Supercritical Fluid Chromatography and Extraction 1996

Supercritical Fluid Chromatography and ExtractionT. L. Chester,* J. D. Pinkston, and D. E. Raynie

The Procter & Gamble Company, P.O. Box 538707, Cincinnati, Ohio 45253-8707

Review Contents

Fluid Behavior and Physicochemical Measurements 488RSupercritical Fluid Chromatography 488R

SFC Theory and Fundamental Measurements 488RMobile Phases 489R(Achiral) Stationary Phases and Columns 490R

SFC Instrumentation, Techniques, and Performance 490RPumping 490RSample Introduction 490ROther Instrumentation and Performance Issues 491RDetection 491R

(Achiral) SFC Applications 493RFats, Oils, and Other Lipids 493RMiscellaneous Food-Related Samples 494RNatural Products and Related Samples 494RAgrochemicals 494RFossil Fuels, Polycyclic Aromatic Compounds, andSynthetic Lubricants

494R

Synthetic Polymers and Oligomers 495R(Achiral) Pharmaceutical Agents and BiologicallyImportant Mixtures

496R

Organometallic Species and MiscellaneousApplications

497R

Chiral SFC 497RSupercritical Fluid Extraction 499R

SFE Theory and Fundamental Measurements 499RSFE Instrumentation, Techniques, andPerformance

499R

Solute Collection 500RExtracting Fluids 500R

SFE-Coupled Techniques 501RSFE/Chromatography 501ROther SFE-Coupled Techniques 501R

SFE Applications 501RFossils Fuels and Environmental Samples 501RPesticides and Herbicides 503RFoods and Fragrances 504RPolymers 506RNatural Products and Drugs 506RMiscellaneous Applications 507R

Other Supercritical Fluid Measurements and RelatedTechniques

508R

Literature Cited 508R

We are happy to report continued growth in both researchand the application of supercritical fluid chromatography (SFC)and extraction (SFE) techniques by analytical chemists. Newfundamental knowledge, new techniques, and many new applica-tions herald further growth in the technical success of analyticalsupercritical fluid techniques.

However, from the consumer-scientist perspective, one of thebig impediments in the growth of SFC and SFE techniques hasbeen the high price of commercial equipment. It has simply beentoo expensive for many laboratories to consider a purchase unlessthey had a specific, overwhelming need. Until recently, suppliershave generally offered only high-capability instruments at high

prices. The apparent marketing strategy among the moreestablished vendors of SFE instruments has been to increase thesophistication, automation level, and price. However, more simpleSFE instruments (with little automation and less expensivepumping) are available and are attracting many new users. Buyersof these entry-level instruments will no doubt return to the marketto meet their automation and capacity needs once they becomefamiliar and satisfied with the underlying technology. However,at the time of this writing, there is still no commercial, entry-level SFC instrument available in many large-market areasincluding the United States. In addition, some manufacturers havenot significantly improved the technical capabilities of theirproducts for years, ignoring even the inexpensive advances freelyreported by independent researchers. Users find it impossibleto perform at levels described by researchers in the literaturewithout the cooperation of their instrument supplier.

This critical review resumes from our last review (1) andcovers the literature reported in Chemical Abstracts throughOctober 1995. We have limited our review to noteworthy articlesusually available in technical libraries worldwide.

We have reviewed supercritical fluid and related techniques.Supercritical fluid techniques were originally distinguished fromconventional techniques by the use of temperatures and pressuresexceeding the critical values of the mobile or extracting phase.Today we often think such a distinction is both arbitrary andmeaningless. There are no rigid boundaries separating high-temperature LC, enhanced-fluidity LC, subcritical fluid chroma-tography (SubFC), SFC, and high-pressure GC as we progressdown this list, although there are some practical differences,particularly when comparing techniques not adjacent to eachother. Conventional LC and GC could, of course, be added totheir respective ends of the list. This would then seamlesslyconnect all (partition) chromatography techniques. The only newrequirement for the intermediate techniques is simply the ap-plication of sufficient pressure at the column outlet to preventinadvertant boiling or phase separation of the mobile phase whenthe temperature is raised or when a very volatile mobile phase ischosen.

