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Anal. Chem. 1984, 56, 2626-2631
Monodisperse Aerosol Generation Interface for Combining Liquid Chromatography with Mass Spectroscopy Ross C. Willoughby’ a n d R i c h a r d F. Browner* School of Chemistry, Georgia Institute of Technology, Atlanta, Georgia 30332
A monodisperse aerosol-based interface for ilquld chromatography/mass spectroscopy (MAGIC-LC/MS) Is described. The unlque features of the interface include the use of a monodisperse aerosol, evaporatlon of solvent at ambient temperature and near atmospherlc pressure, and the use of aerosol-beam gaslsoild separators for pressure reduction and solute enrichment. The Interface can be fitted to the dlrect inlet lock of any mass spectrometer and readliy permits operatlon In both electron impact and chemical ionlzatlon modes. Electron Impact spectra of several low-volatility compounds are found to be essentially Identical wlth reference (NIH) spectra. The Interface provides quanfitatlve, llnear response over more than 2 decades of Injected analyte mass and gives detection limlts In the nanogram range. When used for direct sample Injection without chromatographic separation, lnjectlon rates of up to 60 samples per hour can be achleved.
The mass spectrometer is probably the ideal detector for liquid chromatography, as it is capable of providing both structural information and quantitative analysis for separated compounds. The limitations to combining liquid chromatography with mass spectrometry have, however, made the development of suitable interfaces a major challenge. A number of on-line interfaces have been developed for highperformance liquid chromatography/mass spectrometry interfacing (HPLC/MS) (1-12), based on several operating principles. The subject has also been discussed in many reviews (13-18). Unfortunately, the fundamental incompatibilities which exist between the HPLC and mass spectrometry have still not been fully resolved. This has meant that many current interfaces involve a considerable degree of compromise in the operating conditions of either the chromatograph or the mass spectrometer. The development of an LC/MS interface that allows the use of a wide range of ionization modes, including electron impact, is clearly desirable. Electron impact (EI) ionization has not been fully exploited to date for on-line detection with HPLC, largely because of the difficulty in removing solvent from the analyte stream. Currently only the moving belt interface completely supports the E1 mode of ionization. Most LC/MS interfaces operate by using some “soft ionization” technique, which places considerably less demand on the efficiency of solvent vapor removal. The major limitation of such techniques is that much structural information is lost along with the ability to identify unknown compounds by comparison with reference libraries of E1 spectra. The interface described in this study (19) was conceived with several design objectives. The first, and most important, was to have the capability to produce electron impact ionization spectra similar to those obtained by direct probe sampling. The occurrence of minimal sample decomposition in Present address: Stuart Pharmaceuticals, Division of IC1 Americas, Wilmington, DE 19897.
the interface was also a requirement. Additionally, it was necessary that the solute should be transported efficiently to the ion source by using normal HPLC flow rates, with minimal chromatographic peak distortion. Further design objectives were the development of a simple system which would require no major modification to commercially available mass spectrometers or liquid chromatographs and compatibility with a wide range of solvents, including those used in reversedphase chromatography. An aerosol-based interface approach was attempted for several reasons: (1)Solvent can evaporate far more rapidly from drops than from bulk liquids, because of the great difference in surface area. (2) Drops do not significantly interact in flowing aerosol streams (20), and so minimal band spreading may be expected. (3) Production of an aerosol does not require a thermal desorption step as with solute evaporation from belts. Thermal desorption steps are undesirable as they have the potential for causing thermal degradation of the sample (4-7). While aerosol techniques have been widely used in other interfaces (2, 8, 10, 12), little emphasis has been placed on systematic study and control of the nebulization process. The interface developed in this study uses a monodisperse aerosol generator. Monodisperse aerosols exhibit highly uniform behavior, particularly in the rate of solvent evaporation. Appropriate control of this property should lead to efficient solute transport to the ion source while minimizing solvent transport. THEORY OF AEROSOL GENERATION, EVAPORATION, AND TRANSPORT Development of the