Abstract:
A system including a differential mobility spectrometer is described as is a method of operating the system including the differential mobility spectrometer. The method and system involve a) providing ions to the differential mobility spectrometer; b) providing a drift gas to an inlet of the differential mobility spectrometer; c) adjusting a meter to define a selected volumetric flow rate for supplying a modifier liquid to the drift gas; and, d) supplying an actual volumetric flow rate of the modifier liquid to the drift gas, wherein the actual volumetric flow rate is within a percentage deviation from the selected volumetric flow rate.

Description:
This is a non-provisional application of U.S. application No. 61/057,531 filed May 30, 2008. The contents of U.S. application No. 61/057,531 are incorporated herein by reference. 
     INTRODUCTION 
     The present invention relates generally to methods and systems relating to a differential mobility spectrometer. 
     In differential mobility spectrometer systems, a drift gas is typically supplied from a gas source upstream of the differential mobility spectrometer. This drift gas can provide a gas flow through the differential mobility spectrometer. A modifier liquid can be added to the drift gas. Modifiers can be vapors that provide selectivity by clustering with ions to different degrees, thereby shifting these ions differential mobilities. Examples of modifiers can include alcohol such as isopropyl alcohol, water, as well as hydrogen and deuterium exchange agents. 
     SUMMARY 
     In accordance with an aspect of a first embodiment of the invention, there is provided a spectrometer system comprising: a) a differential mobility spectrometer for receiving ions from an ion source; b) a drift gas supply for providing a drift gas for flowing through the differential mobility spectrometer; and, c) a modifier supply for supplying an actual volumetric flow rate of a modifier liquid to the drift gas supply, wherein the modifier supply comprises a meter for setting a selected volumetric flow rate, the meter is adjustable to change the selected volumetric flow rate, and the actual volumetric flow rate is within a percentage deviation from the selected volumetric flow rate. 
     In accordance with an aspect of a second embodiment of the invention, there is provided a method of operating a system including a differential mobility spectrometer. The method comprises a) providing ions to the differential mobility spectrometer; b) providing a drift gas to an inlet of the differential mobility spectrometer; c) adjusting a meter to define a selected volumetric flow rate for supplying a modifier liquid to the drift gas; and, d) supplying an actual volumetric flow rate of the modifier liquid to the drift gas, wherein the actual volumetric flow rate is within a percentage deviation from the selected volumetric flow rate 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The skilled person in the art will understand that the drawings described below are for illustration purposes only. The drawings are not intended to limit the scope of the applicant&#39;s teachings in any way. 
         FIG. 1 , in a schematic diagram, illustrates a differential mobility spectrometer/mass spectrometer system including a curtain gas supply and a pump for providing a volumetric flow amount of modifier liquid to the curtain gas in accordance with an aspect of a first embodiment of the present invention. 
         FIG. 2 , in a schematic view, illustrates a differential mobility spectrometer including a curtain gas supply and a pump for providing a volumetric flow amount of modifier liquid to the curtain gas in accordance with an aspect of a second embodiment of the present invention. 
         FIG. 3 , in a schematic view, illustrates a differential mobility spectrometer including a gas supply and a pump for providing a volumetric flow amount of modifier liquid to the gas in accordance with an aspect of a third embodiment of the present invention. 
         FIG. 4  illustrates CV scans for three different compounds as the concentration of a modifier added to a curtain gas increases. 
         FIG. 5  illustrates CV scans for Temazepam where the entire curtain gas flow is bubbled through 2-propanol such that the proportion of modifier liquid contained within the curtain gas remains substantially the same, but the absolute quantity of modifier liquid introduced to the drift gas increases with the increases in the total curtain gas flow rate. 
         FIG. 6  illustrates CV scans for Temazepam with bubbling of the curtain gas through a modifier liquid. 
         FIG. 7  illustrates CV scans for Temazepam in which a substantially fixed amount of 2-propanol is dispensed into a curtain gas flow for a five hour time period. 
         FIG. 8  illustrates, in a series of panes, mobility CV scans for 6 isobaric compounds with different volumetric flow rates of modifier liquid. 
