Patent Application
20230118135
The present teachings are directed to systems and methods for mass spectrometry in which a DC offset voltage applied between at least two components of the spectrometer is employed to facilitate declustering or fragmentation of ions.
Mass spectrometry (MS) is an analytical technique for determining the elemental composition of test substances with both qualitative and quantitative applications. MS can be useful for identifying unknown compounds, determining the isotopic composition of elements in a molecule, determining the structure of a particular compound by observing its fragmentation, and quantifying the amount of a particular compound in a sample. Mass spectrometers detect chemical entities as ions such that conversion of the analytes to charged ions must occur during the sampling process. During the ion formation process, some adduct ions can be formed, e.g., via solvation.
It is known that a voltage applied between an inlet orifice of a mass spectrometer and the first vacuum lens element (e.g., a skimmer or an ion guide) can increase the internal energy of incoming ions and solvated clusters to promote declustering or fragmentation of the ions. The effectiveness of such declustering and/or fragmentation, however, decreases as the orifice size increases. For example, effective declustering requires greater voltage offsets for systems having larger orifice sizes.
Accordingly, there is a need for improved systems and methods for mass spectrometry, which allow utilizing large orifice sizes and concurrently allow effective declustering and/or fragmentation of ions introduced into a mass spectrometer.
In one aspect, a mass spectrometer is disclosed, which comprises an orifice plate having an orifice for receiving a plurality of ions, a first multipole ion guide disposed in a first chamber positioned downstream of said orifice plate, and a second multipole ion guide disposed in a second chamber positioned downstream of said first chamber. A first ion lens is disposed between the first and the second multipole ion guides. A third multipole ion guide is positioned in a third chamber positioned downstream of the second chamber. A second ion lens is positioned between the second and third chambers. The mass spectrometer further includes a tunable DC voltage source for applying a tunable DC offset voltage to at least one of said first, second, and third multipole ion guides and/or at least one of said first and second ion lenses for increasing the axial kinetic energy of the ions so as to cause at least one of declustering and/or fragmentation of at least a portion of the ions.
In some embodiments, each of the first, the second and the third multipole ion guide comprises a plurality of rods arranged to allow the passage of ions therebetween. In some embodiments, each of the first, the second and the third multipole ion guides comprises a series of stacked rings through which ions can pass.
In some embodiments, the tunable DC offset voltage is applied to increase the axial energy of the ions within an expansion zone of the second and the third multipole ion guide.
In some embodiments, the DC voltage is configured to cause declustering of at least some of adduct ions present in the ion flux without causing fragmentation thereof. By way of example, in some such embodiments, the applied DC voltage can be, for example, in a range of about 0 V to about 300 V, e.g., in a range of about 10 V to about 200 V, e.g., in a range of about 20 V to about 140 V. In some embodiments, the applied DC voltage can increase the axial kinetic energy of the ions so as to cause fragmentation of at least a portion of the ions.
In some embodiments, the orifice has a diameter of at least about 0.6 mm, e.g., in a range of about 0.7 mm to about 3 mm, e.g., in a range of about 1 mm to about 1.5 mm.
In some embodiments, the tunable voltage source is configured to vary the applied DC voltage in a range of 0 to about 300 V, e.g., in a range of about 10 V to about 200 V, e.g., in a range of about 20 V to about 140 V.
In some embodiments, the first chamber is maintained at a pressure in a range of about 5 Torr to about 15 Torr. In some such embodiments, the second chamber is maintained at a pressure in a range of about 1 to about 5 Torr. Further, in some embodiments, the third chamber is maintained at a pressure in a range of about 3 mTorr to about 12 mTorr.
In some embodiments, in addition to the above DC offset voltage, a DC float voltage, for example, in a range of about −10 V to about 10 V (this float voltage can also be a range of different values. For instance on ToF, it might be up to +/−500 V), can be applied to any of the first, the second, and the third multipole ion guide. In some embodiments, another voltage source is provided for applying the DC float voltage(s) to these ion guides.
In some embodiments, the mass spectrometer can include one or more radiofrequency (RF) sources for applying RF voltage(s) to at least one of said first, said second and said third multipole rods for focusing ions passing therethrough.
A variety of ion sources can be employed for generating a plurality of ions. By way of example, in some embodiments, an atmospheric pressure ion source can be employed.