interface necessitated fundamental studies in certain areas of nebulization, and pressure reduction. These topics will be discussed briefly here, with emphasis on theoretical principles. Some experimental studies that were necessary to verify the theoretical treatments will also be described. Generation. The interface developed in this study relies on the uniform breakup of a high-velocity cylindrical liquid jet, under the action of natural instabilities. When this approach is used, it is possible to produce highly uniform drops. With cylindrical-jet breakup, the energy for drop formation comes from the internal kinetic energy of the liquid stream producing the jet. Pneumatic nebulization, on the other hand, involves the breakup of a liquid stream through interaction with a high velocity gas jet, and the primary energy for the drop formation comes from the gas jet. The cylindrical-jet breakup process allows the control of many aerosol generation parameters that are not accessible with conventional pneumatic nebulization. First, the size of the drops can be selected by varying the jet diameter. Second, the direction of the jet can also be precisely controlled, using various steering techniques. Once the liquid has formed a cylindrical jet, the liquid will quickly break up into drops. The processes governing the breakup of the jet into drops depend upon the mode of interaction of the jet with the gaseous medium and the growth of specific disturbances on the surface of the liquid jet. Ex-
0003-2700/84/0356-2626$01.50/00 1984 American Chemical Society
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DROP DIAMETER (vm) Figure 1. Drop-size distributions for pneumatically and MAGgenerated aerosols. Fraunhofer diffraction measurements of aerosols generated from (0)Perkin-Elmer cross-flow pneumatic nebulizer, (a)monodisperse aerosol generator (MAG), 6-Hm orifice. Ordinate axis represents normalized mass of aerosol present in each measured size Interval shown on graph. I t should be noted that the size Intervals are not uniform.
perimental observation of liquid jet breakup was first reported by Savart (21). Rayleigh (22-24) showed that axisymetric instabilities on the jet surface, which exceed the circumference of the jet, grow exponentially. Eventually, a point is reached where the column of liquid is divided into detached masses separated by a common interval. Rayleigh determined the maximum degree of instability to be when X = 4.5080, where X is the wavelength of disturbance and D is the diameter of the liquid jet. In the development of a nebulization device for the production of monodisperse drops, the application of Rayleigh breakup would be ideal. Growth of instabilities of constant frequency on the surface of a jet would result in uniform breakup of the jet, forming drops with dimensions corresponding to the wavelength of maximum instability. There are two possible approaches to the use of Rayleigh breakup for aerosol production; one involves the artificial introduction of surface instabilities; the second allows random disturbances to cause the breakup of the jet, with certain preferred frequencies dominating. The first approach to jet breakup used in these studies was to artificially induce surface instability in order to select the exact frequency of liquid jet breakup and, consequently, control the drop size. It was later determined that the use of externally induced instabilities was unnecessary, and it proved possible to produce drops with a narrow size distribution from random breakup processes alone
(25). Figure 1shows drop-size distributions for two aerosols, one generated from a cylindrical-jet monodisperse aerosol generator (MAG) (25),the other from a typical high efficiency pneumatic nebulizer. The distributions were obtained on the primary aerosol a few millimeters beyond the point of generation, using a laser Fraunhofer diffraction technique. The MAG-produced aerosol has a much narrower size distribution than that produced by the pneumatic nebulizer and for practical purposes can be considered as monodisperse. The breadth of the distribution with the MAG is approximately *20%.
Coagulation. An important aspect of aerosol generation, that has been neglected in earlier interface designs, is the coagulation of drops which can take place rapidly after formation, unless corrective action is taken. This process can cause an initially narrow drop distribution to broaden soon after generation. Significant aerosol coagulation, which is likely to occur in any dense stream of drops moving at high velocity, will alter the size distribution of the jet and increase the loss of drops due to settling or impaction. Figure 2 shows
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DROP OIAMETER (vm) Flgure 2. Effect of coagulation on drop-size distribution: increasing distance from point of aerosol generation.
