Patent Publication Number: US-2011049360-A1

Title: Collision/Reaction Cell for a Mass Spectrometer

Description:
FIELD OF THE INVENTION 
     The present invention relates generally to structures for controllably fragmenting ions in a mass spectrometer, and more particularly to collision/reaction cells utilizing radio frequency multipole structures. 
     BACKGROUND OF THE INVENTION 
     Radio frequency (RF) multipoles are commonly used in mass spectrometers and similar instruments to efficiently transportions within vacuum regions. Typically, an RF multipole consists of a set of parallel elongated electrodes arranged around a central longitudinal axis. RF voltages are applied to the electrodes in a prescribed phase relationship to generate an oscillatory field that radially confines ions within the multipole interior volume while the ions traverse the RF multipole from an inlet end to an outlet end. 
     Certain mass spectrometers utilize collision cells, in which an RF multipole is placed within an enclosure pressurized with a collision gas, such as nitrogen or argon. Precursor ions that enter the collision cell collide with molecules or atoms of collision gas and undergo dissociation to yield product ions. The degree and pattern of fragmentation may be controlled by adjusting the kinetic energy at which the precursor ions enter the collision cell as well as the collision gas pressure. The resultant product ions are transported along the central axis of the multipole to the outlet end thereof, and are thereafter passed to downstream regions of the mass spectrometer for further processing and/or mass analysis. 
     It is known that product ions having low mass-to-charge ratios (m/z&#39;s) may tend to develop unstable trajectories in collision cells, causing them to be lost via contact with electrode surfaces or ejection from the multipole interior volume. Loss of low-m/z ions in the collision cell is undesirable, since they may carry information useful for identification or structural elucidation of analyte molecules. The stability of an ion in an RF quadrupole (the most commonly employed multipole in collision cells) is governed by the value of the Mathieu stability parameter q, which is proportional to the amplitude of the applied RF voltage and inversely proportional to the m/z of the ion. Typically, the RF voltage amplitude is selected such that the q of the precursor ions entering the quadrupole is about 0.2. Under these conditions, product ions having m/z&#39;s of less than 0.22 times the precursor m/z will have q&#39;s greater than 0.908 (the stability limit for an RF-only quadrupole) and will develop unstable trajectories. For example, if the RF voltage amplitude is tuned to set q=0.2 for a precursor m/z of 500, product ions having m/z&#39;s of less than 110 will be lost in the quadrupole and will not be available for detection in the downstream mass analyzer. The value of m/z below which ions are unstable (referred to in the art as the low mass cut-off, or LMCO) may be reduced by decreasing the RF voltage amplitude, but doing so will tend to reduce the transmission efficiency of heavier ions. 
     Another problem associated with prior art multipoles is that a small manufacturing error, such as a slight bowing or angular misalignment of an electrode, may produce trapping regions within the multipole interior volume that retain ions or impede their axial movement. This unintended trapping phenomenon, which may also arise from the accumulation of contaminants on electrode surfaces during operation of the mass spectrometer, reduces the rate at which ions may be removed from the multipole interior, which is particularly problematic for tandem mass spectrometry applications where it is highly desirable to remove ions from the collision cell quickly so that a large number of experiments (for example, multiple MRM transitions) may be performed across an elution peak. The rate at which ions are drawn through a multipole may be increased by superimposing an axial DC field (sometimes referred to as a “drag field”), which is described in U.S. Pat. Nos. 5,847,386 by Thomson et al. and 7,067,802 by Kovtoun. However, incorporating the additional structures and electronics required for producing the DC axial field may significantly increase manufacturing cost and complexity. 
     SUMMARY 
     Roughly described, a multipole constructed in accordance with an embodiment of the present invention includes at least four elongated electrodes arranged around a longitudinal axis, and an RF voltage source for applying RF voltages to the electrodes in a prescribed phase relationship. The electrodes are formed and positioned such that the value of the radial spacing r 0  (the distance from the axis to the inner surface of each of the electrodes) increases from the inlet end to the outlet end of the multipole. In one implementation, the electrodes have uniform cross-sections, and are angled outwardly from the inlet end. In a second implementation, electrodes having tapered cross sections are positioned in mutually parallel relation. 
