry platform 100 can include components as displayed in the block diagram of
In various embodiments, the ion source 102 generates a plurality of ions from a sample. The ion source can include, but is not limited to, a matrix assisted laser desorption/ionization (MALDI) source, electrospray ionization (ESI) source, atmospheric pressure chemical ionization (APCI) source, atmospheric pressure photoionization source (APPI), inductively coupled plasma (ICP) source, electron ionization source, chemical ionization source, photoionization source, glow discharge ionization source, thermospray ionization source, and the like.
In various embodiments, the mass analyzer 104 can separate ions based on a mass-to-charge ratio (m/z) of the ions. For example, the mass analyzer 104 can include a quadrupole mass filter analyzer, a quadrupole ion trap analyzer, a time-of-flight (TOF) analyzer, an electrostatic trap mass analyzer (e.g., ORBITRAP mass analyzer), Fourier transform ion cyclotron resonance (FT-ICR) mass analyzer, and the like. In various embodiments, the mass analyzer 104 can also be configured to fragment the ions using collision induced dissociation (CID) electron transfer dissociation (ETD), electron capture dissociation (ECD), photo induced dissociation (PID), surface induced dissociation (SID), and the like, and further separate the fragmented ions based on the mass-to-charge ratio.
In various embodiments, the mass spectrometry platform 100 can include multiple mass analyzers. In this way, mass analysis can be performed on two sets of ions at the same time. Additionally, the mass analyzers may have different mass accuracies and/or resolutions, such as a high-resolution electrostatic trap mass analyzer and a lower resolution quadrupole mass analyzer or ion trap mass analyzer.
In various embodiments, the ion detector 106 can detect ions. For example, the ion detector 106 can include an electron multiplier, a Faraday cup, and the like. Ions leaving the mass analyzer can be detected by the ion detector. In various embodiments, the ion detector can be quantitative, such that an accurate count of the ions can be determined.
In various embodiments, the controller 108 can communicate with the ion source 102, the mass analyzer 104, and the ion detector 106. For example, the controller 108 can configure the ion source 102 or enable/disable the ion source 102. Additionally, the controller 108 can configure the mass analyzer 104 to select a particular mass range to detect. Further, the controller 108 can adjust the sensitivity of the ion detector 106, such as by adjusting the gain. Additionally, the controller 106 can adjust the polarity of the ion detector 106 based on the polarity of the ions being detected. For example, the ion detector 106 can be configured to detect positive ions or be configured to detected negative ions.
Resolving quadrupole-based mass spectrometers are limited in the speed that they can perform SRM and SIM experiments due to the time it takes to change the state of the resolving DC field on the device. This device and others in the instrument traditionally require waiting for a settling time before the instrument can be utilized to make appropriate measurements.
There are multiple time delays that contribute to the delay caused by changing quadrupole states. The settling time for the RF can be relatively short, and flight time through the collision cell has improved with axial fields. The biggest time delay is the time it takes the resolving DC to achieve a stable value at the new state.
In various embodiments, the settling time of a quadrupole can be dramatically reduced by implementing control methods disclosed herein which are based around measuring the response of the device and then formulating a prediction of how to drive a device to gain improved precision and control.
Traditionally the resolving DC is set by controlling the output of a high voltage variable DC output which is then fed through a filter. This filter is critical to achieve the precision needed for the quadrupole to accurately filter ions out of the ion beam. This filter also prevents unwanted RF waveforms from traveling back into the DC rod driver and causing problems such as instability and even circuit damage.
This filter adds an intrinsic time delay between the rod driver and the quadrupole. This time delay can be on the order of hundreds of microseconds to tens of millisecond or more, which limits the number of SRM or SIM measurements that can be performed per second. While the time delay of the filter can be reduced, it is usually at the cost of power or filter quality so there are limits to what can be done.
Additionally, the RF prevents using the voltage on the quadrupole as feedback to get precise voltage control. Instead, the rod driver output is typically used for feedback instead. However, the delays introduced by the filter mean the voltage on the quadrupole lags the feedback used in controlling the voltage. This can be problematic.