how the drop-size distribution of an initially monodisperse stream can shift significantly to larger drops, along the jet axis, as the observation distance from the jet orifice is increased. Initial breakup of the liquid jet occurs very close to the aerosol generator orifice. Therefore, it is necessary to disperse the drop stream soon after the Rayleigh breakup process occurs in order to prevent coagulation. A high-velocity has stream, introduced at 90° to the liquid jet, provides a simple means of dispersion. Evaporation. The first objective of any aerosol-based LC/MS interface is to efficiently separate solvent from solute. This requires optimization of conditions which favor solute enrichment without significant solute evaporation loss or thermal degradation. The rate of solvent loss is dependent on the processes of heat and mass transfer, which collectively control the overall rate of evaporation. Since the evaporation process requires a great deal of energy from some external source, the heat flow to the surface of the drop by conduction is of primary importance. Assuming the surface is saturated with solvent molecules, the rate of mass flow or diffusion away from the surface will also affect the evaporation process. At atmospheric pressures, the rate of evaporatidn is governed by the Maxwell equation (26). As the pressure of the drop surroundings is reduced, the transport of heat to the surface of the drop is also reduced; consequently,the evaporation rate decreases with pressure reduction. Therefore, the evaporation rate for a given drop should be greatest at pressures close to atmospheric. This concept led to the development of an interface with an atmospheric pressure desolvation chamber, which should allow more rapid desolvation of aerosol drops than low-pressure desolvation chambers. This topic is treated in greater depth elsewhere (27). Solute Transport and Solvent Removal. The decision to evaporate the drops at pressures close to atmospheric creates a problem in pressure reduction for the ion source. The introduction of dispersion gas at flow rates up to 1L/min, together with solvent vapor at flow rates up to hundreds of milliliters per minute, calls for an efficient method of gas removal frorfi the enriched solute particles. The most promising approach to separating particles from gases appears to be an aerosol beam technique. By this means, high-mass particles can be separaed from relatively low-mass gases when the aerosol is expanded into a vacuum, because of momentum differences. Murphy and Sears (28) were the first to generate aerosol beams, using this approach with smoke particulates. They used three successive vacuum chambers to isolate particles in the core of an expanded smoke aerosol. Israel and Friedlander (29)designed an aerosol-beam apparatus to study the effects of flow, pressure, nozzle configuration, and particle size on gas and particle flow through a skimmer. A prime objective
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ANALYTICAL CHEMISTRY, VOL. 56, NO. 14, DECEMBER 1984
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Figure 3. Schematic diagram of MAGIC-LC/MS. (Nl) nozzle 1; (N2) nozzle 2;(Sl) skimmer 1; (S2)skimmer 2. in the design of an aerosol-beam separator for an LC/MS interface was to minimize the expansion angle of the particle beam. This allows the use of small skimmer diameters, which in turn leads to greater pressure reduction in the ion source, while still maintaining efficient solute transport through the interface.
EXPERIMENTAL SECTION The complete LC/MS system (Figure 3) was composed of three sections: the liquid chromatograph, the interface, and the mass spectrometer. (The interface system described is the subject of a pending patent application.) Liquid Chromatograph. The chromatographic system used an LDC Constametric 11, dual-cylinder pump (Milton Roy, Riviera Beach, FL). All tubing was 1/16-inch stainless steel tubing, with zero-dead-volume fittings. A 2 pm pore size prepump filter was used to exclude coarse particles from the pump check valves. Sample solutions were injected by syringe into a six port valve (Valco), using a 50-pL sample loop. A 0.2 Fm pore size zerodead-volume preaerosol generator filter was additionally placed in line, as a precaution against possible orifice clogging from fine particles present in either the sample loop or the solvent stream. All studies in the development stage of the interface were performed by direct injection from the sample loop into the interface without using a column. For chromatographic separations, a column (150 mm X 3.9 mm i.d.) packed with octadecylsilica ( 5 - ~ m particle size) was used (Waters Associates, Milford, MA). Interface. The interface was configured in three sections: (1) aerosol generator, (2) desolvation chamber, and (3) two-stage aerosol-beam pressure reducer. Monodisperse Aerosol Generator. The monodisperse aerosol generator (MAG) (Figure 4) produces a dense, pencil-like aerosol in a laminar flow gas stream. This device has been described in more detail elsewhere (25). In essence, the MAG operates by letting high-pressure effluent from the chromatographic column pass through a small-diameter glass orifice to form a fine liquid jet. The jet breaks up under natural Rayleigh forces to form uniform drops, which are then dispersed with a gas stream