Patent Document

FIELD OF THE INVENTION  
       [0001]     The invention is in the field of evaporative light scattering detection.  
       BACKGROUND  
       [0002]     Evaporative light scattering detectors (ELSDs) are used routinely for Liquid Chromatography (LC) analysis. In an ELSD, a liquid sample is converted to droplets by a nebulizer. As the droplets traverse a drift tube, the solvent portion of the droplets evaporates, leaving less volatile analyte. The sample passes to a detection cell, where light scattering of the sample is measured. ELSDs can be used for analyzing a wide variety of samples.  
         [0003]     The present inventors identify the nebulizer as a limit on the effectiveness of the detection capabilities of ELSDs. One problem with conventional nebulizers is that complete solvent evaporation does not occur in the drift tube. The expanding trajectory and variable sizes of the droplets produced by conventional nebulizers contributes to the incomplete evaporation and erratic measurement performance. Droplets enter the detection cell and cause scattering that is detected. The scatter effect of droplets is indicated in conventional ELSDs by the fact that substantial scattering is detected in the absence of analytes. This droplet scattering creates a large level of background noise. Accordingly, with typical ELSDs, it is only possible to measure differential scattering, where scattering from the analyte is much greater than that from incompletely volatilized solvent droplets.  
         [0004]     Droplets that are too small to carry sufficient analyte are also produced within the distribution of droplets produced by a conventional nebulizer. The small droplets result in analyte particles that are too small to contribute to the detection signal. However, the small droplets increase solvent vapor pressure in the drift tube. Higher vapor pressure retards evaporation in the drift tube. Incomplete evaporation leads to the background noise from scattering caused by droplets as discussed above.  
         [0005]     If the droplet size distributions and evaporation rate were constant in the conventional ELSD nebulizers, then the resultant background noise could, to a certain degree, be accounted for in the measurement. However, the rate of incomplete droplet vaporization and their distribution (size and number) tends to change randomly with time. This causes uncertainty in the analyte signal, in addition to the substantial level of background noise.  
         [0006]     One conventional strategy for addressing the droplet distribution problem of conventional nebulizers is to remove larger droplets. An impactor has been used in the drift tube of conventional ELSDs to intercept large droplets, which are collected and exit the drift tube through an outlet drain. Additional condensation collects on the walls of the drift tube due to the divergence of spray from the nebulizer, and also drains from the outlet drain. A percentage of the divergent spray that exits via the outlet drain includes properly sized droplets with analyte. Excluding larger droplets produced by a conventional nebulizer proves difficult in practice because the nature of the droplet distribution depends strongly on three factors: mobile phase composition, mobile phase flow rate and carrier gas flow rate. The dependence is highly interactive, which makes the spray hard to control and difficult to model. These undesirable nebulizer characteristics place extraordinary demands on the structural design of ELSD units, making their design very complicated and highly empirical.  
       SUMMARY OF THE INVENTION  
       [0007]     A focused droplet nebulizer of the invention produces substantially uniform droplets of a predetermined size. Droplets are pushed out through a small outlet orifice by the contraction of a chamber. The droplets can be carried on a substantially non-divergent path in a drift tube. A piezo membrane micro pump acts in response to an electrical control signal to force a droplet out of the outlet orifice. The nebulizer can operate at frequencies permitting a stream of individual droplets of the predetermined size to be sent along the substantially non-divergent path in the drift tube of a preferred embodiment ELSD device. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0008]      FIG. 1  illustrates an evaporative light scattering detector (ELSD) including a focused droplet nebulizer in accordance with a preferred embodiment of the invention;  
         [0009]      FIG. 2  illustrates the focused droplet nebulizer of  FIG. 1 ;  
         [0010]      FIGS. 3A and 3B  illustrate a piezo membrane micro pump of the nebulizer of  FIGS. 1 and 2 ;  
         [0011]      FIG. 4  illustrates a structure for reduced flow sampling of effluent in accordance with an embodiment of the invention;  
         [0012]      FIG. 5  illustrates a structure for reduced flow sampling of effluent in accordance with another embodiment of the invention;  
         [0013]      FIG. 6  illustrates a structure for reduced flow sampling of effluent in accordance with another embodiment of the invention; and  
         [0014]      FIGS. 7A and 7B  illustrate an optical detection cell of the ELSD of  FIG. 1 . 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0015]     The problems inherent with the use of a conventional nebulizer ultimately limit performance in evaporative light scattering detectors (ELSDs). Size, complexity, and cost are also adversely affected by the nebulizer. The invention provides a focused droplet nebulizer. A nebulizer of the invention produces substantially uniform sized droplets. Preferred embodiment nebulizers also provide a precisely controlled droplet production rate and deliver droplets along a focused path. An ELSD of the invention uses a focused droplet nebulizer to reduce background noise and improve the state of ELSD detection.  