The resolving DC on a quadrupole is a result of the convolution of the impulse response of the DC rod driver output filter and the output of the DC rod driver. Solving for the filter response will yield an appropriate DC rod driver output to give us the optimal resolving DC on the quadrupole rods. Specifically, the impulse response of the filter can be characterized while the RF is off, allowing direct measurement of the RF on the output side of the filter. Using this information, the long delay imposed by the DC rod driver filter can be compensated for mathematically to create an optimum input drive signal so that the filter output closely matches the desired DC voltage on the quadrupole rods. Advantageously, this can significantly reduce settling times and reduce time lost during an experiment waiting for the DC voltage on the quadrupole to stabilize.
The process can be demonstrated using the exemplary DC rod driver output filter 200 shown in
The impulse response function can be represented as a 1D vector ‘h’. This can be turned into a Toeplitz matrix A by shifting each column by 1 compared with the one before it. Optionally, matrix A can be turned into a circulant matrix H by padding the final edges of the matrix by the length of the h vector. This padding allows us to perform solutions with discrete Fourier transforms instead of full matrix operations, thus tremendously speeding the calculations. As a result, the output of the filter can be determined according to A*x=b, where x is the 1D vector of the rod driver output (the input to the filter) and b is the resulting output of the filter.
In various embodiments, the mathematical relationship between the rod driver output and the output of the filter can be used to determine a rod driver output required to achieve the desired output from the rod driver filter. However, solving this problem with no other constraints can result in solutions that are typically not physically feasible. In general, the unconstrained solution can have slew rates and bandwidths orders of magnitude larger that the DC rod drive can physically provide. Additionally, the unconstrained solution can require voltage outputs much larger than can be physically provided.
Rather than solving for the unconstrained solution, a constrained problem can be constructed and solved with convex optimization methods. This constrained problem's solution can be used to provide practical solution that can be implemented with hardware. It is desirable to have extremely close output value tracking while minimizing big deviations that occur when actually changing states. Limits can be placed on the slew rates of the input signal and the input magnitude. Additionally, it can be desirable to limit the amount of power the DC rod driver power supply must provide. In various embodiments, the amount of ripple the input will have can be limited in order to limit pulling from the positive and negative DC rod driver supplies during any given transition. Using both rails for a given transition results in wasted power that does not go into the final voltage value on the quadrupole rod. This can be expressed as
where D is the matrix that gives the element by element derivative of x when multiplied, E is the matrix that gives the derivative of Dx result, and c and f are weighting terms. Additional constraints can be element-wise evaluations. R is the rail min and max values and S is the slew rate limit.
In various embodiments, it may be desirable to restrict the input x values to be integers. This constraint allows to naturally obtain DAC output values from the solution. This can also naturally incorporate a dithering effect to gain better output resolution than the DAC would naturally be thought to have by exploiting the higher speed of the DAC and rod driver than what the analog bandwidth of the filter has.
One of skill in the art would understand that other similar formulation of this problem can yield practical results. For example, all of the norms in the minimization statement can be replaced with an l2-norm value or Huber function or other valid convex options. These can also be mixed and matched. For example, a l2-norm value can be used for the second derivative but not for the other terms. In various embodiments, c and f may be set to zero, relying on the additional constraints to satisfy the physical capability of driving the output.
The desired output of the DC rod driver filter can be used to calculate the required voltage from the DC rod driver to achieve the desired output of the DC rod driver filter. However, the solution needs to provide physically feasible values to achieve the improved result on the quadrupole rod.
The result of solving the problem for the exemplary DC rod driver filter 200 of
At 404, the input to the DC rod driver filter to achieve a desired output can be calculated using the determined impulse response. In various embodiments, the input can be determined when building a method and can be used for all subsequent uses of the method. In other embodiments, a library can be generated of often used changes and the method can be built using the library of inputs. In yet other embodiments, the input can be calculated at the beginning of a run or a series of runs.
At 406, the DC rod driver can produce the calculated input for the DC rod driver filter and the output of the DC rod driver filter can be provided to the rods of the multipole.
