Abstract:
A high performance liquid chromatography system employs a nebulizer with a flow restriction at the exit of its mixing chamber to produce finer droplets, and an adjustable impactor for increased control over droplet sizes. Downstream of the mixing chamber, the nebulizer can incorporate tubing that is permeable to the sample liquid, to promote aerosol drying through perevaporation. A condensation particle counter downstream of the nebulizer uses water as the working medium, and is adjustable to control threshold nucleation sizes and droplet growth rates. A particle size selector employing diffusion, electrostatic attraction or selection based on electrical mobility, is advantageously positioned between the nebulizer and the CPC.

Description:
[0001]    This application claims the benefit of priority based on Provisional Patent Application No. 60/857,609, entitled “System for Separating Non-volatile Analytes and Measuring Analyte Concentrations,” filed Nov. 7, 2006. 
     
    
     BACKGROUND OF THE INVENTION 
       [0002]    The present invention relates to systems for measuring minute concentrations of constituents dissolved in liquids, and more particularly to systems that employ analyte separation and aerosol generation to distinguish constituents and measure their concentrations. 
         [0003]    A variety of instruments are used for identifying and measuring concentrations of solutes in liquid media. Separators can employ any one of several analyte separation techniques, e.g. liquid chromatography, high performance liquid chromatography (normal or reversed phase), ion exchange chromatography and gel permeation chromatography. Analyte separation involves moving liquid and dissolved constituents, known as the mobile phase, through a stationary phase, e.g. a stainless steel column or tube packed with 5-10 mm silicon beads. As the liquid passes through the column, different analytes become separated from one another due to differing rates at which they travel through the stationary phase. The liquid leaving the stationary phase is comprised of spatially separated concentrations of the individual analytes. As a result, a continuous measurement of the liquid stream yields a chromatogram in which indications of relatively high concentration are temporally separated from one another to suggest the presence of different analytes. The chromatogram corresponds to the physical separation of the analytes at the column exit, by recording the different times at which different analyte concentrations leave the column. The exit times are useful in identifying the analytes involved. 
         [0004]    Among the techniques for measuring analyte concentrations, several involve generating aerosols based on the mobile phase exiting the column. In one of these, known as evaporative light scattering, a nebulizer is used to generate droplets of the solution eluting from the separator column. The droplets dry as they are carried by air or another gas, forming a stream of non-volatile residue particles. As the particles are moved past a laser beam, each particle that intersects the beam scatters light, with larger particles scattering light at higher intensity. Thus, the amplitude of a photodetector output provides a measurement of particle size, which in turn provides an indication of analyte concentration. 
         [0005]    To enhance measurement of small analyte concentrations, the particle stream can be directed through a condensation particle counter (CPC), in which the particles travel through a region saturated with the vapor of a working medium that condenses onto the non-volatile residue particles that exceed a threshold diameter, “growing” each particle into a considerably larger droplet that is more easily detected by optical means. 
         [0006]    In another technique, known as evaporative electrical detection, the solution leaving a separator column is nebulized to provide an aerosol stream, with the droplets again dried to provide a particle stream. The particle stream is brought into a confluence with a stream of ions, to apply a size-dependent electrical charge to the non-volatile residue particles. An electrically conductive filter collects the particles and generates an electrical current indicative of analyte concentration. 
         [0007]    While the systems are well suited for a variety of applications, they are subject to difficulties that limit their utility. One of these is the lack of sensitivity sufficient for detecting and measuring extremely low analyte concentrations. As environmental standards for exposure to various contaminants become more stringent, and as product testing and manufacturing techniques are directed to applications that require more accurate measurement of constituents or have a reduced tolerance to certain constituents, there is an ever increasing need to measure smaller amounts of analytes with accuracy. 
         [0008]    Another difficulty concerns bubble formation due to gasses dissolved in the water or other liquid entering the nebulizer. Bubbles can be formed when the liquid flow rate is below the natural aspiration rate, with the liquid drawn into the nebulizer at a pressure below atmospheric pressure. The bubbles eventually break free and tend to disrupt residue concentration measurements downstream of the nebulizer. 
         [0009]    A further system problem, relating to the condensation particle counter, concerns the use of butyl alcohol or similar fluids with low vapor mass diffusivity for growing the residue particles into droplets. Such liquids tend to be flammable, toxic, and produce noxious odors. Frequently they are subject to health and environmental regulations that restrict their use in indoor environments. In addition, the liquids require equipment for supplying, collecting and recirculating the liquid involved, and in some cases for separating the liquid from water. 
         [0010]    Another persistent problem, due to relatively long fluid flow paths within and between the nebulizer and CPC, is the relatively long time elapsed between a change in the concentrations of analytes in a given liquid sample, and the detection of the change. The longer paths allow more time for axial diffusion, which ultimately has a negative impact on the instrument response. 
         [0011]    Another difficulty with conventional condensation particle counters is the limited dynamic range typical of many CPC designs, due primarily to the increase in coincidence events that accompanies increased particle concentration. 
         [0012]    Accordingly the present invention has several aspects, directed to one or more of the following objects:
       to provide a system for detecting analyte concentrations based on droplet growth and optical droplet sensing based on nonflammable and nontoxic working media;   to provide, in systems using nebulizers to generate liquid sample aerosols, more rapid and effective evaporation to dry the nebulizer output;   to provide a process for extending the dynamic range of a condensation particle counter;   to provide a nebulizer with a mixing chamber better suited to generate finer aerosol droplets;   to provide an optical detector with enhanced flexibility for determining particle nucleation thresholds and for accommodating a wider variety of condensation media; and   to remove smaller, more volatile particles from the aerosol to enhance volatile analyte detection.       