         [0016]     A preferred embodiment focused droplet nebulizer includes a piezo membrane micro pump. The piezo membrane micro pump has an inlet with a check valve that allows liquid to flow one way into the pump. When the piezo membrane expands, liquid is drawn into the pump and when the piezo membrane contracts, liquid is forced out a tiny outlet orifice. This creates a small single droplet. The check valve ensures that little liquid flows back through the inlet port. The droplet output is strictly controlled by an electrical signal. In other embodiments, a plurality of orifices and/or piezo membrane elements are used to produce parallel droplet streams.  
         [0017]     Dimensions of the focused droplet nebulizer are set to produce droplets of a predetermined size. Dimensions may be set, for example, to produce droplets anywhere within in the approximate range of between 10 and 100 μm, which are sizes typically of interest in ELSD systems. Droplets in a particular physical embodiment constructed in accordance with the invention have a very narrow size distribution, typically 5% standard deviation. Applied to an ELSD, substantially all droplets will contribute to the detection signal. The rate of droplet production is controlled independently by electrical signal, e.g. a periodic signal, fed to the micro pump. Thus, the rate of droplet formation can be easily varied so as to optimize the signal to noise ratio. The droplet size is independent of droplet production rate and is not strongly dependent on liquid composition. There is substantially no divergence in the droplet path, typically 1-2 degrees standard deviation. Operation can be independent of the flow rate of the carrier gas. Piezo element micro pumps have a relatively low cost, tolerate a wide range of organic and aqueous liquids, and have a relatively long lifetime.  
         [0018]     Preferred embodiments of the invention will now be discussed with reference to the drawings. The particular exemplary devices will be used for purposes of illustration of the invention, but the invention is not limited to the the particular illustrated devices.  
         [0019]      FIG. 1  illustrates a preferred embodiment ELSD including a focused droplet nebulizer. A liquid chromatography (LC) column  100  provides effluent  102  (a.k.a. the mobile phase) to the focused droplet nebulizer  104 . The focused droplet nebulizer also is provided with carrier gas  106 . A controller  107  controls the droplet production of the focused droplet nebulizer  104 . Under control of signals from the controller  107 , the nebulizer  104  produces droplets of a predetermined size that depends upon the physical characteristics of a piezo membrane micro pump in the focused droplet nebulizer. For example, droplets in the approximate range of between 10 and 100 μm, which are of interest to ELSD systems, are readily produced by a piezo membrane micro pump.  
         [0020]     The focused droplet nebulizer  104 , under control of the controller  107 , produces substantially uniformly sized droplets, e.g., droplets having a very narrow size distribution, typically 5% standard deviation. The rate of droplet production is controlled readily by an electrical signal, e.g., a periodic signal, provided to the micro pump by the controller  107 . The rate of droplet formation can be varied by the controller  107  to optimize the signal to noise ratio. This can be an automatic optimization provided by the controller  107 , or can be an optimization conducted with operator input to the controller  107 . Droplet size is independent of droplet production rate and is substantially independent of liquid composition.  
         [0021]     The focused droplet nebulizer  104  sends the uniformed sized droplets on a substantially non-divergent focused path, typically 1-2 degrees standard deviation, into the flow of carrier gas down a drift tube  108 , which is a heated section of tubing through which gas/droplets flow, and in which evaporation occurs. The mobile phase (solvent) tends to evaporate as the droplet stream passes along drift tube  108 . The gas stream enters an optical cell  110 , which is the detection module of the unit. The stream passes through the cell  110  and out an exit port  112  as a waste gas steam  114 .  