This is not really a new requirementsthe column outlet isalready pressurized (to 1 atm) in conventional techniques like LC.Chromatography would have developed much differently if theaverage temperature and pressure of our planet were somewhatdifferent. We should not limit ourselves to such default conditionsand to the classical techniques when better selectivity or fasterdiffusion is available by making simple changes. We should alsopoint out that we can just as easily make a similar list for extractionbeginning with conventional liquid extraction techniques, ultrasonic-enhanced liquid extraction (where the temperature and pressureare raised in microscopic volumes of the sample), acceleratedsolvent extraction (where the temperature and pressure are raiseduniformly in a way to keep the liquid phase from boiling), SFE,steam distillation, and ordinary distillation.

Anal. Chem. 1996, 68, 487R-514R

S0003-2700(96)00017-0 CCC: $25.00 © 1996 American Chemical Society Analytical Chemistry, Vol. 68, No. 12, June 15, 1996 487R

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The critical point (or mixture critical point) of a fluid is verymeaningful in terms of fluid properties, but any single-phase fluidcan be used successfully as a mobile or extracting phase.Therefore, we strongly recommend that the term supercritical beignored, or at least discounted, and it should certainly not beinterpreted as limiting in any way.

FLUID BEHAVIOR AND PHYSICOCHEMICALMEASUREMENTS

In SFC, it is necessary to operate the mobile phase underconditions where phase separation does not occur from the timethe sample components reach the column until all the peaks arerecorded by the detector, even as pressure, temperature, orcomposition are changed either spatially or temporally, on purposeor by default. When a liquid sample is injected into an SFCinstrument, the phase behavior and mass transfer of the newmixture of sample plus mobile phase must be considered. In SFE,it is essential that separate matrix and extracting fluid phasesalways be maintained. Thus, understanding phase transitions influid mixtures is necessary for success.

Although most phase-behavior studies are done using viewcells and will not be reviewed, SFC and SFE techniques can alsobe used in these studies. Meier et al. directly coupled an SFCinstrument to a variable-volume cell to determine the compositionof mixtures of CO2 and R-tocopherol and compared the results tothose obtained using near-IR and gravimetric sampling methods(2). Kordikowski and Schneider, through a phase-behaviorinvestigation, determined the effect of quinoxaline and octanediolmodifiers on the extraction separation of decanol and decanoicacid using CO2 (3). Stadler used SFC measurements to predictCO2/hydrocarbon phase behavior (4). And Ziegler et al. used aflow injection procedure, essentially open-tubular SFC without astationary phase, to map the critical loci of binary mixtures of CO2

with 13 common solvents (5).Other thermophysical properties can be measured by SFC and

SFE. Cortesi, Spicka, et al. reviewed the use of SFC for measuringpartial molar quantities, interaction parameters, and diffusioncoefficients (6, 7). Cortesi et al. also determined the partial molarvolume of alcohols in CO2 using SFC. They showed that therelationship between partial molar volumes at infinite dilution andretention, which is strictly true at the mobile-phase critical point,is useful away from the critical point (8). Lee and Holdermeasured mass-transfer coefficients of solutes from packed bedsusing SFC (9). Zhao et al. reported their use of a microsuper-critical fluid extraction coupled to SFC to measure the solubilitiesof materials in CO2 (10). Coutsikos et al. used SFE-LC to measurethe solubility of phenols in CO2 (11). Johannsen and Brunnerdescribed an SFC system to determine solubilities in CO2 andmeasured the solubilities of theophylline and theobromine in CO2

(12, 13). Hansen and Bruno measured solubilities in supercriticalfluids by injecting saturated solutions into a liquid chromatograph(14).