     
    
    
     DETAILED DESCRIPTION OF THE EMBODIMENTS 
     Referring to  FIG. 1 , there is illustrated in a schematic view, a differential mobility spectrometer/mass spectrometer system  200  in accordance with an aspect of a first embodiment of the present invention. The differential mobility spectrometer/mass spectrometer system  200  comprises a differential mobility spectrometer  202  and a first vacuum lens element  204  of a mass spectrometer (hereinafter generally designated mass spectrometer  204 ). Mass spectrometer  204  also comprises mass analyzer elements  204   a  downstream from vacuum chamber  227 . Ions can be transported through vacuum chamber  227  and may be transported through one or more additional differentially pumped vacuum stages prior to the mass analyzer indicated schematically as mass analyzer elements  204   a . For instance in one embodiment a triple quadrupole mass spectrometer may comprise three differentially pumped vacuum stages, including a first stage maintained at a pressure of approximately 2.3 Torr, a second stage maintained at a pressure of approximately 6 millitorr, and a third stage maintained at a pressure of approximately 10 −5  Torr. The third vacuum stage may contain a detector, as well as two quadrupole mass analyzers with a collision cell located between them. It will be apparent to those with skill in the art that there may be a number of other ion optical elements in the system, which have not been described. 
     The differential mobility spectrometer  202  comprises plates  206  and electrical insulator  207  along the outside of plates  206 . The plates  206  surround a drift gas  208  that drifts from an inlet  210  of the differential mobility spectrometer to an outlet  212  of the differential mobility spectrometer  202 . The insulator  207  supports the electrodes and isolates them from other conductive elements. For example, the insulator may be fabricated from ceramic or Teflon™. The outlet  212  of the differential mobility spectrometer  202  releases the drift gas that may flow into an inlet  229  of the vacuum chamber  227  and mass spectrometer  204 . 
     The differential mobility spectrometer  202  is contained within a curtain chamber  218 , defined by a curtain plate or boundary member  219 , and supplied with a curtain gas from a curtain gas supply  220 . Specifically, curtain gas from curtain gas supply  220  can flow through curtain gas conduit  220   a  at flow rates determined by flow controller  220   b . The system  200  also comprises a LC pump and modifier supply  214  for pumping precise amounts of a modifier liquid into the curtain gas conduit  220   a  at T-juncture  216 . Specifically, LC pump  214  comprises a meter (not shown), which can be changed to set a selected volumetric flow rate of the modifier liquid into the juncture  216 . Based on this adjustment of the meter, the LC pump  214  is then operable to provide an actual volumetric flow rate of the modifier liquid to the juncture  216  and into curtain gas conduit  220   a  to mix with the curtain gas. 
     It will be apparent to those of skill in the art that LC pump  214  could be replaced with a syringe pump or other accurately controllable dispensing devices for dispensing the modifier liquid. Whatever dispensing device is used, this device can be sufficiently accurate such that the actual volumetric flow rate is within a relatively small percentage deviation of the selected volumetric flow rate. For example, this percentage deviation may be as little as 2% of the selected volumetric flow rate, or even as little as 0.2% of the selected volumetric flow rate. This actual volumetric flow rate and small percentage deviation can be maintained for hours or days as required. Again, during this dispensing period, which may be as little as an hour, or as long as several days, the percentage deviation can be maintained below at least 2%, and possibly below 0.2% of the selected volumetric flow rate. 
     The differential mobility spectrometer  202  is contained within a curtain chamber  218  defined by a curtain plate or boundary member  219  and supplied with the curtain gas from the curtain gas supply  220  via curtain gas conduit  220   a . When the curtain gas is released into the curtain chamber by the curtain gas conduit  220   a , it can contain a precisely metered quantity of modifier liquid from LC pump  214 . Ions  222  are provided from an ion source (not shown) and are emitted into the curtain chamber  218  via curtain chamber inlet  224 . The pressure of the curtain gases in the curtain chamber  218  can be maintained at or near 760 Torr. This pressure can provide both a curtain gas outflow  226  out of curtain gas chamber inlet  224 , as well as a curtain gas inflow  228  into the differential mobility spectrometer  202 , which inflow  228  becomes the drift gas  208  that carries the ions  222  through the differential mobility spectrometer  202  and into the vacuum chamber  227 . As the curtain gas within the curtain chamber  218  can include a precise proportion of modifier liquid by carefully controlling the flow controller  220   b  and LC pump  214 , the drift gas  208  can also comprise a precisely determined percentage of modifier. Optionally, the system  200  may comprise a mixing chamber instead of, or in addition to, the curtain chamber. This mixing chamber could be located in the curtain gas conduit  220   a  upstream from the differential mobility spectrometer. In such an embodiment, the mixing chamber could facilitate mixing of the modifier liquid and the curtain gas. 