         [0022]     The basis of the detection method is the amount of light scattered within the detection cell  110 . Ideally, scattering will arise only from substances (analytes) dissolved in the mobile phase and scattering from the mobile phase per se will be negligible. In the ideal case, all mobile phase molecules will be converted to gas in the drift tube  108 , and will produce little or no scattering in the optical cell  110 . Analytes, if present, will not vaporize but will be left as airborne particles, which produce substantial light scattering as they pass through the optical cell  110 . Thus, if the mobile phase  102  contains an analyte, light scattering will be observed within the cell  10 , whereas if the mobile phase  102  contains no analyte, little or no light scattering will be observed within the cell  110 . With this situation, whenever an analyte exits the LC column, an analyte peak (strong scattering by particles) will be observed above the baseline (weak scattering by solvent).  
         [0023]     Evaporation is highly efficient in the ELSD of  FIG. 1 , as the focused droplet nebulizer  104  produces substantially uniform sized droplets along a substantially non-divergent path. The problems of conventional nebulizers that include droplet size distributions and divergent sprays are avoided and background noise in the detection signal is substantially reduced. The conventional nebulizers include a spray nozzle that produces a large number of too small and too large droplets on a divergent spray. The particles that are too small do not contribute to the signal; however, they increase the solvent vapor pressure, which decreases the efficiency of the drift tube by retarding solvent evaporation. The large droplets tend to undergo incomplete vaporization and their distribution (size and number) changes randomly with time. Thus, they produce baseline noise in the absence of analyte as well as uncertainty in the analyte signal itself. The ELSD of  FIG. 1  solves such problems.  
         [0024]      FIG. 2  shows the focused droplet nebulizer  104  of  FIG. 1 . The focused droplet nebulizer makes use of a piezo membrane micro pump  202 . Piezo membrane (aka diaphragm) micro pumps use, for example, a piezo-ceramic element as the diaphragm/membrane. Piezo membrane micro pumps are available from a number of commercial sources.  
         [0025]     Within the focused droplet nebulizer  104 , the piezo membrane micro pump  202  receives the mobile phase  102 . The mobile phase  102  enters the micro pump  202 , which is centrally mounted in a gas manifold  204 . Carrier gas  206  enters the manifold  204  and exits into the drift tube  108  in a concentric manner around the micro pump  202 . The gas manifold gives a uniform flow of gas to carry the droplets into the drift tube  108 . Substantially uniform droplets  210  are produced by the micro pump  202  at a size determined by the micro pump outlet orifice and at a rate determined by the frequency of the signal applied to the micro pump piezo by the controller  107 . The droplet path is substantially non-divergent and unidirectional as shown and is carried along by the carrier gas stream  208 .  
         [0026]      FIGS. 3A and 3B  illustrate additional details and operation of the micro pump  202  of the nebulizer  104 . The micro pump  202  has a body  302  that defines a chamber  303 . Each of an inlet  304  and outlet orifice  306  includes a check valve  308 . A piezo membrane/diaphragm  310  is an integral part of the chamber body  302 .  FIG. 3A  illustrates a liquid intake action. An electrical signal (pulse) is sent to the piezo membrane  310  from the controller  107 , causing it to move such that the chamber volume is increased and liquid is pulled into the chamber body through the inlet  304 . The check valve  308  on the outlet orifice  306  eliminates flow into the chamber through the outlet orifice  306 .  FIG. 3B  illustrates droplet formation and expulsion, which occurs when the piezo membrane  310  moves such that the chamber volume is decreased and liquid is forced through the outlet orifice  306  in the form of a droplet. The check valve  308  on the inlet  304  eliminates liquid flow back through the inlet  304 . The rate of droplet formation is controlled by the pulsing rate, up to about 5 kHz. Each pulse results in one droplet being expelled by the pump for “drop on demand” operation. The substantially uniform predetermined droplet size is controlled by the size of the chamber  303  and the diameter of the outlet orifice  306 .  
         [0027]     Due to the substantially consistent drop size and substantially non-divergent path, the ELSD of  FIG. 1  will have a noise reduction because large droplets of conventional devices are eliminated. The ELSD will also have a higher detection signal because the droplets are uniformly sized and propagate on a path wherein substantially all of the droplets make a contribution to the detection signal. Lower carrier gas rates are required. The focused droplet nebulizer  104  also has a reduced size compared to typical conventional nebulizers. Since evaporation is more efficient, the internal size of the drift tube  108  can be decreased and the drift tube can be operated at lower temperatures than used in current typical commercial devices. Lower temperature operation can minimize signal loss for analytes that tend to partially vaporize, often referred to as semi-volatiles.  