introduced at right angles to the liquid flow direction. The glass orifices are drawn from a thick-walled capillary tube by initially heating one end until the walls collapse. The sealed tips are then opened by rubbing with 400-grade silicon carbide paper until an orifice of the desired diameter is obtained. Meticulous cleaning of the tips is necessary to remove particles on the inner surfaces. This is best carried out by a process of repeated ultrasonic bathing, rinsing, and air blowing. In some instances boiling in detergent baths was also necessary. The glass tips were sealed to the aerosol generator body with a Teflon gasket. In this study, tips with 10 wm i.d. holes were used, producing uniform drops of approximately 20-wrn diameter. The aerosol generator body was machined from 316-grade stainless steel, to minimize particle formation from corrosion of the metal surfaces which might cause partial or complete clogging of the aerosol generator tips. The aerosol generator chamber body was made from aluminum. A glass ball joint was attached to the aluminum body with epoxy, making removal from the desolvation
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@===!I t LC EFFLUENT
Figure 4. Monodisperse aerosol generator (MAG). chamber quite simple. O-ring seals allowed the chamber to be operated at pressures either above or below atmospheric pressure, as desired, while excluding air from the interface. The absence of air in the interface is desirable as it may cause rapid oxidation of the ion source filament. A coaxial stainless steel tube was entered at the base of the aerosol generator body (Figure 4). The inner tube carried the column effluent up into the glass tip. The outer tube allowed column effluent to bypass the orifice and proceed either to waste or to a secondary detector. When splitting was used, the split ratio was set with a needle valve (split valve in Figure 4). The MAG operates optimally in the range 0.1-0.5 mL/min. The low end of the range is controlled by the need to have adequate liquid velocity at the orifice to form a jet, and the upper end is set by the ability to adequately desolvate the aerosol in the interface. The LC pump used was not designed to operate at such low flows and showed substantial pulsing under these conditions. Consequently, the split valve was used in some studies in an attempt to reduce pulsing of the jet by allowing the pump to be run at 1-2 mL/min, with the excess going to waste. Splitting was not used in the determination of detection limits. The stream of drops emerging from the glass orifice was dispersed at right angles with a high-velocity gas stream. Effective dispersion called for accurate alignment of the gas and liquid streams. This was accomplished with an X-Y precision adjuster (Ealing Optical) attached to the gas jet. The adjuster moved on O-ring seals, thereby keeping the chamber gas tight. The position of the glass orifice was fixed. Desolvation Chamber. The dispersed drops move at high velocity and require sufficient time in the desolvation chamber to ensure effective solvent evaporation. The glass desolvation chamber was designed to allow evaporation to occur at or near atmospheric pressure, prior to pressure reduction. The chamber internal diameter (40 mm) was large enough to prevent impaction of the drops on the chamber walls. The length (30 cm) allowed adequate time for solvent evaporation, even for less volatile solvents such as water. Residual solvent within the solute particles was not of primary concern here. As will be discussed later, any such residue appears to have little influence on the ionization behavior of the species. Heating tape was also wrapped around the desolvation chamber. This served not t o raise the aerosol temperature above ambient but to replace the latent heat of vaporization necessary for solvent evaporation. Without some heating of the chamber, the exterior would sometimes frost up. The glass chamber was fitted with a glass ball joint, making operations such as alignment with the aerosol generator and disassembly quite simple. The aerosol, together with solvent vapor, entered a 0.25-in. stainless steel tube at the end of the chamber and proceeded through a ball valve into the aerosol-beam separators. The valve allowed the high-pressure part of the interface to be isolated from the vacuum region, if required. It thus facilitated necessary modifications to the aerosol generator, while avoiding the need to close the ion source valve. Aerosol-Beam Separator. Figure 5 shows the two-stage aerosol-beam separator, which allows pressure reduction from an
ANALYTICAL CKMISTAY. VOL. 56. NO. 14. DECEMBER 1984 SEPARATOR+ 1