 
       SUMMARY OF THE INVENTION 
       [0019]    In general, the invention is drawn to a system for analyzing liquid samples including an analyte separator, an aerosol generator for producing an aerosol stream of suspended particles derived from the liquid output of the separator, and a particle sensing device responsive to the particles for measuring analyte concentrations. 
         [0020]    One aspect of the invention is a system for measuring analyte concentrations in liquids. The system includes an analyte separation stage adapted to separate different analytes in a liquid sample primarily into different regions within the liquid sample. This produces a separation stage output in which a plurality of different analytes are so separated. A nebulizing stage, downstream of the analyte separation stage, is adapted to generate an aerosol stream composed of droplets of the separation stage output suspended in a carrier gas. An evaporation stage, downstream of the nebulizing stage, is adapted to substantially evaporate the liquid whereby the aerosol leaving the evaporation stage is composed of residue particles of the different analytes suspended in the carrier gas. A saturation stage, disposed downstream of the evaporation stage, is maintained substantially at a first temperature, and adapted to merge the aerosol with a working medium vapor having a mass diffusivity higher than a thermal diffusivity of the carrier gas, to substantially saturate the aerosol with the working medium vapor. A condensation stage, disposed downstream of the saturation stage, is maintained at a second temperature above the first temperature, and adapted to merge further working medium vapor with the substantially saturated aerosol to supersaturate the aerosol and thereby cause droplet growth through condensation of the working medium onto the residue particles. A sensing stage, downstream of the condensation stage, is adapted to optically sense the droplets and generate electrical signals useful in indicating analyte concentrations. 
         [0021]    In preferred systems, the saturation stage, condensation stage and sensing stage are provided by a condensation particle counter (CPC). These systems can use water, whose vapor has a relatively high mass diffusivity, as the working or condensing medium. Using water avoids the health and environmental concerns associated with butyl alcohol and other perflourinated hydrocarbons. This eliminates the need to supply, store and recover such fluids, and to separate such fluids from the water. 
         [0022]    When water is used as the working medium, the aerosol stream is saturated with water vapor and proceeds to a condensing region surrounded by wetted walls that are heated to provide a temperature higher than that of the saturated aerosol stream. Maximum supersaturation occurs at the center of the aerosol flow, given that the water vapor and heat both travel radially inward, and the mass diffusivity of water exceeds the thermal diffusivity of air. 
         [0023]    One advantage of using water as the working fluid in the CPC is a substantially higher threshold at which spontaneous nucleation (also called homogeneous nucleation) occurs, compared to a CPC in which working medium is butyl alcohol. An improved coincidence correction process also contributes to a considerably higher permitted particle throughput rate. As a result of these advantages, the concentration information is available virtually in real time, and can encompass concentrations ranging from a single part per trillion to ten parts per million in the single count mode. If desired, a photometric mode can be employed to increase the upper limit to over one part per thousand. 
         [0024]    Another aspect of the invention is a system for analyzing liquids. The system includes an analyte separator adapted to separate different analytes in a liquid sample primarily into different regions within the liquid sample, thereby to produce a separator output in which a plurality of different analytes are so separated. A nebulizer is fluid coupled to receive at least a portion of the separator output, and to generate an aerosol composed of droplets of the liquid suspended in a carrier gas. A conduit structure is provided for guiding travel of the aerosol in an aerosol stream away from a merger zone of the nebulizer. At least a portion of the conduit structure is permeable to the liquid, to promote an evaporation of the liquid and migration of the vapor through that portion of the conduit to an exterior thereof as the aerosol is conveyed along the conduit structure. The aerosol leaving the conduit structure is composed of residue particles of the analytes suspended in the carrier gas. A concentration indicating component is disposed to receive the aerosol leaving the conduit structure, and is adapted to indicate analyte concentrations based on the residue particles received. 
         [0025]    The concentration indicating component can comprise a droplet growth component disposed downstream of the conduit structure to receive the aerosol and merge the aerosol and a working medium vapor, to supersaturate the aerosol and thereby cause droplet growth through condensation of the working medium onto the residue particles. In this case, the concentration indicating component further includes a droplet sensing component, downstream of the condensation component, adapted to optically detect the droplets and generate electrical signals indicating analyte concentrations. 
         [0026]    The conduit structure can be incorporated into the nebulizer, or can be provided as a length of tubing running between the nebulizer and the droplet growth component, e.g. a condensation particle counter. A preferred material for the tubing or nebulizer interior wall is a copolymer available from E. I. duPont de Nemours and Company of Wilmington, Del. under the brand name “Nafion.” So long as the ambient environment surrounding the tubing or nebulizer is less humid than the aerosol, the liquid evaporates and migrates outwardly through the wall in a process referred to as “perevaporation,” resulting in a rapid drying of the aerosol stream. In addition to water, the Nafion tubing can remove alcohols, amines and ammonia from the aerosol stream. The more rapid removal of vapors can permit a considerably shorter aerosol pathway between the nebulizer and the CPC. A key feature of the Nafion conduit structure is that it facilitates vapor removal at lower temperatures, for improved detection of volatile analytes. 
         [0027]    The nebulizer can incorporate a heating element just downstream of the impactor, and an inlet downstream of the heating element for admitting dry air to dilute the aerosol stream and reduce the dew point of the liquid vapor. 