Hitchen and Dean reviewed the properties of supercriticalfluids and their use in extraction and chromatography (15).Brunner covers the fundamentals of supercritical fluids and theiruse in separations in a new book (16).

SUPERCRITICAL FLUID CHROMATOGRAPHYThe most exciting and rapidly growing area in SFC is chiral

separations. In organizing the SFC section we have grouped allthe chiral references together rather than mixing them through

the sections on stationary phases, applications, etc. We will beginwith general SFC.

Several noteworthy reviews of SFC have recently appeared(17-20). Saito et al. edited a new book on SFC and SFE (21).Chapters of particular interest to new readers include fundamentalproperties of supercritical fluids (22) and fundamentals of SFEand of packed-column SFC (23).

Revillion looked at SFC along with several other methods toovercome shortcomings of size exclusion chromatography (24).We should point out that size exclusion chromatography can beperformed with supercritical mobile phases in some situations.

We reported last time of Ettre’s leadership in creating a newIUPAC nomenclature standard for chromatography (25). Smithproduced a supplement to the IUPAC standard adding additionalterms necessary to describe SFC (26).

SFC Theory and Fundamental Measurements. Shang etal. reported measuring enthalpies and entropies of transfer on SFCcolumns as a function of mobile-phase density and showed that apoint of intersection of extrapolated Van’t Hoff plots is character-istic of the stationary phase (27). Hagege et al. studied theretention of alkanes, alkylbenzenes, and chloroalkanes, relatingretention with various enthalpies. They concluded hydrophobicinteractions mainly control retention when using pure CO2 mobilephase and also described interactions between polar functionalgroups (28).

Yun et al. showed the importance of measuring the voidvolume in chromatographic systems (including SFC) in which amobile-phase component may become part of the stationary phasethrough adsorption. This work defines different types of voidvolumes and adsorbed-phase volume, discusses excess and totaladsorption, and reviews experimental methods (29). Liu et al.used tracer pulse chromatography to measure the decrease invoid volume caused by four different mobile phases adsorbed toa stationary phase of a chromatographic column at 77 K (30).Volumetric isotherms were generated, and the values of the vander Waals b constants for four mobile phases were estimated andfound in agreement with accepted values. While the experimentaltemperatures were much lower than what is used in SFC, themobile-phase densities are similar. This work certainly makesus reconsider the stationary phase and how it might change whenthe density of the mobile phase is varied. Berger reported thatplots of log of the retention factor vs density in packed-columnSFC, combined with van Deemter curves, suggest the formationof a thick film of adsorbed mobile phase on the stationary-phasesurface (31). Afrane and Chimowitz used the Bragg-Williamsapproximation for molecular interaction and correlated andpredicted the adsorption of high-pressure supercritcal CO2 incontact with various chromatographic stationary phases (32).

Retention and Selectivity. Lesellier et al. characterized 29 ODSstationary phases with carotenoids and PAHs and determined themechanism of carotenoid retention in LC and SubFC. This workilluminates retention differences in planar and nonplanar com-pounds and shows the similarity between LC and SubFC (33).We already know from numerous studies that there is nodiscontinuous transition between SubFC and SFC. Wang et al.studied the retention of homologs in SFC (34). Hadj-Mahammedet al. studied the retention of flavones on open-tubular SFCcolumns (35). Larkins and Olesik studied the effect of soluteshape for stilbene and stilbene-like solutes on retention by a glassycarbon stationary phase. They concluded the extent of π-π

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interactions between the solutes and the stationary-phase surfacewere controlled by solute shape (36).