In a related aspect, a mass spectrometer is disclosed, which comprises an orifice plate having an orifice for receiving a plurality of ions, wherein said orifice has a diameter of at least about 0.6 mm, e.g., in a range of about 0.7 mm to about 3 mm. A first multipole ion guide is disposed in a first chamber positioned downstream of the orifice plate. A second multipole ion guide is disposed in a second chamber positioned downstream of the first chamber. A first ion lens is disposed between the first and the second multipole ion guides. A third multipole ion guide is disposed in a third chamber positioned downstream of the second chamber. A second ion lens is disposed between the second and the third chambers, and a tunable voltage source is provided for applying a tunable DC offset voltage offset between said second multiple ion guide and said second ion lens. The tunable voltage source can adjust the applied DC voltage to increase the axial kinetic energy of the ions so as to cause at least one of declustering and fragmentation (or both) of at least some of the ions.
In some embodiments, each of the first, the second, and the third ion guide can include a plurality of rods arranged to allow the passage of ions therebetween. The rods can be arranged in a variety of different geometries, such as quadrupole, a hexapole, a dodecapole, among others.
In some embodiments, the first chamber is maintained at a pressure in a range of about 5 Torr to about 15 Torr, the second chamber is maintained at a pressure in a range of about 1 Torr to about 5 Torr, and the third chamber is maintained at a pressure in a range of about 3 mTorr to about 12 mTorr.
In some embodiments, the tunable voltage source is configured to vary the applied voltage in a range of about 0 to about 300 V, e.g., in a range of about 10 V to about 140 V.
In some embodiments, at least one of the multiple ion guides, e.g., the second ion guide, is maintained at a DC float voltage in a range of about −200 V to about +200 V, e.g., in a range of about −100 V to about +100 V. In many embodiments, all of the elements positioned upstream of where the declustering/fragmentation occurs are floated together at the same voltage. In some such embodiments, another voltage source is provided for applying a tunable DC offset voltage to the multipole ion guide, the second ion lens or any combination of ion guides and lenses. In some such embodiments, the tunable DC offset voltage can facilitate fragmentation of at least some of the ions.
In some embodiments, the mass spectrometer can include one or more radiofrequency (RF) sources for applying RF voltage(s) to at least one of the first, the second and the third multipole ion guides for radially confining and focusing the ions as they pass through the ion guide.
The multipole ion guides can be implemented in a variety of different configurations. By way of example, they can be implemented as a quadrupole, a hexapole, a dodecapole configuration, or a geometry with any number of rods. The ion guides can also be formed by employing rings rather than rods.
In some embodiments, at least one radiofrequency (RF) source applies RF voltage(s) to at least one of the first, the second and the third multipole ion guides for focusing the ions passing therethrough.
In a related aspect, a method for mass spectrometric analysis of a sample using a mass spectrometer is disclosed, where the spectrometer comprises an orifice plate and three chambers disposed in tandem downstream of said orifice plate, wherein an ion guide is positioned in each of said chambers and wherein a first ion lens is disposed between said first chamber and said second chamber and a second ion lens is disposed between said second chamber and said third chamber. The method includes the steps of ionizing a sample so as to form a plurality of ions, receiving the plurality of ions through said orifice, passing the ions through said three chambers, and applying a DC offset voltage to at least one of said ion guides and/or ion lenses so as to cause at least one of declustering or fragmentation of at least some of the ions. In some embodiments, at least some of the ions can be adduct ions.
In some embodiments, the pressure in the first chamber can be maintained in a range of about 5 Torr to about 15 Torr, the pressure in the second chamber can be maintained in a range of about 1 Torr to about 5 Torr, and the pressure in the third chamber can be maintained in a range of about 3 mTorr to about 12 mTorr.
Further understanding of various aspects of the present teachings can be obtained by reference to the following detailed description in conjunction with the associated drawings, which are described briefly below.
The present disclosure relates generally to systems and methods for mass spectrometry in which a DC voltage (herein also referred to as DC offset voltage) is employed to generate an electric field that can increase the axial kinetic energy of ions entering a mass spectrometer so as to facilitate at least one of declustering or fragmentation of at least a portion of the ions.
The flow chart of
As depicted in the flow chart, a sample is ionized so as to form a plurality of ions. In some embodiments, the plurality of ions can include one or more adduct ions (e.g., solvated ions). The ions are received through the orifice of the mass spectrometer. The ions are transmitted through the three chambers. Further, a DC voltage, e.g., a tunable DC offset voltage, is applied to at least one of the ion guides and/or at least one of the ion lenses so as to cause at least one of declustering and fragmentation of at least some of the ions within the third chamber.
In this embodiment, the orifices 10a/12a are sufficiently large to allow the incoming ions to enter the chamber 26. By way of example, any of the orifices 10a/12a can be substantially circular with a diameter in a range of about 0.6 mm to about 10 mm.