     RF multipoles constructed in accordance with embodiments of the present invention may be particularly useful for implementation in a collision/reaction cell, wherein the electrodes are disposed within an enclosure to which collision/reaction gas is added. By increasing r 0  from the inlet end to the outlet end of the RF multipole, the value of the Mathieu parameter q of an ion is progressively reduced in the direction of ion travel, resulting in a reduced effective low-mass cutoff and the availability of greater numbers of low-m/z ions for mass analysis. In addition, the RF multipoles may have decreased sensitivity to manufacturing or assembly errors and may promote higher ion transmission rates. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       In the accompanying drawings: 
         FIG. 1  is a symbolic depiction of a mass spectrometer having a collision cell that incorporates an RF multipole constructed in accordance with a first embodiment of the invention, wherein the electrodes are angled outwardly to provide a monotonically increasing r 0 ; 
         FIG. 2  is an elevated side view of the RF multipole depicted in  FIG. 1 ; 
         FIG. 3  is an end view of the RF multipole, depicting the inlet end; 
         FIG. 4  is an end view of the RF multipole, depicting the outlet end; 
         FIG. 5A  is a product ion spectrum acquired by a triple quadrupole mass spectrometer having a collision cell of conventional design; 
         FIG. 5B  is a corresponding product ion spectrum acquired by a triple quadrupole mass spectrometer having a collision cell constructed in accordance with an embodiment of the invention; 
         FIG. 6  is an elevated side view of a second embodiment of the RF multipole, wherein the electrodes are tapered to provide a monotonically increasing r 0 ; and 
         FIG. 7  is an inlet end view of the second embodiment of the RF multipole. 
     
    
    
     DETAILED DESCRIPTION OF EMBODIMENTS 
       FIG. 1  depicts a triple quadrupole mass spectrometer  100  that incorporates a collision/reaction cell  105  having an RF multipole  110  constructed according to a first embodiment of the invention. It will be understood that certain features and configurations of mass spectrometer  100  are presented by way of illustrative examples, and should not be construed as limiting the invention to implementation in a specific environment. An ion source, which may take the form of an electrospray ion source  115 , generates ions from an analyte material, for example the eluate from a liquid chromatograph (not depicted). The ions are transported from an ion source chamber  120 , which for an electrospray source will typically be held at or near atmospheric pressure, through several intermediate chambers  125 ,  130  and  135  of successively lower pressure, to a vacuum chamber  140  in which resides a triple quadrupole mass analyzer having a first quadrupole mass filter (QMF)  145 , collision/reaction cell  105 , and a second QMF  150 . Efficient transport of ions from ion source  115  to vacuum chamber  140  is facilitated by a number of ion optic components, including quadrupole RF ion guides  155  and  160 , a skimmer  165 , and electrostatic lenses  170  and  175 . Ions may be transported between ion source chamber  120  and first intermediate chamber  125  through an ion transfer tube  180  that is heated to evaporate residual solvent and break up solvent-analyte clusters. Intermediate chambers  125 ,  130  and  135  and vacuum chamber  140  are evacuated by a suitable arrangement of pumps to maintain the pressures therein at the desired values. In one example, intermediate chamber  125  communicates with a port of a mechanical pump (not depicted), and intermediate pressure chambers  130  and  135  and vacuum chamber  140  communicate with corresponding ports of a multistage, multiport turbomolecular pump (also not depicted). 
     First QMF  145  and second QMF  150  each consist of four elongated electrodes to which RF and resolving DC voltages are applied. As is known in the art, the m/z ranges of the transmitted ions are determined by the amplitudes of the RF and resolving DC voltages (respectively designated as U and V), and ions having a desired range of m/z values may be selected for transmission by appropriately adjusting the values of U and V. Each QMF may be “parked” by temporally fixing the values of U and V such that only a single ion species is transmitted, or may instead be “scanned” by progressively changing U and/or V such that the m/z of the transmitted ions varies in time. 
     Collision/reaction cell  105  includes a multipole  110 , constructed in accordance with embodiments of the present invention, located within an interior region  185  to which a collision/reaction gas is controllably supplied via a suitable collision gas source, such as a conduit  190  that receives gas from a suitable supply arrangement. The interior region  185  is defined by enclosure  192 , which may be partially formed by entrance and exit lenses  194  and  196 , and which enables development of an elevated pressure relative to the pressure of the vacuum chamber  140  which collision/reaction cell  105  is located. When configured as a collision cell, collision/reaction cell  105  is filled with a collision gas conventionally consisting of one or a mixture of generally unreactive or inert gases, such as nitrogen or argon, and the collision gas pressure within collision/reaction cell  105  is typically in the range of 0.5-10 millitorr. In an alternative reaction cell configuration, collision/reaction cell is filled with gas and/or reagent ions selected to react with the sample ions. 
     In operation as a conventional triple quadrupole mass spectrometer, a subset of ions entering vacuum chamber  140  is selectively transmitted by first QMF  145 . The transmitted ions (“precursor ions”) enter collision cell  105 , and a portion of the ions undergo energetic collisions to produce fragments (“product ions”). The product ions and residual precursor ions are passed to second QMF  150 , which transmits ions within a selected range determined by the amplitudes of the applied RF and resolving DC voltages. The ions transmitted by second QMF  150  strike detector  198 , which generates a signal representative of the numbers of ions impinging thereon. The detector signal is received and processed by control and data system (not depicted), which may be implemented as any one or combination of application-specific circuitry, general purpose and/or specialized processors, and software logic. 