         [0028]    Another aspect of the invention is a system for analyzing liquid samples. The system includes an analyte separator adapted to separate analytes in a liquid sample primarily into different regions within the liquid sample, to produce a separator output in which a plurality of different analytes are so separated. A nebulizer is fluid coupled to receive at least a portion of the separator output in a merger zone thereof, to generate an aerosol composed of droplets of the liquid suspended in a carrier gas. An evaporation stage, downstream of the nebulizer, is adapted to substantially evaporate the liquid whereby the aerosol leaving the evaporation stage is composed of residue particles of the different analytes suspended in the carrier gas. An electrostatic selector is disposed downstream of the evaporation stage and adapted to selectively remove, from the aerosol, residue particles having sizes less than a predetermined threshold. A concentration indicating component downstream of the selector is adapted to generate analyte concentration information based on residue particles received from the selector. 
         [0029]    The concentration indicating component can comprise an optical particle counter adapted to cause growth of droplets through condensation of a working medium onto the residue particles, then optically sense the resulting droplets to generate indications of analyte concentrations. 
         [0030]    In one version of the system, the electrostatic selector comprises a unipolar electrical charging device, e.g. a corona discharge element generating multiple ions to merge with the aerosol and charge the particles. This is followed by an ion trap selectively biased to remove the ions and particles having higher electrical mobilities. In another version of the system, the selector comprises a neutralizer which applies a bipolar charge to the aerosol particles, followed by a differential mobility analyzer (DMA). An aspect of this version is that the DMA can be used to remove residue particles on both sides of a desired range of particle electrical mobilities, in effect setting an upper limit as well as a lower limit for particle retention. Either of these versions can be used to improve the response to volatile analytes. In addition, analyte concentration information can be generated by means other than optical particle counting. 
         [0031]    Yet another aspect of the invention is a device for generating an aerosol composed of multiple droplets of a liquid. The device includes a housing forming a mixing chamber having (i) a liquid entrance for receiving a sample liquid into the chamber, (ii) a primary orifice having a first diameter for receiving a pressurized gas into the chamber for merger with the sample liquid to generate an aerosol composed of multiple droplets of the sample liquid suspended in the gas, and (iii) a secondary orifice having a second diameter for conducting the aerosol out of the chamber. The second diameter is less than a major dimension of the mixing chamber taken in a direction substantially perpendicular to an axis of the secondary orifice, so as to restrict flow out of the mixing chamber to generate a back pressure in opposition to entry of the sample liquid and the pressurized gas into the chamber. 
         [0032]    In contrast to previous nebulizers in which the chamber exit is simply open to the downstream components with a diameter equal to that of the chamber, the exit orifice in the present nebulizer has a diameter less than that of the chamber, and more preferably less than half the chamber diameter. The diameter reduction provides a constriction which produces a higher kinetic energy mixing of the gas and separator eluent in the merger zone. As a result, the nebulizer generates smaller droplets. The secondary orifice also helps direct the aerosol towards the impactor raising the impactor efficiency 
         [0033]    Another factor reducing droplet size is a close axial positioning of an impactor, just downstream of the secondary orifice. The more closely spaced impactor removes a greater proportion of the larger droplets, reducing baseline concentration (noise) for improved dynamic range in generating analyte concentration data. 
         [0034]    In a preferred version of the nebulizer, the impactor axial spacing from the secondary orifice is adjustable through movement of the impactor. For example, a threaded mounting of the impactor to the nebulizer frame allows axial position adjustment by turning the impactor about its longitudinal axis. The average size of droplets in the aerosol leaving the nebulizer can be increased or decreased by respectively enlarging or reducing the axial spacing between the secondary orifice and the impactor. 
         [0035]    The droplet size also can be adjusted by changing or selecting the secondary orifice. Reducing the diameter of the secondary orifice is believed to increase back pressure and reduce droplet size. It has been found useful to provide a secondary orifice with a diameter larger than that of the primary orifice. The ratio of the secondary orifice diameter to the primary orifice diameter can range from slightly above one, to about two in versions that incorporate a secondary orifice. 
         [0036]    A further aspect of the invention is a device for optically detecting fine particles in an aerosol. The device includes a housing having an inlet for receiving an aerosol consisting essentially of substantially dry submicrometer residue particles suspended in a carrier gas, and a passage for conveying the aerosol in a steady stream through the housing along a saturation region and along a supersaturation region downstream of the saturation region. A holding component, disposed along the passage, is adapted to contain a condensing medium in liquid form and to release the condensing medium in vapor form as the aerosol is conveyed along the passage. A first temperature maintenance device, disposed proximate the passage along the saturation region, is adapted to maintain the saturation region substantially at a first temperature. A second temperature maintenance device, disposed proximate the passage along the supersaturation region, is adapted to maintain the supersaturation region substantially at a second temperature different from the first temperature. A controller operably associated with the temperature maintenance devices for selectively setting the first temperature, the second temperature, and a difference between the first and second temperatures, to selectively vary a nucleation threshold at which the particles are capable of serving as nuclei for condensation of the working medium to grow droplets. A droplet detector, disposed at a sensing location downstream of the passage, is adapted to sense the droplets resulting from said condensation as they pass the sensing location. 
         [0037]    In detectors (e.g. condensation particle counters) that use working media with mass diffusivities higher than the thermal diffusivity of air or another gas, the controller and temperature maintenance devices are configured to maintain the second temperature within a higher range than that of the first temperature, for a supersaturation region that is warmer than the saturation region. Conversely, in a CPC using lower mass diffusivity media such as butyl alcohol, the first temperature is maintained within the higher range to insure that the supersaturation region is cooler than the saturation region. In either event, the difference between the first and second temperatures can be selectively adjusted to influence droplet nucleation and growth. For example, increasing the difference between the first and second temperatures lowers the nucleation threshold, tending to increase the number of particles sensed and therefore counted. 
         [0038]    In another version of the device, the first and second temperature ranges are substantially overlapping, in which case the controller can be used to select either the saturation region or the supersaturation region as the warmer region. 