The ion guide 36 can have a variety of different configurations. By way of example, in some embodiments, the ion guide 36 can be in the form of a quadrupole rod set while in other embodiments, the ion guide 36 can be in the form of a hexapole or a dodecapole rod set. More generally, the ion guide 36 can include any number of rods. Further, in some embodiments, the ion guide can be formed by using a series of stacked rings.
A vacuum pump 42 can apply a negative pressure to the chamber 26 to maintain the pressure in the chamber within a desired range. By way of example, in some embodiments, the pressure within the chamber 26 can be in a range of about 5 Torr to about 15 Torr.
A power supply 40 (herein also referred to as a voltage source) applies radiofrequency (RF) voltage(s) to the rods of the ion guide 36 for radially confining and focusing the ions 24 as they pass through the ion guide 36.
An aperture 32 disposed in an ion lens IQ00 that is positioned downstream of the ion guide 36 allows the passage of ions from the chamber 26 into a downstream chamber 45 in which another multipole ion guide 56 is positioned (herein also referred to as QJET region). A vacuum pump 42b can apply a negative pressure to the chamber 45 such that in some embodiments the pressure within the chamber 45 is maintained, for example, in a range of about 1 Torr about 5 Torr.
While in this embodiment the multipole ion guide 56 has a quadrupole configuration, in other embodiments it can have other configurations, such as a hexapole or a dodecapole configuration. In other embodiments, it can comprise any number of rods or can be formed using a series of stacked rings.
The voltage source 40, or another voltage source, can apply RF voltage(s) to rods of the ion guide 56 to radially confine and focus the ions 24 as they pass through the ion guide 56. An ion lens IQ0 separates the chamber 45 from the chamber 46. An aperture 11 provided within the ion lens IQ0 allows the passage of the ions 24 from the chamber 45 into the chamber 46.
A vacuum pump 42c may be included to apply a negative pressure to the chamber 46 so as to maintain the pressure within this chamber, for example, in a range of about 3 to about 8 mTorr. A multipole ion guide 60 is positioned within the chamber 46. The voltage source 40 or another voltage source can apply RF voltage(s) to the rods of the ion guide 60 for radially confining and focusing the ions 24 as they pass through the ion guide 60. As discussed in more detail below, the application of accelerating DC voltage(s) to one or more components positioned upstream of the chamber 46 can increase the axial kinetic energy of the ions 24 so as to cause declustering or fragmentation of at least a portion of the ions within the chamber 45 and/or chamber 46, depending on where the voltage difference is applied.
A mass analyzer Q1 is disposed in a chamber 47 that is positioned downstream of the chamber 46. A vacuum pump 42d applies a negative pressure to the chamber 47 so as to maintain the chamber 47 at a pressure of less than 5e−5 Torr. In this embodiment, stubby rods 62 are also positioned within the chamber 47. In this embodiment, the mass analyzer Q1 includes four rods that are arranged in a quadrupole configuration while in other embodiments, the mass analyzer can be arranged according to other configurations, such as time of flight (ToF).
It will be understood by those of skill in the relevant art that in other embodiments, pumping configurations other than those disclosed herein can be employed. For example, according to some embodiments a single pump can be employed to evacuate multiple stages of the mass spectrometer. Further, in some embodiments, one or more of the vacuum pumps may be excluded completely, to eliminate pumping in a given stage. In some embodiments, the pumping may be achieved at any of the stages by employing multiple pumps. For example, the pumps 42c and 42d may include a combination of a roughing pump and a turbomolecular pump. It will also be understood that not all mass spectrometer components have been shown. For instance in some embodiments, the mass analyzer might comprise a triple quadrupole system with two mass analyzing quadrupoles and a collision cell between them for fragmenting ions.
An ion lens IQ1 is disposed between the chambers 46 and 47 to focus the ions as they pass from the chamber 46 into 47. Similar to the other ion lenses employed in this embodiment, the ion lens IQ1 can be formed as a metal plate in which an orifice is provided to allow passage of the ions therethrough. In other embodiments, any of the ion lenses can be formed as a stacked set of plates having orifices that are substantially aligned to allow the passage of ions therethrough.
In this embodiment, a DC voltage source 50 (e.g., a tunable DC voltage source) applies a DC voltage differential between the ion lens IQ0 and the rods of the Q0 ion guide so as to accelerate the ions as they pass through the orifice associated with the IQ0 lens to enter the Q0 region. The acceleration of the ions can increase their axial kinetic energy and hence cause declustering of at least some of the adduct ions, if any, present in the flux of ions and/or fragmentation of at least some of the ions, as they pass through the gas expansion into the subsequent lower pressure region. In this embodiment, the Q0 ion guide is maintained at a float voltage in a range of about −100 V to about +100 V, e.g., about −10 V in this embodiment (e.g., by using another voltage source not shown in the figure). Thus, the DC voltage source 50 provides an additional DC offset potential above the electric potential applied to the Q0 electrodes (which is about −10 V in this embodiment).