     As illustrated in  FIG. 1 , the first vacuum lens element  204  of the mass spectrometer  204  can be contained within a vacuum chamber  227 , which vacuum chamber can be maintained at a much lower pressure than the curtain chamber  218 . In accordance with an aspect of an embodiment of the present invention, the vacuum chamber  227  can be maintained at a pressure of 2.3 Torr by a vacuum pump  230  while the curtain chamber  218  and an internal operating pressure of the differential mobility spectrometer  202  can be maintained, as mentioned above, at a pressure of about 760 Torr. 
     Optionally, either or both of juncture  216  and curtain chamber  218  can include a heater  217  for heating the mixture of the curtain gas and the modifier liquid to further control the proportion of modifier liquid in the curtain gas. 
     Referring to  FIG. 2 , there is illustrated in a schematic diagram, a differential mobility spectrometer system  300  in accordance with an aspect of a second embodiment of the present invention. For clarity, elements of the system  300  of  FIG. 2  that are analogous to elements of the system  200  of  FIG. 1  are designated using the same reference numerals as in  FIG. 1 , with 100 added. For brevity, the description of  FIG. 1  is not repeated with respect to  FIG. 2 . 
     As shown, the differential mobility spectrometer system  300  of  FIG. 2  resembles a portion of the system  200  of  FIG. 1 , but lacks the mass spectrometer and vacuum chamber elements of  FIG. 1 . Accordingly, the differential mobility spectrometer  300  of  FIG. 2  can be installed upstream of any number of different mass spectrometer elements, or may simply be installed upstream of a region of reduced pressure, as shown, which draws the ions  322  and drift gas  308  through the differential mobility spectrometer  302 . Alternatively, there may be a detector downstream of the outlet of the differential mobility spectrometer  302  such as a Faraday cup or other ion current measuring device. 
     The differential mobility spectrometer  302  is contained within a curtain chamber  318 . The curtain chamber  318  is supplied with a curtain gas from a curtain gas supply  320  in a manner similar to that described above in connection with  FIG. 1 . 
     Referring to  FIG. 3 , there is illustrated in a schematic view, a differential mobility spectrometer system  400  in accordance with an aspect of a third embodiment to the present invention. For clarity, elements of the system  400  of  FIG. 3  that are analogous to corresponding elements of the system  300  of  FIG. 2  are designated using the same reference numerals, with 100 added. For brevity, the descriptions of  FIGS. 1 and 2  are not repeated with respect to  FIG. 3 . 
     The differential mobility spectrometer  400  of  FIG. 3  is even simpler than the system  300  of  FIG. 2  in that a differential mobility spectrometer  402  of the system  400  is not contained within a curtain chamber. 
     As shown, a carrier or drift gas supply  420  can supply a carrier gas to the differential mobility spectrometer  402  via carrier gas conduit  420   a . The carrier gas can flow at flow rates determined by a flow controller  420   b . At juncture  416 , the carrier gas conduit  420   a  is coupled to a modifier liquid supply conduit  414   c . Modifier Liquid can be pumped into the carrier gas conduit  420   a  by LC Pump  414   b , which itself draws the modifier liquid from modifier supply  414   a . Downstream of juncture  416 , the carrier gas mixed with the modifier liquid can flow into the differential mobility spectrometer  402  via inlet  410  to become the drift gas  408 . Ions  422  are released into the differential mobility spectrometer  402  via side inlet  421 . 
     Referring to  FIG. 4 , CV scans for 3 different compounds as the concentration of a particular modifier, 2-propanol, provided to the curtain gas by the LC pump  214  changes are illustrated. For these data, the total curtain gas inflow to the curtain chamber  218  was maintained substantially constant at 7 L/min. The 3 compounds are Clobazam, Dianabol and Temazepam. 