         [0039]    Thus, analyte measuring systems configured according to the present invention generate more reliable concentration information in virtually real time and over a wider range of residue concentrations. 
     
    
     
       IN THE DRAWINGS 
         [0040]    For a further understanding of the above and other features and advantages, reference is made to the following detailed description and to the drawings, in which: 
           [0041]      FIG. 1  is a block diagram of a liquid chromatography system configured in accordance with the present invention and employing high performance liquid chromatography; 
           [0042]      FIG. 2  is a schematic view of part of the system; 
           [0043]      FIG. 3  is a sectional side elevation of a nebulizer of the system; 
           [0044]      FIG. 4  is a sectional view taken along the line  4 - 4  in  FIG. 3 ; 
           [0045]      FIG. 5  is an enlarged view showing part of  FIG. 4 ; 
           [0046]      FIG. 6  is a sectional elevation of a condensation particle counter of the system; 
           [0047]      FIG. 7  is a graphical representation of certain electrical signals used in of the system; 
           [0048]      FIGS. 8 and 9  illustrate alternative embodiment condensation particle counters used with the system; 
           [0049]      FIGS. 10 ,  11  and  12  illustrate portions of alternative systems that incorporate particle selection features; 
           [0050]      FIG. 13  is a schematic view of an alternative arrangement for drying an aerosol as it is conveyed from a nebulizer mixing region; 
           [0051]      FIG. 14  schematically illustrates part of an alternative system with a “mixing type” condensation particle counter; and 
           [0052]      FIG. 15  illustrates part of an alternative system condensation particle counter incorporating photometric particle detection. 
       
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
       [0053]    Turning now to the drawings, there is shown in  FIG. 1  a diagram of a high performance liquid chromatography (HPLC) system  16  for identifying and measuring concentrations of non-volatile residue constituents dissolved in water or another liquid. The system includes a high performance liquid chromatography pump  18  for supplying water or another solvent as a carrier liquid (mobile phase) through a conduit  20  at a predetermined constant flow rate, e.g. 1 milliliter per minute. An injection valve  22  along conduit  20  is coupled to a syringe  24  containing a liquid sample and operable in stepped fashion to introduce substantially instantaneous injections of the liquid sample into the carrier liquid stream. The injections do not undergo any substantial mixing with the carrier liquid, but instead form plugs of the liquid sample that remain substantially separate from the carrier liquid. The liquid sample includes a base liquid such as water, acetonitrile (CH 3 CN), or alcohols, along with non-volatile residue and other analytes or constituents dissolved in the base liquid. 
         [0054]    Beyond valve  22 , the carrier liquid (mobile phase) and plugs travel at the predetermined flow rate into a high performance liquid chromatography column  26 . Column  26  includes a stainless steel tube loaded with a stationary phase, e.g. silicon beads as noted previously. The liquid sample plugs move through column  26  along with the carrier liquid. As each plug proceeds through the column, different constituents travel through the column at different rates, depending largely on their chemical attraction to the stationary phase as compared to their chemical attraction to the mobile phase. Materials having stronger interaction with the stationary phase tend to travel more slowly, as compared to materials having stronger interactions with the mobile phase. As a result, different constituents tend to become concentrated in different regions of each liquid sample plug as it travels through column  26 . Consequently, each plug as it leaves column  26  has distinct regions with different concentrations of different constituents, separated from one another temporally as well as spacially since the with liquid sample is moving at the predetermined flow rate as it leaves the HPLC column. 
         [0055]    A conduit  28  transfers either all or a predetermined fraction of the HPLC column output to a pneumatic nebulizer  30 . The nebulizer also receives air, nitrogen or another gas under pressure from a pressurized gas source  32 . Within nebulizer  30 , the liquid sample and compressed gas are merged to generate an aerosol including droplets of the liquid sample suspended in the gas. 
         [0056]    Most of the liquid provided to nebulizer  30 , over 95 percent and typically closer to 100 percent, is not used to form droplets, but instead is drained from the nebulizer through a waste conduit  33 . 
         [0057]    The aerosol stream is dried to reduce the aerosol droplets to suspended residue particles. Then the aerosol stream is provided to a condensation particle counter (CPC)  34 . As the aerosol travels through the CPC, it is first saturated with water from a working fluid supply  36 . Then, the aerosol is channeled through a condensation or supersaturation region in which the residue particles act as nuclei for condensation. The residue particles “grow” into considerably larger droplets that are optically detected and counted to generate non-volatile residue concentration information. The concentration information is provided to a microprocessor  38 . The microprocessor provides the information to a video display terminal  40  to generate a continuously updated record of non-volatile residue concentrations in the liquid sample. 
         [0058]    CPC  34  includes an exit  44  through which the aerosol is drawn by a pump  120  ( FIG. 2 ) out of the CPC. In addition, excess aerosol not used in the particle count and excess water are exhausted as noted in connection with  FIGS. 2 and 6 . 
         [0059]      FIG. 2  illustrates in more detail the portion of system  16  downstream of HPLC column  26 . The liquid output of HPLC column  26  is provided through a bulkhead fitting  46  into a merger zone  48  of nebulizer  30 , at a flow rate determined by the flow rate through the HPLC column and the fraction of the column output directed to the merger zone. In system  16 , a suitable flow rate is one milliliter per minute. 