By way of example, the DC voltage source 50 can apply a voltage differential in a range of about 0 to about 300 V, e.g., in a range of about 10 V to about 200 V, e.g., in a range of about 20 V to about 140 V, between the ion lens IQ0 and the rods of the Q0 ion guide. The applied DC voltage can be adjusted to cause declustering of adduct ions present in the ion flux, if any, without causing significant fragmentation thereof. Alternatively, the applied DC voltage can be adjusted to cause fragmentation of at least some of the ions. In some such embodiments, at least some of the adduct ions and the ions that are not in the form of clusters can undergo fragmentation. In some embodiments, an applied DC voltage in a range of about 0 V to about 200 V can be employed for declustering the adduct ions and an applied DC voltage in a range of about 0 V to about 400 V can be employed for causing ion fragmentation. Alternatively, the ions comprising background interference can be accelerated and fragmented as they pass into the Q0 region to improve the signal-to-noise ratio for compounds of interest.
The downstream Q1 can provide mass analysis of the fragment ion products in a manner known in the art.
As noted above, the applied DC voltage employed to increase the axial kinetic energy of the ions can be applied across various components of the mass spectrometer positioned upstream of the Q0 region. By way of example, in another embodiment of the present teachings, the voltage source 50 applies a DC voltage differential between the rods of the QJET ion guide (56) and the ion lens IQ0 so as to accelerate the ions in the QJET region as they approach the IQ0 lens so as to increase their axial kinetic energy and hence facilitate their declustering and/or fragmentation within either the Q0 region or upstream QJET region. By way of example, similar to the previous embodiments, in such embodiments, the applied DC voltage can be in a range of about 0 to about 200 V, e.g., in a range of about 10 V to about 140 V.
The following Examples are provided for further elucidation of various aspects of the present teachings and are not intended to be limiting of the scope of the invention.
A triple quadrupole mass spectrometer similar to that depicted above including a dodecapole ion guide in the first vacuum stage, a quadrupole ion guide in the second vacuum stage and a quadrupole ion guide in the third vacuum stage was employed to obtain the data. The pressures in the three vacuum stages were 6 Torr, 2 Torr, and 6 mTorr. Initially, the DC offset voltage was set to 0 V such that all lens elements from the DJET to Q0 region were maintained at the same potential. Under these conditions, no additional ion heating was expected in the interface region, resulting in a codeine adduct/protonated ion ratio of about 29%. A time=1 min, the DC offset voltage was increased to 10 V such that all lenses from the DJET to IQ0 were maintained at 0 V, while the Q0 rods were maintained at −10 V. This small offset potential applied between the IQ0 lens and Q0 was sufficient to cause the onset of declustering, as evidenced by a decrease in the adduct signal (
A further 10 V increase in the DC offset potential to 20 V was introduced at time=2 min, resulting in a further decrease in the number of cluster ions while maintaining the signal level for the protonated codeine. The final ratio of cluster/protonated ion was 6.8%.
Thus, the data presented in
As noted above, an offset DC voltage as disclosed herein can also be used for ion fragmentation. Minoxidil is a small molecule that is relatively easy to fragment in an MS/MS instrument.
Referring to
The data presented in above
Referring to
Liquid chromatography-Mass spectrometry (LC/MS) experiments were conducted with a sample of 1 pg/μL taurocholic. The data are presented in
When the DC offset voltage was set to 0 V, the peak height for deprotonated taurocholic acid was 75,000 cps and the background continuum was relatively high, resulting in a S/N ratio of 67.5. The DC offset voltage was then increased to 50 V as shown in
The data presented in
For the data presented in Example 6, the DC offset potential was applied as shown in
The present teachings have demonstrated declustering and fragmentation using potential offset between QJET and IQ0 and IQ0 and Q0. It will be apparent to those having ordinary skill in the art in view of the present teachings that any means of increasing the axial energy of the ions into the Q0 region can accomplish declustering and fragmentation as discussed herein. For example, the increase in the axial kinetic energy of ions can be achieved by using DC offset potentials between a variety of components of the system.
Those having ordinary skill in the art will appreciate that various changes can be made to the above embodiments without departing from the scope of the invention.
This application claims priority to U.S. provisional application No. 62/993,965 filed on Mar. 24, 2020, entitled “Three Stage Atmosphere to Vacuum Mass Spectrometer Inlet with Additional Declustering in the Third Stage,” which is incorporated herein by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IB2021/052326 | 3/19/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 62993965 | Mar 2020 | US |