Gonenc et al. investigated the effects of temperature, pressure,and mobile-phase density on solute solubility and retention in SFC.Mobile-phase partial molar volumes of solutes were determinedand linked to pressure dependence of retention. This work, inturn, indicates solute/stationary-phase interactions (37). Ibanezet al. studied the effects of temperature and density on micro-packed columns in SFC. Their use of column diameters less than1 mm, combined with highly porous, large-diameter (greater than100 µm) packings, results in columns with very high permeability(38). Heaton et al. developed a packed-column SFC retentionmodel based on solubility parameters. The model treated phenyl-substituted solutes, five different stationary phases, and methanolmodifier up to 20% in CO2 (39). Hagege et al. compared theretention of cyanoalkanes and cyanoalkylbenzenes to alkaneretention on alkyl and cyanoalkyl-bonded stationary phases. Theyfound silanophilic interactions with the underlying silica to beimportant in the retention mechanism (40). Jones et al. investi-gated the effect of temperature (at 80 and 150 °C) on selectivityfor a variety of probes on eight stationary phases in open-tubularSFC. Selectivities for polar stationary phases were highly tem-perature dependent, but nonpolar phases showed only smalltemperature dependence (41). Kot et al. demonstrated selectivitytuning in packed-column SFC and developed a method to separate16 polycyclic aromatic hydrocarbons (PAHs) in under 7 min (42).Hanson found much larger selectivity shifts using polar packingsthan using nonpolar packings with variations of pressure, tem-perature, and modifier. This resulted in a loss in resolution atlow densities with polar stationary phases for the particularsteroids used as model solutes combined with the particularstationary phase used (43). This work further emphasizes thatselectivity can be easily and widely tuned in SFC.

Lee and Olesik found that elevating the temperature inenhanced-fluidity LC results in large increases in solute diffusioncoefficients which improve separation efficiency and shortenanalysis time. However, they also found that selectivity (amongPAHs) decreased as the temperature was raised. They showedthat an isocratic enhanced-fluidity separation could produce thesame quality separation of PAHs in about the same time asgradient-elution LC (44).

Unified Chromatography. This technique bridges all partitionchromatography, essentially combining the characteristics of LC,SFC and the other intermediate techniques, and GC together.Martire et al. continued their development of a unified theory ofchromatography (45, 46). Robinson et al. built a unified chro-matograph to perform GC followed by SFC on the same column.This allowed the elution by SFC of sample components retainedthroughout the GC conditions (47). Shen et al. examined theretention behavior of carboxylic acid methyl esters in SFC andfound that the results fit well with a theory of unified chromato-graphic retention (48). Tong and Bartle found that band broaden-ing can occur during the mobile-phase change in unified chro-matography and showed how to minimize this through optimization(49).

Pressure Drop and Efficiency. There continues to be a varietyof conclusions regarding the effect of column pressure drop inopen-tubular and packed-column SFC. Cramers et al. numericallydescribed efficiency in packed and open-tubular SFC columns.Density gradients over the length of the column result in changes

in the retention factor, but velocity and diffusion coefficientchanges also occur. The net effect is that open tubes have fairlyuniform efficiency and packed columns have increasing plateheight along the column (50). Blomberg et al. reviewed theperformance of open-tubular and packed-column SFC (51). Theymentioned using evaporative light scattering as a means ofuniversal detection with modified mobile phases and showedexamples of mobile-phase composition programming. Theyconcluded that open-tubular columns are preferred for separatingcomplex mixtures and isomers and for applications requiring neatCO2 as mobile phase. Open-tubular columns can produce highplate counts, but analysis times are relatively long in such cases.Packed columns can produce much faster separations, but, theyreport, pressure drop prevents the generation of high platenumbers. This is contrasted by Berger and Blumberg, who reportthat under practical conditions efficiency losses do not occur inpacked-column SFC (52). Koehler et al. examined the influenceof mobile-phase velocity, column length, and pressure drop inpacked-column SFC. They found that there was no detrimentaleffect caused by pressure drop and that efficiency can be increasedwithout significant penalty by using longer columns (53, 54). Oneway to minimize pressure drop in packed columns is to preparecolumns with large particles and low packing densities. This isthe approach reported by Ibanez et al. (38, 55, 56). They havemade micropacked columns with pressure drops near that oftypical open-tubular columns. Karlsson et al. investigated howretention data from single open-tubular (OT) SFC columns couldbe used to predict retention on coupled columns. Good agree-ment resulted without the need to correct for pressure drop (57).Jaermo et al. also investigated the effects of pressure drop onserially coupled OT-SFC columns (58).