     The arrangement of electrodes in multipole  110  may be more clearly explained with reference to  FIGS. 2 ,  3  and  4 , which respectively depict multipole  110  in elevated side view, inlet end view, and outlet end view. Multipole  110  includes four elongated electrodes  205   a,b,c,d  arranged at equal radial spacing from the axial centerline at each point along the multipole length. Each electrode  205   a,b,c,d  has a rectangular cross-section of longitudinally invariant dimensions. The central axes of electrodes  205   a,b,c,d  are angled outwardly in the direction of ion flow (by a splay angle α defined by the intersection of the electrode major axis with the central longitudinal axis or an axis parallel thereto) so that the value of the inscribed circle radius r 0  (the radius of the circle lying in a radial plane of the multipole that is tangent to the electrode inner surfaces) increases in a monotonic fashion from multipole inlet end  210  to multipole outlet end  215 . In the example shown, the value of r 0  increases linearly from inlet end  210  to outlet end  215  according to the equation: 
         r   0   =r   0,inlet   +x/L *( r   0,outlet   −r   0,inlet ) 
     where x is the distance from inlet end  210 , L is the multipole length, and r 0,inlet  and r 0,outlet  are the values of the inscribed circle radius at inlet end  210  and outlet end  215 , respectively. The electrodes may be precisely fixed in the desired geometry and spacing using ceramic holders or suitable equivalent, in a manner known in the art. 
     In alternative embodiments of the invention (such as the one discussed below), the variation of r 0  with distance along the multipole may follow a non-linear relation, such as a polynomial or logarithmic function. In order to avoid creating undesirable trapping regions, the increase of r 0  with distance along the multipole should be monotonic. It is further noted that although electrodes having rectangular cross-sections are depicted in  FIGS. 2-4 , the invention should not be construed as being limited to any particular electrode shape, and electrodes having other cross-sectional shapes (e.g., circular, hyperbolic) may be substituted. It is still further noted that the electrodes may be axially segmented into two or more sections in order to, for example, enable development of a DC axial field by applying different DC potentials to the electrode sections. It is further noted that in alternative embodiments of the invention, the electrodes may be spaced at different distances from the axial centerline at any given point along the multipole length, provided that the radial spacing for each electrode increases from the inlet end to the outlet end of the multipole. 
     As known in the art and described above, an RF field that radially confines ions within multipole  110  is established by applying RF voltages in a prescribed phase relationship to electrodes  205   a,b,c,d .  FIG. 3  depicts an RF voltage source  310  that applies a first RF voltage to opposed electrodes  205   a,c  and a second RF voltage, having an amplitude and frequency equal to and a phase opposite to that of the first RF voltage, to opposed electrodes  205   b,d . The Mathieu stability parameter q, which governs whether the trajectory of an ion within multipole  190  will be stable and hence whether the ion will reach outlet end  215 , is proportional to the RF voltage amplitude and inversely proportional to the m/z of the ion and the square of the electrode radial spacing (r 0   2 ). By angling electrodes  205   a,b,c,d  outwardly, the value of q for an ion of a given m/z located at outlet end  215  is reduced by a factor of (r 0,inlet /r 0,outlet ) 2  relative to the value of q that the ion would have at the outlet end of a conventional multipole having a fixed radial spacing of r 0,inlet . This decrease in q (which can alternatively be expressed as a decrease in the m/z of ions having a given q) with distance along the multipole allows the RF amplitude to be selected to provide good confinement of the relatively high m/z precursor ions entering multipole  105  while retaining a substantial portion of the relatively low m/z product ions formed by dissociation of the precursor ions in the downstream regions of the multipole. 
     Selection of an appropriate splay angle at which to arrange the electrodes will depend on the desired reduction in q and various operational and design considerations, primarily determined by the range product to precursor mass difference and the expected manufacturing tolerances. Typically, a splay angle and electrode length will be selected to yield a ratio of r 0  at the outlet end to r 0  at the inlet end that is at least 1.1, and more preferably at least 1.2. According to one illustrative implementation, each electrode  205   a,b,c,d  has a square cross section of 0.157 in.×0.157 in. (4 mm×4 mm) and a length of 8 in. (203.2 mm). Electrodes  205   a,b,c,d  are arranged at a radial spacing of 0.081 in. (2.06 mm) at inlet end  210  and are angled outwardly at a splay angle of about 0.19° so that the radial spacing at outlet end  215  is increased to 0.107 in. (2.72 mm). In this implementation, the q for an ion of a given m/z at outlet end  215  is (0.081/0.107) 2 =57% of its q at inlet end  210 . 