         [0060]    Air from source  32  is provided through a solenoid valve  50  to a regulator  52  and measured using a pressure transducer  54 . Downstream, the air passes through a high efficiency particle air (HEPA) filter  56 , and then is supplied via an entrance  58  to merger zone  48  at a pressure of 30 psi and a flow rate of 0.6 liters per minute through a conduit  60 . Air also is provided to an aerosol conditioning zone  62  of nebulizer  30  through a conduit  64 . Conduit  64  includes either a valve or a control orifice  66  for limiting the air flow to a rate of about 2.7 liters per minute. 
         [0061]    Nebulizer  30  includes a reservoir  68  in fluid communication with the merger zone. The reservoir collects most of the mobile phase supplied through conduit  28 , i.e. the liquid not used to form the aerosol droplets. A pump  70  is coupled to the reservoir for evacuating the waste liquid from nebulizer  30 . 
         [0062]      FIGS. 3-5  illustrate nebulizer  30  in more detail. The inclined orientation shown is advantageous for liquid drainage and evacuation, although not critical. A housing of the nebulizer has several integrally coupled sections, including a stainless steel housing section  72  that encloses merger zone  48 , a steel housing section  74  forming the aerosol conditioning zone, and a housing section  76  providing the reservoir. Housing section  72  supports a fitting  78  for receiving the air or other compressed gas from conduit  60 . This housing section also supports an impactor  80 , through a threaded engagement that permits adjustment of the axial spacing between impactor  80  and merger zone  48 . 
         [0063]    With reference to  FIG. 4 , housing section  72  further supports a thermoelectric device  82  that functions to maintain a stable temperature of about 30° C. in the vicinity of merger zone  48 . More particularly, the thermoelectric device extracts heat from housing section  72  and transfers it to a heat sink  84 . The thermoelectric device also may function as a heater for the nebulizer. The constant temperature promotes consistent droplet formation. Housing section  72  further supports bulkhead fitting  46 , which secures conduit  28  used to transfer the sample liquid from HPLC column  26  to merger zone  48 . 
         [0064]    As best seen in  FIG. 5 , merger zone  48  takes the form of a cylindrical chamber in a Teflon orifice housing  73 . A sapphire orifice plate  86  defines an entrance or primary orifice to receive pressurized gas into the chamber from conduit  60 . A sapphire orifice plate  88  defines an exit or secondary orifice through which the merged liquid and gas leave the chamber. In addition, a liquid receiving entrance  90  conducts the sample liquid into the chamber. 
         [0065]    In one suitable version of nebulizer  30 , primary orifice  86  has a diameter of 0.006 inches, and secondary orifice  88  has a diameter of 0.008 inches. The chamber has a diameter of 0.020 inches, and an axial length, i.e. space in between orifice plates  86  and  88 , of 0.020 inches. 
         [0066]    More generally, the secondary orifice diameter is larger than the primary orifice diameter, yet less than the diameter of the cylindrical chamber. As compared to prior devices in which there is no secondary orifice and the chamber is simply open at the exit end, there is a back pressure due to the secondary orifice which increases the feed pressure to the merger zone and results in a higher kinetic energy mixing of the liquid and compressed gas. This advantageously results in smaller sample liquid droplets in the aerosol leaving the merger zone. 
         [0067]    As the size of the secondary orifice is reduced, the droplet size is reduced and the back pressure is increased. When the sample liquid is water, it has been found satisfactory to form the secondary orifice and the primary orifice at a diameter ratio of 2 to 1 as indicated by the diameters given above. For a sample liquid with a boiling point lower than water, the preferred diameter ratio is closer to 1, yet the secondary orifice remains larger than the primary orifice. 
         [0068]    The higher energy in the merger zone more effectively breaks up the liquid. The secondary orifice also appears to improve the efficiency of the impactor downstream. The ratios of primary and secondary orifice diameters can be selected to vary the pressure at the liquid entrance to the merger zone, relative to atmospheric pressure. Depending on the diameter ratio, air inlet pressure and liquid flow rate (as determined by the HPLC pump), the liquid pressure can be adjusted from below atmospheric pressure to a pressure nearly equal to the inlet air pressure. Keeping the liquid near atmospheric pressure is advantageous for reducing measurement errors due to outgassing. 
         [0069]    As seen in  FIG. 5 , impactor  80  is disposed coaxially with merger zone  48 , spaced apart in the axial direction from orifice plate  88 . The impactor cooperates with housing section  72  to form a thin, somewhat hemispherical path to accommodate the flow of air and droplets beyond the merger zone. The smaller droplets tend to follow the air flow, while the larger droplets tend to collide with impactor  80  and are removed from the aerosol stream. Thus, the aerosol moving into conditioning zone  62 , upwardly and to the right as viewed in  FIG. 3 , includes only those droplets below a size threshold determined largely by the axial spacing between secondary orifice  88  and impactor  80 . The size threshold is increased by increasing the axial spacing, and reduced by moving the impactor closer to orifice plate  88 . 
         [0070]    The droplets impinging upon impactor  80  may remain on the impactor momentarily, but eventually descend to reservoir  68  to be removed from the nebulizer as needed through pump  70 . If desired, impactor  80  may be formed of sintered metal to provide a porous structure that more effectively prevents the larger, impacting droplets from interfering with the aerosol flow. 
         [0071]    As the aerosol stream proceeds along conditioning zone  62 , it is heated by an electrical heating element  92  to a temperature of 35-100° C., depending on the mobile phase and analyte volatility. This evaporates the sample liquid, transforming the aerosol into a particle suspension rather than a droplet suspension by the time it reaches CPC  34 . A temperature sensor  94  at the end of conditioning zone  92  is operable in conjunction with the heating element to maintain the desired temperature within the conditioning zone. The aerosol is merged with the air flow from conduit  64  through a fitting  96  to provide a diluted aerosol flow of about 3.3 liters per minute to CPC  34 . Dilution reduces the dew point to sustain droplet evaporation and reduces the aerosol particle concentration as the aerosol leaves the nebulizer through a fitting  98 . 