     In the case of each of these compounds, it is clear that the concentration of modifier in the curtain gas has a dramatic effect on CV peak position. This is most apparent as the proportion of modifier liquid increases from 0 L/min to 1.4 L/min, which results in a dramatic leftward shift in the peak. In the case of Dianabol, subsequent increases in the proportion of modifier liquid will shift the peaks further leftward; however, in the case of Clobazam and Temazepam, further increases in the proportion of modifier appear to shift the peak toward the right—that is, back toward the peak for trace one, albeit only part way. 
     More specifically, referring to the graph for Clobazam, the first trace, designated 1, is shown far to the right, with a peak at approximately 6 volts. Trace  1  represents the case in which no modifiers are contained within the curtain flow. Then, when the portion of curtain flow containing the modifier increases to 1.4 L/min, the peak shifts sharply to the left, such that the peak of trace  2 , is located somewhere between −20 and −25 volts. Perhaps somewhat counter intuitively, however, as the portion of the curtain flow containing the modifier is further increased, the resulting traces  3  to  10  shift progressively rightward again, such that the voltage for each of these peaks monotonically increases as the portion of flow containing modifiers increases from 2.1 L/min. 
     The situation is otherwise in the case of Dianabol. Specifically, trace  1 , representing no Modifier liquids included within the curtain flow, is far to the right, with a peak slightly below 10 volts. When the portion of flow containing modifiers is increased to 1.4 L/min, the peak shifts sharply to the left, such that the peak of trace  2  is slightly below −10 volts. As the portion of flow containing modifiers is further increased, the peaks shift further leftward, such that the peaks for traces  7  to  10  are all below −20 volts. 
     In the case of Temazepam the situation is more complicated. Again, trace  1  representing the case in which no modifier is added to the curtain flow has a peak of slightly above 10 volts. Then, when the portion of flow containing modifiers is increased to 1.4 L/min, the peak shifts sharply leftward to trace  2 , having a peak somewhere between −25 volts and −22 volts. Further increasing the portion of flow containing modifiers from 1.4 L/min to 2.8 L/min shifts the peaks of the resulting traces further leftward, such that the peak of trace  4  is around −30 volts. However, increasing the portion of flow containing modifiers from 2.8 L/min to 4.9 L/min leaves the peaks for the resulting traces substantially unchanged in position. Further increasing the portion of flow containing modifiers from 4.9 L/min to 7.0 L/min can, as shown by traces  8 , to  10 , shift the resulting peaks of these traces gradually rightward, such that the peak for trace  10 , representing 7.0 L/min containing modifiers, is now above −30 volts. 
     The control of the modifier introduction rate to the curtain gas can be very important to achieve reproducible mobility peak positions. This contention is supported by all of the graphs of  FIG. 4 , which show how peak position can shift greatly, and perhaps surprisingly, based on the proportion of modifier liquid within the curtain gas. Given that CV scans can continue for hours, or even days, if there is significant uncontrolled variation in the proportion of modifier liquid added to the curtain gas, then there can be a very significant drift of the CV position for the compound of interest over this selected time interval, be it measured in hours or days. This can be highly problematic as for quantitative analyses, the CV can be tuned at the start of runs and fixed for the duration at the initial optimum (i.e. at the initial peak). If the drift in CV position is sufficient, then the actual measured signal can drop by a significant factor, despite the shifted peak height being substantially the same as the height of the initial peak. 
     Referring to  FIG. 5 , there are illustrated CV scans for Temazepam where the entire curtain gas flow is bubbled through 2-propanol (the modifier liquid). In this case, the proportion of modifier liquid contained within the curtain gas remains substantially the same; however, the total curtain gas flow rate changes to vary the mass of the modifier liquid introduced to the drift gas. Again, the observed CVs for Temazepam vary with the total curtain gas flow rate, and as a result the total modifier flow rate, despite the proportion of modifier remaining constant. 
     More specifically, as shown, the first trace, representing curtain gas flow rates of 2 L/min has a peak at approximately −31 volts. Then, as the curtain gas flow rate increases and the resulting quantity of modifier liquid increases, the traces migrate leftward, until trace  8 , representing a curtain gas flow rate of 25 L/min (and a correspondingly larger amount of modifier liquid) has a peak at somewhere between −35 and −34 volts. Traces  2 - 7  represent, respectively, curtain gas flow rates of 5 L/min, 8 L/min, 11 L/min, 14/min, 17 L/min and 20 L/min. Differential mobility separation occurred with 4300 volts applied in all cases. 