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ngun 5. AaoaroCbeern q m r n i a . initial value close to atmospheric in the desolvation chamber to a final value close to 1V torr in the ion source. In addition to pressure reduction, the separator allows solute particles to be preferentially transferred through the system, while dispersion gas and solvent vapor are pumped away. This results in high analyteta-solvent enrichment. The aerosol-beam separator consists of two nozzle/skimmer devices, arranged in series (see also Figure 3 for labeling of nozzlea and skimmers). The separator was designed to allow ready interchange of nazles and skimmers. in order to test the effect of nozzle and skimmer diameters and shapes on the interface performance. The separation between each skimmer and nozzle could also he varied from 0 to 15 mm. The separator design was rather complex in this developmental model but gave the flexibility ne&88aTyfor system optimization. Two X-Y-Zdevice positioners were used for control of the nozzle-skimmer alignment under vacuum. Both 0-ringa and hall eeals were used to vacuum seal all moving surfaces. The nozzles and skimmers were made of glass sealed to metal surfaces with Teflon gaskets. The separation chambers were also made of glass, which allowed observation of aerosol flow, particularly important near the nozzle and skimmer surfaces. The following nozzle/skimmer internal diameters were used for the studies desnibed in this paper (Figure3): (1)evaporation chamber to first aerosol-beam separator chamber (Nl),0.5 mm; (2) fmt aerosol-beamseparator to second aeml-beam separator (Sl),1mm; (3) fmt aerosol-heam separator to second aerosol-beam separator (N2), 1mm; (4) second aerosol-beam separator to mass Spectrometer ion source (SZ),1 mm. Separations between the nozzles and skimmers were all set at 5 mm. The first aerosol-beam separator chamber wan pumped with a 303 L/min mechanical pump, which allowed the pressure to be maintained at between 2 and 10 torr, depending on the o p erating conditions. The seeond chamber was operated with a 150 L/min roughing pump, which maintained the pressure at between 0.1 and 1 torr. The Mass Spectrometer. The mass spectrometer ueed for all development work on the interface was a HewlettPackard 5930A dodecapole instrument, in which a single 5-in. diffusion pump evacuate9 both source and mass analyzer. Spectral scanning and all LC/MS runs were cnrried out on a Varian Mat 112s mass spectrometer, using a Spectrosystem 200 data system for mass spectral data storage and analysis. Laser-Scattering Drop-Size Memursments. Dropsize distributions of aerosols generated both pneumatidy and with the monodisperse generator were made by using a h e r Fraunhofer diffraction instrument (Malvern Instruments, Malvern, Worcestershire, U.K.).The noninstmive nature of the measurement and the ability to obtain good spatial resolution were particularly helpful in this work.
RESULTS AND DISCUSSION The analytical performance of the interfa- WBB studied for a number of solvent/solute mixhma Major pinta of interest were (1)the degree of similarity between E1 spectra generated with the present interface and reference E1 spectra, (2) the linearity of the system response for solvents of various polarity and volatility (Figures 6 and 7). (3) analytical precision, and (4) peak shape.
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Analyacal cvved fa varbu8 solutes in MeoH: (a) DloCtyl phmalate(mle 149). (b)naphtha*ne (m/e 128). and (c) bene (mle 78).
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mle Fimm 8. ElecWn hpact mass specburn of p h e n w a r i n e moohydrochlalde; sohrem, H,O.
Electron Impact Spectra. The ability of the interface to generate E1 spectra is illustrated in Figures 8 and 9 which show representative spectra (phenylhydrazine monochloride in H 2 0 and 2-propylquinezolin-4-one in MeOH) selectd from a wide range of compounds studied. The spectra were compared with NIH reference spectra and were found to be identical in all respects, within expected instrument-to-instrument variability. Other classes of compounds. including plant alkaloids, also gave classical E1 mass spectra effectively identical with those from direct probe introduction. Additionally, a number of compounds of relatively high volatility such as benzene and naphthalene were tested in order to determine whether theae would be transported with adequate
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efficiency to the ion source. All the volatile compounds tested gave good response and again generated standard E1 spectra. Quantitation. Analytical curves for dioctyl phthalate, naphthalene, and benzene in methanol are shown in Figure 6. The signals were obtained by single-ion monitoring at a suitable peak for each compound. Sample solutions were made by serial dilution of 1/1000 w/v standards. For simplicity, the sample loop was operated without a column, with 50-yL injections. All areas were normalized to account for variations in gain, full-scale voltage, and chart speed. Peak areas are expressed as an average of three to six sample injections. The error bars express iu.n-l. Relative error is expressed as (a,-,/average peak area) X 100. With the present interface, full mass spectral scans with electron impact ionization can readily be obtained for analyte concentrations in the range of 100 ng/s. Detection limits with single-ion monitoring, expressed as absolute mass in the injected sample, are in the region of 10 ng for low molecular weight compounds such as naphthalene and in the region of 1 ng for higher molecular weight compounds such as those shown in Figure 10 (50-yL injection). It can be seen that excellent linearity is obtained for all the compounds studied over approximately a 2 orders of magnitude analytical range. As anticipated, the slopes of the curves differ, indicating varying sensitivity of the ion source and detector for the different compounds. It is likely that the linear response actually extends