         [0072]    With reference to  FIG. 2 , the aerosol proceeds from nebulizer  30  to an aerosol mixer  100 , and then to condensation particle counter  34 . 
         [0073]    A secondary gas may be introduced into nebulizer  30  at a location upstream of the nebulization region as indicated at  99  ( FIG. 2 ). The secondary gas sweeps dead space in the nebulization region resulting in a faster response, reduced axial diffusion, and less smearing of the output due to mixing. 
         [0074]      FIG. 6  illustrates condensation particle counter  34  in more detail. The CPC includes a droplet growth column  102  including a substantially rigid cylindrical outer wall  104  and a porous cylindrical inner liner or wick  106  formed of a ceramic. Wick  106  is adapted to receive and hold water or another condensation medium, and thereby provide vapor to an internal passage  108  surrounded by the wick. If desired, wick  106  can be mounted removably to facilitate inspection and convenient replacement. A lower, saturation region  110  of passage  108  is maintained at a near ambient temperature, e.g. at 20° C. A thermoelectric device  111  is optionally used to maintain the saturation region temperature. A heating element  112  is used to maintain an upper, droplet growth region  114  of the chamber at an elevated temperature, e.g. 60° C. As the aerosol from nebulizer  30  proceeds upwardly through passage  108 , it becomes saturated along region  110 . As the aerosol travels through region  114 , it becomes supersaturated with the vapor. All particles in the aerosol having at least a threshold size become nucleation sites for droplet growth due to water condensation. 
         [0075]    As the particles proceed upwardly through growth region  114 , two counteracting phenomena are at work. First, due to the elevated temperature the wetted wick generates increased water vapor, which travels radially inward away from the wick toward the center of passage  108 . This of course promotes condensation onto the particles. Second, as the aerosol is heated, the higher temperature tends to discourage condensation. However, because of the relatively high mass diffusivity of water vapor, the water vapor reaches the center of passage  108  more quickly than the heat. Consequently the particles and their immediately adjacent air, even while being warmed, remain sufficiently cool for supersaturation and the resulting condensation and droplet growth. 
         [0076]    A laser diode  116  and photodetector  118  are disposed above droplet growth column  102  proximate the aerosol stream. Each droplet alters or interrupts light transmission to the photodetector to generate an analog electrical pulse. The pulses are digitized and provided to processor  38 , and the pulse count yields the non-volatile residue concentration. 
         [0077]    With reference to  FIG. 2  as well as  FIG. 6 , a pump  120  draws the aerosol out of CPC  34  through a flow metering orifice  121  and provides it to a waste outlet  122 , along with a dilution air flow of about 0.8 liters per minute from a conduit  123 . A sample flow of the aerosol in the range of 100-300 milliliters per minute is provided to passage  108  from a CPC inlet  125 . Excess aerosol flows through an exhaust exit  127  to waste outlet  122 . The CPC receives the water or other condensation medium from working fluid supply  36 , preferably a 250-500 cc bottle. 
         [0078]    As seen in  FIG. 6 , CPC  24  includes a reservoir  124  fluid coupled to the working fluid supply through a solenoid valve  126 . Water is provided from reservoir  124  to wick  106 , to insure that the wick remains wetted to provide water vapor along the saturation and growth sections. The solenoid valve normally is closed. When a level sensor  128  in the reservoir senses that the water level in the reservoir has receded below a predetermined threshold, it opens valve  126  to replenish the water supply in the reservoir. Reservoir  124  can be provided with a fitting for draining excess water if desired. 
         [0079]    As noted previously, the use of water as the condensing fluid avoids health and environmental concerns associated with butyl alcohol and other perflourinated hydrocarbons in CPC  34 . 
         [0080]    A feature of CPC  34  is that when the particulate concentration increases, the sensitivity is reduced. One factor contributing to this result is that as more particles within a given volume serve as nucleation sites, the heat generated by condensation lowers the supersaturation ratio. This in turn raises the threshold (minimum particle size) for particle nucleation, improving the overall dynamic range of the detector. Another, more prominent factor is the increase in coincidence events with increased concentration. As each droplet intersects the coherent energy beam from diode  116  to generate the corresponding pulse, it also creates a time interval during which any other droplet also intersecting the beam is prevented from generating a pulse, and thus goes undetected. 
         [0081]    With reference to  FIG. 7 , the signal generated by a droplet intersecting the beam is represented by an analog pulse  130 . The broken line labeled “V DIS ” represents a threshold voltage for droplet detection. More particularly, the voltage V DIS  is provided to the negative input of a comparator amplifier  132 . The sensed analog voltage is provided to the positive input of the amplifier. The output of amplifier  132  is a series of digital pulses corresponding to the analog pulses. For example, digital pulse  134  has a pulse width “t” corresponding to the discriminator time for pulse  130 , i.e. the time interval during which the voltage of pulse  130  remains above the discriminator voltage. 
         [0082]    The digital pulses produced by amplifier  132  are provided to a resistance capacitance network having a resistance R and a capacitor having a capacitance C. The capacitor is charged during each digital pulse, i.e. whenever the output of amplifier  132  is at the high level. The RC network generates an output V DT  which increases with the charge to the capacitor. Accordingly, voltage V DT  represents the total discriminator time for a given sampling interval. Concentration is calculated every 0.10 seconds. 
         [0083]    The time constant for the RC circuit is preferably about equal to the signal sampling time, and considerably greater (by orders of magnitude) than the expected widths of the digital pulses. 