       FIGS. 5A and 5B  illustrate the effect of outwardly angling the electrodes of a collision cell quadrupole on transmission of low-mass product ions. The spectra depicted in  FIGS. 5A and 5B  were acquired under substantially identical conditions in a triple quadrupole mass spectrometer operated in product ion monitoring mode at a precursor m/z of 614 (corresponding to perfluorotributylamine ions produced by electron impact ionization of a calibration gas mixture).  FIG. 5A  is the product ion spectrum obtained using a conventional (invariant r 0 ) collision cell, whereas  FIG. 5B  is the product ion spectrum obtained using a collision cell with splayed electrodes constructed according to an embodiment of the invention. It is easily discernible that certain low m/z fragment ion peaks that are present in the  FIG. 5B  spectrum (namely, the peaks that appear at nominal m/z&#39;s of 50 and 69) are not seen or have much lower intensity in the  FIG. 5A  spectrum, indicating that such product ions were transmitted at significantly greater efficiency in the splayed electrode collision cell relative to the conventional collision cell. 
     In addition to reducing q at and adjacent to outlet end  215  and lowering the low mass cutoff, increasing r 0  with distance along the multipole provides other benefits. As alluded to above, manufacturing errors or tolerances associated with the formation and positioning of electrodes in conventional multipoles having an invariant r 0  may create small convergent regions in which ions may be unintentionally trapped. Such convergent regions may also be created during operation of a mass spectrometer by deposition of contaminants on electrode surfaces. The unintended and undesirable creation of trapping regions in multipoles is avoided or minimized by outwardly angling the electrodes or otherwise increasing the electrode radial spacing with distance along the multipole (such as by tapering the electrodes, discussed below in connection with  FIGS. 6 and 7 ), such that any narrowing of the radial spacing arising from manufacturing errors or contaminant deposition is compensated for by the increase in radial spacing with length inherent to multipoles constructed according to embodiments of the present invention. 
     It is has been further noted by the applicant that increasing r 0  in the direction of ion travel produces a pseudo-potential gradient that urges ions towards outlet end  215  of multipole  110 . This effect may increase the rate at which ions are transported through multipole  110  and prevent stalling and unintended trapping of ions, particularly when collision cell  105  is operated at a relatively high pressure. Furthermore, the creation of a motive force arising from the pseudo-potential gradient may avoid the need (and associated cost and complexity) to provide structures for establishing an axial DC field. 
     Multipoles constructed in accordance with the present invention, i.e., having axially increasing r 0 , may be utilized in other environments and for other purposes than collision/reaction cells. For example, multipoles of this general description may be employed as RF ion guides to transportions through regions of a mass spectrometer. In this implementation, ion transport efficiency may be advantageously increased by establishment of a pseudo-potential gradient that moves ions toward the outlet, as discussed above. 
       FIGS. 6 and 7  respectively depict elevated side and outlet end views of a multipole  605  constructed according to a second embodiment of the invention. Multipole  605  includes four elongated electrodes  610  (two of which are hidden from view in  FIG. 6 ) arranged at equal radial spacing about an axial centerline  615 . Each electrode  610  extends from an inlet end  620  to an outlet end  625 , and is arranged with its central axis  630  parallel to axial centerline  615 . To provide increasing r 0  in the direction of ion travel, each electrode  610  is tapered such that its cross-section decreases monotonically from inlet end  620  to outlet end  625 , thereby monotonically increasing the distance between axial centerline  615  and the inner surface of electrode  610 . To facilitate machining, each electrode  610  may have a circular lateral cross-section, although other cross-sectional shapes may be utilized and are within the scope of the invention. In  FIGS. 6 and 7 , electrodes  610  are formed to provide a non-linearly increasing r 0 , but may in other implementations be formed to provide an r 0  that increases linearly with distance. 
     Although each of the multipoles described and depicted herein are quadrupoles (i.e., have exactly four electrodes), the concept of arranging or forming electrodes in an RF multipole to establish increasing r 0  may be extended to multipoles having a larger number of electrodes (e.g., hexapoles or octopoles). Furthermore, while the multipoles described and depicted herein have substantially straight axially centerlines, other embodiments may have a curved axial centerline, such as collision/reaction cells or ions guides that describe a 90-degree bend or are U-shaped. 
     In certain implementations of the invention, the multipole electrodes may be specially adapted (e.g., with a resistive coating) to enable application of a DC potential difference to ends of the electrodes in order to create a DC axial field. A desired DC axial field may also be established using a set of supplemental electrodes arranged adjacent to or around the main electrodes, as known in the prior art. 
     It should also be appreciated that RF multipoles constructed according to the present invention, i.e., with increasing r 0  from the inlet end to the outlet end, may be employed for purposes and in environments other than in a collision cell. For example, an RF multipole of this general description may be employed to efficiently transportions within an intermediate pressure region of the mass spectrometer located between the ion source and the mass analyzer(s). Other beneficial uses may occur to those of ordinary skill in the art. 
     Finally, it is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.