over a wider range than that studied here, as no significant deviations from linearity were observed at the extremes of the ranges. Influence of Solvent. Figure 7 shows the effect of different solvents on the analytical curve for dioctyl phthalate (DOP). For all solvents studied, the response was linear over approximately 2 orders of magnitude. However, the relative peak area for a given concentration appeared to decrease with decreasing solvent volatility. The vapor pressures of hexane, methanol, and acetonitrile at 398 K are 270, 244,and 167 torr, respectively. As the response is solvent dependent, this would make quantitation more difficult when using gradient elution chromatography. There is no obvious explanation for the solvent volatility effect on the signal. However, this phenomenon may possibly be due to cooling effects of the more volatile solvents. Rapid evaporation would result in a sudden temperature drop of the solute, lowering its vapor pressure and, consequently, reducing solute evaporation in the desolvation chamber. Another possible explanation of solvent effects could relate to the ability of the mass spectrometer to pump the solvent vapor from the ion source chamber. There was no measurable difference in the observed source pressure with the use of different solvents. However, the base
Figure 10. Total ion chromatogram for mixture of enzyme substrates, separated on reversed-phase C18column, in 9010 MeOH/H,O mixture, UV detector trace included for comparison: (a) N - [ I-methyl-2-(phe-
nylthio)ethyl]acetamide, (b) N-[2-(@-hydroxyphenyl)thio)ethyl]acet-
amide. line had a slight negative slope when polar solvents were used at higher liquid flow rates through the aerosol generator. In addition to the DOP studies, interface performance was tested using aqueous buffer solutions. Typical solutions contained ammonium acetate or ammonium carbonate in water/methanol mixtures. No problems related to the interface were found with these solutions. The MAG showed no tendency to block, and solvent was as readily removed with the aqueous buffer solutions as with any of the other solvents tested. Problems of salt buildup in the ion source may be anticipated after extended operating periods, but these are not specific to the MAGIC-LC/MS interface. Influence of Solute Volatility. An important aspect of an LC/MS interface performance is the ability of the system to transport volatile as well as involatile solutes. Information from chromatographic separations of solutes with a wide range in volatility would be less valuable if the more volatile solutes were lost in the interface. Figure 7 shows response to be linear for benzene (bp 353.3 K), naphthalene (sublimes at ambient temperatures), and DOP (bp 657.2 K). These data show the ability of the interface to effectively transport volatile solutes in addition to low volatility or involatile solutes. Theory predicts that the efficiency of transport through the interface will be greatest for involatile solutes. Nevertheless, the ability of the system to also detect compounds with high volatility is a valuable attribute. Measurement Precision. The relative error for six replicate measurements was typically less than 5%. However, there are several trends in the precision measurements that are worthy of mention. Best precision was obtained at sample masses intermediate between the extremes of the range examined. For example, the data for dioctylphthalate in methanol (Figure 7, curve b) show that larger samples (2lW ng/s) give poorer precision than smaller samples. For example, the DOP/MeOH curve shows a 21% relative error for a 1300 ng/s injection, compared to a 3% relative error for a 280 ng/s injection. The relative error increased at low concentrations where background noise became significant. Long-Term Stability, The system was stable for extended operating periods. Thorough internal cleaning of the MAG orifice and LC transfer lines before assembly allowed the MAG to be run routinely without blockage for several weeks at a time. When operating under optimum conditions, day-to-day repeatability of peaks was approximately &lo%.
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Chemical Ionization Spectra. Chemical ionization (CI) spectra can be obtained with the MAGIC-LC/MS system as readily as for GC/MS measurements. Solvent removal is sufficiently complete that any desired reagent gas can be introduced to the ionization chamber and will generate CI spectra identical with those found with direct probe sample introduction. Methane and isobutane were both tested in these studies and generated the expected spectra. This flexibility allows the selection of the most appropriate gas for any particular analysis. Band Spreading. An important consideration with any LC/MS interface is the degree of band spreading that it may introduce. Band spreading may result from dispersion in either the liquid or aerosol streams. Liquid dispersion was kept to a minimum by the use of zero-dead-volume fittings. Aerosol dispersion was not anticipated to present any particular problem, as it has been demonstrated that band spreading in a laminar flow gas stream is generally less than for the equivalent distance traveled in a liquid stream (20). Repeated 50-pL injections from a sample loop, without a chromatographic column, showed band spreading of