         [0084]    There is a tendency of V DT  to underestimate the actual dead time, and the tendency becomes stronger as particle or droplet densities increase. In accordance with the present invention, system  16  is tested with challenges of known particle sizes and concentrations to determine the relationship between particle concentration and network output V DT  to determine a correction function or constant. The resulting constant corrects V DT  to particle or droplet concentrations, and is stored to microprocessor  38 . Then, in conjunction with providing network output V DT  to the microprocessor, the stored function is applied to the voltage to determine particle concentrations. In general, the function is used to determine concentration based on a numerical particle count divided by a product of an adjusted sampling time and the flow rate, which is proportional to the concentration of non-volatile analyte exiting HPLC column  26 . The adjusted sampling time is determined by subtracting the discriminator time from the actual sampling time. Thus, a correction factor is applied to the numerical count to yield a higher concentration than the count otherwise would indicate, taking into account the factors noted above. 
         [0085]    In one preferred version of the HPLC system, the condensation particle counter can be tuned to exhibit a desired threshold size for droplet growth and a desired droplet growth rate.  FIG. 8  schematically shows a CPC  136  with a thermoelectric device  138  surrounding a droplet growth column  140  along a saturation region  142 , and a heater  144  surrounding the growth column along a droplet growth region  146 . A controller  148  is operable to individually set the temperatures of devices  138  and  144 , thus to set the temperatures in the respective regions. 
         [0086]    Controller  148  is used to adjust a saturation region temperature T S  and a growth region temperature T G  with respect to each other, as well as individually. An increase in the difference between temperatures T G  and T S  lowers the nucleation threshold, and thus increases the number of particles counted by the CPC for any given aerosol exhibiting a range of particle sizes. In addition, the rate of droplet growth can be increased by raising both temperatures T G  and T S  by a given amount, retaining the difference between these temperatures. This adjustment, likewise, tends to increase the particle count resulting from a given aerosol sample. 
         [0087]    In accordance with another aspect of the invention, the HPLC system includes a condensation particle counter equipped to use a variety of different working or condensing liquids, for example both water and butyl alcohol. Effective use of both of these fluids requires a reversal in the saturation region temperature T S  and growth region temperature T G . 
         [0088]    To this end,  FIG. 9  shows a CPC droplet growth column  150  including a saturation region  152  and a droplet growth or condensation region  154  downstream of the saturation region. An upstream thermoelectric device  156  surrounds the growth column along saturation region  152 . A downstream thermoelectric device  158  surrounds the column along the condensation region. A controller  160  is operably coupled to the thermoelectric devices to determine temperatures T S  and T G  along the saturation and growth regions, respectively. 
         [0089]    As noted above, the mass diffusivity of water exceeds the thermal diffusivity of air. As a result, particles traveling through droplet growth region  154  are being warmed, yet can serve as droplet growth sites because they remain sufficiently cool to condense the surrounding water vapor. 
         [0090]    In contrast, the vapor of butyl alcohol has a mass diffusivity lower than the thermal diffusivity of air. In this case, the saturating temperature T S  is set higher than the droplet growth region temperature T G . In this arrangement, although the tendency of the wick to generate vapor is reduced along the droplet growth region, this is overcome by the reduced temperature of the particles, which increases their capacity to serve as condensation sites. 
         [0091]    According to several alternative liquid chromatography systems, the dried aerosol is selectively modified to remove smaller more volatile components. For example,  FIG. 10  illustrates part of an HPLC system  160  in which a filter assembly  162  is positioned along the aerosol path between a nebulizer  164  and a condensation particle counter  166 . The filter assembly incorporates a series of diffusion screens  168  designed to entrap particles with high diffusion coefficients, i.e. particles sufficiently small to be driven in irregular paths due to random collisions with gas molecules. While larger particles tend to travel linearly through the diffusion screens, smaller particles tend to collide with the screen wires and are retained by surface-attractive forces. 
         [0092]    The number of diffusion screens  168  can be changed to selectively alter the size distribution of the aerosol particles leaving filter assembly  162 . In particular, increasing the number of screens captures and removes a larger proportion of the aerosol particles from the aerosol stream. As a result of this selective filtration, CPC  166  produces an increased signal response for volatile components. 
         [0093]      FIG. 11  schematically illustrates part of another alternative HPLC system  170  configured to electrostatically remove smaller particles from the aerosol stream between a nebulizer  172  and condensation particle counter  174 . In this system, a conduit  176  conveys the dried aerosol away from the nebulizer towards a merger zone  178  which also receives a carrier gas conveyed by a conduit  180 . A corona discharge needle  182 , biased to a voltage +V, applies a unipolar charge to the carrier gas, in this case creating positive ions. At merger zone  178 , the aerosol and the ionized gas combine to form positively charged reside particles and positive ions that travel downstream along a conduit  184 . 
         [0094]    An ion trap  186 , disposed along conduit  184 , includes an electrically grounded conductive cylindrical wall  188  and a conductive rod  190  electrically isolated from the wall. Rod  190  is negatively biased to a voltage −V to create an electrical field between the rod and the surrounding wall. 
         [0095]    As the aerosol passes through ion trap  186 , the electrical field causes the ions and the smaller particles, i.e. the higher electrical mobility components, to precipitate onto wall  188 . The larger particles tend to continue flowing downstream toward CPC  174 . 
         [0096]    The ion trap voltage −V can be adjusted to selectively increase or decrease the maximum diameter of particles removed from the aerosol by the ion trap. Also, it is to be understood that various modifications can be employed to yield the same result e.g. reversing the polarities of rod  190  and corona discharge needle  182 , biasing wall  188  in addition to or in lieu of rod  190 , etc. 