Mobile Phases. CO2 and modified CO2 mobile phases forSFC have always had the disadvantage of poorly dissolving manypolar solutes, particularly those having high water solubility.However, the diffusion rate benefits of SFC can be approachedwith enhanced-fluidity chromatography, where CO2 or anotherviscosity-reducing modifier is added to a liquid mobile phase. Therequired instrumentation is identical to SFC instrumentation,mainly because of the requirement of elevating the pressure atthe outlet to keep the mobile phase from phase separating. Cuiand Olesik have recently applied this approach to reversed-phaseLC with methanol/water/CO2 mobile phase resulting in significantefficiency and analysis time improvements (59). This approachrequires knowledge of the phase behavior of the mobile phase inorder to appropriately specify pressure and temperature limits.

Blackwell and Schallinger investigated the eluotropic strengthand selectivity of fluoroform compared to CO2 and CO2/methanolfor the analysis of naphthalene derivatives. They found thatfluoroform is much stronger than the other mobile phases at thesame temperature and pressure but is weaker under the samereduced conditions (60). These authors also investigated hydro-fluorocarbon and perfluorocarbon mobile phases. They found theperfluorocarbons studied to be much stronger than CO2, CO2/methanol, and fluoroform (61).

It is common to see binary mixtures, such as CO2/methanol,offered premixed in cylinders for use as SFC mobile phase orSFE fluid. Via et al., however, showed that the composition ofthe fluid delivered changes as the cylinder contents are consumed.The modifier concentration in the delivered fluid more thandoubled over the use life of the cylinder (62). This suggests that

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work requiring accurate (or precise) fluid compositions mayrequire dynamic mixing in a two-pump system or careful mixingof each charge individually when a single syringe pump is used.

Raynie et al., used ammonia as the mobile phase in investigat-ing the chromatographic performance of an (ethylvinyl)benzene-divinylbenzene polymeric stationary phase (see the next section)(63).

(Achiral) Stationary Phases and Columns. Much workhas been done developing and evaluating chiral stationary phases.Please look at the Chiral SFC section for a summary of thisinformation.

Steenackers and Sandra reported coating 25- and 50-µm-i.d.columns with films of SE-54 up to 2 µm thick (64). Such thickfilms add needed sample capacity to narrow columns but, ofcourse, increase retention and increase pressure requirementsof the SFC instrument. Solute retention factors would be ∼10times larger than with columns having more conventional 0.1-0.25-µm film thicknesses used at the same temperature andpressure. Thus, thick-film columns will hardly be practical untilsignificantly higher pressures are made available on commercialOT-SFC instruments.

SFC has long been successfully used for the analysis of fatsand other lipids. Additional information on double-bond numberand position requires stationary phases with increased selectivityfor those features. Dobson et al. published a general review ofargentation methods, including SFC (65). Blomberg and Demi-buker used argentation SFC to separate triacylglycerols of sampleslike rapeseed and fish oil (66). Tanaka et al. described a stationaryphase of silver-loaded ceramic for SFC. They successfully usedthis to purify docosahexaneoic acid ethyl ester from tuna oil bysemipreparative SFC (67).

Raynie et al., using ammonia as the mobile phase, investigatedthe chromatographic performance of an (ethylvinyl)benzene-divinylbenzene polymeric stationary phase. Although there wassome loss in efficiency after exposure to ammonia, this polymericphase was much more stable than conventional silica-basedpackings (63).