In various embodiments, this approach can also be used to improve scanning over a mass range when applied to abrupt changes in the scan rate or pauses in a scan. The next example represents the results for starting at a static value and then immediately starting scanning at 50,000 amu/s with a pause at the top and then a scan back down at 50,000 amu/s. This scan could be used for a hybrid SIM/SRM and full scan. SIM/SRM is desirable because of the improved detection limit. However, as the voltage is fixed, a SIM/SRM does not provide information about analytes at an m/z not targeted by the SIM/SRM. Being able to scan very quickly could make such a hybrid scan feasible.
As can be seen, the tracking values are extremely close throughout the entire ramp start despite attempting a hard angle change. The typical delay that would need to have a long running head start from lower masses has also been mostly eliminated with this method. This can improve operation when scanning up from low mass (<30 amu), such as for an air/water analysis, and very low masses (<10 amu), such as a light gas analysis looking at hydrogen and helium. The need for a running start to allow for the response delays limits the scan rate that can be used for low and very low masses. In various embodiments, the disclosed methods can be used to scan for masses <10 amu, such as for a light gas analysis, at a scan rate of at least about 1000 amu/sec or for an air water analysis which typically start at about 16 amu at a rate of at least about 16,000 amu/sec. For more typical GC/MS analysis, such as starting around about 30 to 40 amu, scan rates of at least about 50,000 amu/sec is achievable. Generally, the scan rate may be limited to less than about 1,000,000 amu/sec, such as less than about 500,000 amu/sec.
In various embodiments, since the amount of lead that the drive needs to compensate for any given scan rate is automatically included in the output, changes in the scan rate are possible without needing to restart the ramp or missing a portion of the mass range.
At 806, a first set of DC voltages corresponding to a first SIM/SRM state can be applied to the rods of the quadrupole while detecting the ions that pass through the quadrupole. Additionally, corresponding RF potentials can be applied to the rods of the quadrupole such that ions within a specific m/z range can pass through the quadrupole. Intensity data can be collected during the SIM/SRM state and correlated to the m/z of ions passing through the quadrupole.
At 808, the DC rod driver can produce an output voltage profile designed create a rapid switch in the output of the DC rod driver filter from the steady state voltage to a voltage ramp. Corresponding changes can be made to the RF potential such that the quadrupole rapidly switches from a SIM/SRM state to a scan over a mass range. The scan can be at a rate of at least about 5,000 amu/sec, such as at least about 10,000 amu/sec, such as at least about 25,000 amu/sec, even at least about 50,000 amu/sec. Intensity data can be collected during the switch and through the ramp and the intensity data can be correlated to the m/z of the ions the pass through the quadrupole.
At 810, the DC rod driver can produce an output voltage profile designed create a rapid switch in the output of the DC rod driver filter from the voltage ramp to a stead state voltage corresponding to a second SIM/SRM state. Corresponding changes can be made to the RF potential such that the quadrupole rapidly switches from scanning over a mass range to the second SIM/SRM state. Intensity data can be collected during the switch and through the second SIM/SRM state and the intensity data can be correlated to the m/z of the ions the pass through the quadrupole.
At 812, a mass spectrum can be generated from the data collected and provided to a user. Additionally, SIM/SRM intensity data can for each of the SIM/SRM states can be provided.
While the present teachings are described in conjunction with various embodiments, it is not intended that the present teachings be limited to such embodiments. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art.
Further, in describing various embodiments, the specification may have presented a method and/or process as a particular sequence of steps. However, to the extent that the method or process does not rely on the particular order of steps set forth herein, the method or process should not be limited to the particular sequence of steps described. As one of ordinary skill in the art would appreciate, other sequences of steps may be possible. Therefore, the particular order of the steps set forth in the specification should not be construed as limitations on the claims. In addition, the claims directed to the method and/or process should not be limited to the performance of their steps in the order written, and one skilled in the art can readily appreciate that the sequences may be varied and still remain within the spirit and scope of the various embodiments.
| Number | Date | Country | |
|---|---|---|---|
| 63121064 | Dec 2020 | US |