         [0097]      FIG. 12  illustrates another alternative approach for electrostatically removing selected particles from the dried aerosol stream before growing droplets, in particular a liquid chromatography system in which a dried aerosol stream emerging from a nebulizer  192  is conveyed through a charging device  194 , then through a differential mobility analyzer (DMA)  196  before reaching a condensation particle counter  198 . 
         [0098]    Charging device  194  may employ a radioactive charger, or oppositely charged unipolar elements such as corona discharge needles. In either event, aerosol entering DMA  196  has a uniform charge distribution. In a further alternative approach, a unipolar charger is used in lieu of device  194 . 
         [0099]    The DMA guides the aerosol along a path between a cylindrical outer wall and an electrically charged rod centered and coaxial with the wall. Ions and charged particles with polarities opposite to that of the rod are attracted toward to rod. Higher mobility components precipitate along an upstream region of the rod. Particles with low electrical mobilities precipitate along a downstream region of the rod. Components having electrical mobilities within a selected range between “high” and “low” travel through a slot in the rod between the upstream and downstream regions. The portion of the aerosol containing these midrange components is provided to CPC  198 . Thus, in addition to removing small particles, this approach entails removing larger particles as well, to confine the analysis to a particular desired range of particle sizes. 
         [0100]      FIG. 13  illustrates part of a further alternative system directed to reducing the length of the aerosol flow path between a nebulizer  200  and a condensation particle counter  202 . Nebulizer  200  is similar to the previously discussed nebulizers in that a sample liquid and a pressurized gas are provided through respective entrance conduits  204  and  206  to a merger zone  208 , from which the resulting aerosol is conducted downstream through a conduit  210 . 
         [0101]    In a departure from the previous nebulizers, conduit  210  is formed by a cylindrical wall  212  that is permeable to the test liquid and adapted to transfer the test liquid vapor to the ambient environment surrounding nebulizer  200  by a process known as perevaporation. To enhance the process, it is desirable to maintain a low relative humidity environment about the nebulizer, although transfer of the sample liquid vapor continues so long as the environment is less humid than the aerosol inside conduit  210 . 
         [0102]    While not illustrated in  FIG. 13 , a heating element can be disposed along conduit  210  to promote evaporation as in previous embodiments. In either event, evaporation of the sample liquid proceeds at a more rapid rate due to the transfer of the vapor to the outside environment. A satisfactory material for wall  212  is sold by E. I. duPont de Nemours and Company of Wilmington, Del. under the brand name “Nafion”. While removing water vapor in this fashion, conduit  210  is similarly adapted for rapid removal of other liquids such as alcohols, amines, and ammonia. Due to the more rapid removal of these liquids, conduit  210  can provide a considerably shorter aerosol path from the nebulizer to the CPC, and yet provide substantially dry residue particles to the CPC for droplet growth. Conduit  210  can be built into the nebulizer as illustrated, or alternatively can be provided as a separate component along the aerosol path from a nebulizer to a condensation particle counter. 
         [0103]    By allowing the test liquid paper to permeate through wall  212  to the ambient environment, conduit  210  tends to lower the dew point of the aerosol. This promotes evaporation without the need to raise the aerosol temperature. The ability to dry the aerosol without heating it considerably enhances the capacity of the system to measure more volatile analytes. 
         [0104]      FIG. 14  illustrates part of an alternative HPLC system in which a conduit  214  conveys a substantially dried aerosol from a nebulizer  216  to an optical particle counter  218 . A conduit  220  conveys pressurized air or another pressurized gas to the optical particle counter. A saturator  222 , disposed along conduit  220 , contains water, butyl alcohol or another working medium in liquid form. A heater  224  along the saturator raises the temperature of the gas, and at the same time promotes evaporation of the working medium to substantially saturate the gas. 
         [0105]    Upstream of optical particle counter  218  is a merger region fluid coupled to conduits  214  and  220  for combing the aerosol and the saturated gas. Due to its lower temperature as compared to the saturated gas, the aerosol upon merger tends to cool the gas, leading to supersaturation and condensation of the working medium onto the aerosol particles. This leads to the growth of droplets, which are optically sensed as before. 
         [0106]      FIG. 15  illustrates a feature that can be incorporated into any of the preceding condensation particle counters to enhance the dynamic range of the system involved. As represented schematically, a condensation particle counter  226  has a droplet growth column  228  disposed to receive dried particles of an aerosol and, through condensation of a working medium, provide as its output an aerosol including suspended droplets  230 . 
         [0107]    Downstream, a laser diode  232  generates a laser beam  234  that intersects the aerosol stream. Light scattered by droplets  230  is received by a photodetector  236  configured to sense droplets  230  individually, providing a signal via a line  238  to a processor  240  each time one of the droplets traverses a viewing volume determined by the intersection of laser beam  234  and the aerosol path. Photodetector  236  further is configured to sense multiple droplets simultaneously by generating an electrical signal having an amplitude proportional to the amplitude of light scattered in concert by multiple particles. This signal is provided to the processor via a line  242 . 
         [0108]    Photodetector  236  provides for high accuracy at low analyte concentrations, based on the droplet count over a given sampling time. When an analyte concentration becomes too high for individual counting, processor  240  is configured to use the active analyte concentration input from line  240 , i.e. the photometric measurement. 
         [0109]    Thus, in accordance with the present invention, a system for monitoring analyte concentrations in water and other liquids generates more reliable information virtually in real time, to facilitate more effective management of processes that depend on analyte identification and measurement. The system can be tuned to adjust nucleation thresholds and droplet growth rates, and accounts for coincidence episodes and thermal depletion to extend the useful range for generation of concentration data based on particle counts.