         [0028]     In the ELSD of  FIG. 1 , the focused droplet nebulizer  104  receives effluent from the LC column  100  at a lower rate than is used in conventional nebulizers. A typical conventional commercial nebulizer accepts a range of mobile phase flow rates and delivers a droplet spray consistent with the experimental liquid flow rate, which may be as high as 5 mL/min. However, the focused droplet nebulizer  104  of the invention uses a piezo membrane micro pump that delivers a fixed flow rate of droplets depending on the predetermined droplet size of the nebulizer  104  and the frequency of the control signal applied by the controller.  
         [0029]     For example, a 100 picoliter (pL) droplet with an 8 kHz signal would require a liquid input flow rate of about 0.05 mL/min, which is much smaller than typical LC liquid flow rates used in a conventional ELSD device. Assuming an unmodified typical LC column  100 , only a fraction of the column effluent will be used by the focused droplet nebulizer  104 . Sampling the mobile phase effluent can be conducted in a manner that represents the actual composition of the effluent at every instant, and without requiring that the entire volume of effluent pass through the micro pump. Thus, the focused droplet nebulizer  104  can be used with a typical conventional LC column  100  with appropriate sampling, or a modified, lower rate LC column can be used.  
         [0030]     Sampling of the effluent for reduced flow into the focused droplet nebulizer  104  can be achieved by various techniques. A structure for reduced flow sampling is shown in  FIG. 4 . In  FIG. 4 , effluent  102  is passed through a tee  402 , with the focused droplet nebulizer  104  attached to relatively short tube  406  of the tee  402 . The focused droplet nebulizer  104  sends liquid through its micro pump&#39;s outlet orifice  306  to the ELSD drift tube  108  (not shown in  FIG. 4 ). Another tube  408  of the tee  402 , is substantially wider and accepts the main portion of the effluent  102 . The tube  406  is also relatively short to keep backpressure relatively low and permit the piezo membrane micro pump in the focused droplet nebulizer  104  to draw as much liquid as is required from the tee  402 . The relative diameters of the tubes  406  and  408  are set to accommodate the flow limit of the focused droplet nebulizer  104 .  
         [0031]     Another structure for reduced flow sampling is shown in  FIG. 5 . The  FIG. 5  structure can handle larger flows than the  FIG. 4  structure. The focused droplet nebulizer  104  is attached to a very small diameter sampling tube  502 , which is in turn mounted so that it penetrates into the interior of a tube  504  that carries the effluent  102 . The focused droplet nebulizer  104  draws as much liquid as is required and provides focused droplet output through its outlet orifice  306 .  
         [0032]     Another structure for reduced flow sampling is shown in  FIG. 6 . A small diameter sampling tube  602  is attached to a main flow tube  604  carrying the effluent  102 . A flow controller  606  delivers a small volume of liquid to a tee  608 . The focused droplet nebulizer  104  is attached to one tube of the tee  608  and excess liquid flows out a waste tube  610 . The flow controller  606  ensures that the focused droplet nebulizer  104  does not experience intolerable back pressure.  
         [0033]     Analyte enters the optical cell  110  after traversing the drift tube  108 . The optical cell is shown in  FIGS. 7A and 7B . As seen in top view ( FIG. 7A ), a light source  702  produces a light beam  704  that travels through the cell  110  and enters a light trap  706 , which minimizes stray light that can interfere with detection of the scattering due to analyte. A gas stream  708  flows through the cell  110  as shown, normal to the light beam  704 . In the side view ( FIG. 7B ) the light beam  704 , not shown, is perpendicular to the plane of the paper. Thus, the gas stream  708  in the cell  110  encounters the light beam near the center of the cell  110 , within a cross section  710 . Analyte particles scatter light and a portion of the scattered light  712  is refocused by a lens  714 , so that the refocused light  716  strikes an optical detector  718 . This detected light is measured and forms the basis for quantitation in the analysis.  
         [0034]     While specific embodiments of the present invention have been shown and described, it should be understood that other modifications, substitutions and alternatives are apparent to one of ordinary skill in the art. Such modifications, substitutions and alternatives can be made without departing from the spirit and scope of the invention, which should be determined from the appended claims.  
         [0035]     Various features of the invention are set forth in the appended claims.

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