Engle et al. used a low-temperature method to generate glassycarbon on fused-silica tubes and evaluated them using SFC (68).

Micropacked Columns. There has been considerable interestin developing SFC columns that overcome the complaints of fairlylong analysis time and low sample capacity characteristic of open-tubular SFC columns. Packed capillary columns promise bigimprovements in these features if packings can be developed withthe same degree of inertness as typical OT-SFC stationary phases.Malik et al. described packed fused-silica columns for SFC in therange of 0.5-10 m in length. They compared conventionalpacking methods with a supercritical CO2 slurry method whichproduced columns both more stable and with better chromato-graphic performance. Efficiencies of over 240 000 theoreticalplates were realized (69, 70). Tong et al. described a similarmethod to produce packed-capillary columns for SFC and LC (71).Haegglund et al. packed a capillary with 8-quinolinol-modified silicaparticles. This stationary phase performed well when a polarmodifier was used in the mobile phase. Selectivity could befurther improved by loading the stationary phase with metal ions(72).

SFC INSTRUMENTATION, TECHNIQUES, ANDPERFORMANCE

Pumping. Early SFC systems usually used syringe pumpsfor delivering mobile phase. Most open-tubular SFC systems stilldo. When flow splitting was required for sample introduction,90% or more of the mobile phase was vented to waste in theinjector. This required high-pressure pumps of 100-250-mLvolume to contain enough mobile phase for a few hours of workwithout refilling.

These pumps are expensive, so effort was justified in exploringways of controlling modifier addition that do not require a secondpump. Saturator devices are one approach that has been triedby several researchers. Goerner et al. recently reported a simpledevice to prepare binary mobile phases based on achievingequilibrium in a saturator (73). Pyo and Ju used HPLC filters todynamically add water or methanol to CO2 (74-76). Theyreported a Teflon high-capacity filter could sustain a constant wateraddition much longer than a saturator column (75). Page et al.used a saturator column to add water to CO2 and produced a watergradient by thermostating the saturator and programming thedensity of the CO2 at the saturator inlet (77).

Ashraf-Khorassani and Levy used a low-cost microbore recip-rocating pump to introduce modifier (78). Francis et al. used ahigh-pressure pulsed valve to introduce methanol modifier into aCO2 mobile-phase stream. The entire apparatus required only onepump (79). Many HPLC pumps can pump CO2 adequately forresearch purposes if the heads are cooled. Workers often simplyput an aluminum pie pan under the pump heads and apply ice.Hancock showed that a Peltier cooling device also works well (80).

Packed-column SFC is usually done today with HPLC-likereciprocating or diaphram pumps. Modifier is simply addedvolumetrically with a second pump. These pumps are notinexpensive, but users coming to SFC from previous HPLCexperience do not seem to mind a two-pump system. OT-SFCno longer requires the big and expensive syringe pumps ifinjection is performed without flow splitting. Several suitableinjection options are described later. Without flow splitting, asyringe pump with just a 10- or 20-mL volume would operate manyhours without requiring refilling. Thousands of dollars could beremoved from the price of an OT-SFC instrument, and thecapabilities improved significantly, if a low-volume pump withhigher pressure capability than today’s offerings were madeavailable on turnkey OT-SFC systems.

Sample Introduction. We hinted earlier that flow-splittinginjection is no longer often used. Many workers also considertimed-split injection obsolete, although it is still practiced widelyin OT-SFC. Both of these sample introduction techniques limitinitial band spreading by keeping the effective injection volumein the low-nanoliter range. Such small sample volumes make traceanalysis impossible with typical detectors. So, work in OT-SFCsample introduction has been aimed primarily at increasing theeffective sample volume, and perhaps secondarily at avoiding thequantitation uncertainties introduced by the older sample-splittingtechniques.