     Referring to  FIG. 6 , CV scans for Temazepam measured over approximately a six hour time period with bubbling of the curtain gas through a liquid modifier prior to introduction to the curtain chamber is illustrated. As illustrated in  FIG. 6 , variation in bubbler results can cause a significant drift of this CV position for this compound over a six hour time period. This can be problematic because for quantitative analysis the CV could be tuned at the start of the run and fixed for duration at the initial optimum (which appears to be approximately −28.4 volts in  FIG. 6 ). The drift in CV position shown in  FIG. 6  could be unacceptable, as particularly for the six hour time point data, a CV of −28.4 volts would drop the measured signal by more than a factor of 2. Considering a full spread in CV optimum demonstrated in  FIG. 6  (in particular the trace for the three hour time period, designated A, and the trace for the six hour time period, designated B) there could be a drop by a factor of 10 in the signal with this range of CV spread of approximately 2.3 volts. 
     Referring to  FIG. 7 , there are illustrated CV scans for Temazepam measured over a five hour time period. In this case, 50 uL/min of 2-propanol was dispensed into approximately 7.7 L/min of curtain gas flow for the five hour period. As can be seen from  FIG. 7 , the CV reproducibility for Temazepam was much better than what was observed with the bubbler demonstrating a full spread of approximately 0.8 volts. In this case, the decrease in signal for Temazepam due to CV drift was less than 10 percent over the course of these experiments. Based on the foregoing, it appears that accurately and precisely dispensing modifier liquids into the drift gas stream for a differential mobility spectrometer system can help quantitative analysis in the presence of modifiers. These results can be further improved by heating to improve reproducibility. 
     Referring to  FIG. 8 , there is illustrated in a series of panes, mobility CV scans for 6 isobaric compounds (m/z 316). Specifically,  FIG. 8  illustrates how selectivity can be tuned using modifier flow rates. Traces for six isobaric compounds are numbered as follows: 1. Bromazepam, 2. Clonazepam, 3. Oxfendazole, 4. Chlorprothixene, 5. Flusilazole, 6. Pamaquine. The lowest pane, pane A, shows DMS separation with 4200 volts applied and a total curtain gas flow rate of 11.9 L/min, with no modifier added. The remainder of the panes, panes B to H, show the effect on selectivity as the volumetric flow of 2-propanol modifier into the curtain gas increases. Increasing the volumetric flow of modifier liquid tends to increase the peak capacity by spreading the peaks over a larger range of CVs; however, the best overall separation shown for the six isobaric compounds is actually achieved in pane F when the modifier flow rate is 1 mL/min, rather than at higher settings. For example, peaks  4  and  5  in pane F, representing chlorprothixene and flusilazole respectively, can be more readily distinguished than the peaks of traces  4  and  5  in pane G when the modifier flow rate is 2 mL/min. Traces  2  and  3 , representing Clonazepam and Oxfendazole respectively, are more readily distinguishable in pane C, representing modifier flow rates of 100 uL/min, and in pane G, representing modifier flow rates of 2 mL/min, than they are in pane F. However, in both of these panes it is much more difficult to distinguish peaks  4  and  5 , while in pane F, it is still possible to distinguish peaks  2  and  3  by selecting high enough on the peaks to exclude the bottom portion at which they overlap. 
     Accordingly, using the data of the type illustrated in panes A to H, selectivity can be enhanced by carefully controlling the amount of modifier liquid added. That is, gradually larger amounts of modifier liquid can be added, and the effect on selectivity observed, such that once adding additional amounts of modifier liquid starts to diminish selectivity, further increases in modifier liquid can be stopped. 
     Other variations and modifications of different embodiments of the present invention are possible. For example, it will be apparent to those of skill in the relevant arts that the foregoing approaches can be applied to both planar and cylindrical field asymmetric wave form ion mobility spectrometer (FAIMS) devices. All such modifications or variations are believed to be within the sphere and scope of aspects of embodiments of the invention as defined by the claims appended hereto.