Greibrokk et al. have led in the development of solvent-ventinginjection for OT-SFC. Their techniques allow automated injectionsof microliter volumes (81-83). Cortes et al. have developed avery powerful injection technique for OT-SFC in which the samplesolvent is eliminated in a venting arrangement; then the solutesare transferred with CO2 and pressure focused near the analytical


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column inlet. This technique accommodates injection volumesup to 100 µL with excellent precision. Unfortunately, thistechnique is not commercially available and is described in arecent patent, leaving the possibilities for widespread adoptionuncertain (84). Chester and Innis demonstrated an inexpensive(virtually free) direct injection technique using a retention gap.By paying attention to the phase behavior of the sample solvent/mobile-phase mixture, a flooded zone is created within theretention gap. The solvent is then evaporated and removedthrough the column, the solutes refocused at the column inlet,and the chromatography performed as usual. Sample volumesup to 0.5 µL were demonstrated without splitting, achieving peakheight and area relative standard deviations of 0.6-1.8% (85).

Daimon and Hirata developed an on-line SFE/OT-SFC systeminvolving trapping of the solutes in the interface (86). Hirata andPawliszyn described an injection procedure in which a polymer-coated fiber is exposed to liquid sample to absorb solutes. Thefiber is then removed and placed in a piece of tubing for desorptionto an OT-SFC column to accomplish a solvent-free solute transfer(87). Ullsten and Markides combined solid-phase extraction andSFE to introduce samples dissolved in polar solvents onto an SFCcolumn. Sample volumes were ∼10 µL (88).

Packed-column SFC injection is still practiced fairly straight-forwardly by most users. Injection volumes in the tens ofmicroliters or more can be routinely accommodated by 4.6-mm-i.d. columns. Arnold and Kleiboehmer described an injectionsystem using a solid-phase extraction cartridge to receive up to100 µL of sample. The sample solvent was evaporated withnitrogen and vented. Then the solutes were transferred to theSFC column with mobile phase (89). Zegers et al. used a similarapproach in which a precolumn is loaded with aqueous sampleand dried with a nitrogen flow. The precolumn was next desorbedwith SFC mobile phase and the solutes were focused at an SFCpacked-capillary column inlet. The largest sample injectionreported was 47 mL, resulting in a detection limit of 0.1 ng/L fora pesticide using thermionic detection (90). Games et al. alsodescribed a solute-focusing sample introduction technique forpacked-column SFC (91).

Gretier et al. (92) and Hirata et al. (93) described solventevaporation techniques for large-volume sample injection inpreparative SFC. Bruno described the use of a vortex tube forcryofocusing and cryotrapping of sample components in SFE andSFC applications (94, 95).

Other Instrumentation and Performance Issues. Changesin the practice of SFC are slowly rendering the older referencematerial obsolete. Two more recent reviews of SFC instrumenta-tion have been published by Greibrokk (96) and by Saito andYamauchi (97).

Postcolumn pressure control is now widely used in packed-column SFC. When the detector can be pressurized, the pressurecontrol device is usually postdetector as well. This downstream/pressure control approach allows control of the outlet pressurewhile the mobile-phase velocity on the column is independentlycontrolled by operating the pump(s) in a controlled-flow mode.(The column inlet pressure becomes the dependent variable.) Thispractice not only provides simultaneous control of both outletpressure and flow rate but also allows volumetric mixing ofmodifier with a two-pump system. Verillon et al. described sucha system (98).

When a passive restrictor is used downstream from the columnto maintain pressure and limit mobile-phase flow, the mobile-phasevelocity on the column is not directly controlled but variesaccording to the inlet pressure and the resistance provided bythe restrictor. The mobile-phase velocity can therefore changeduring programming. Several efforts have been undertaken todevelop programmable restrictors to allow some adjustment ofvelocity in these upstream/pressure control situations. Pyodescribed a two-stage restrictor for pressure- or density-pro-grammed SFC in which the first stage used a temperture-controlled, 7-µm-i.d. tube. It was followed by a linear restrictor.The temperature of the first stage was programmed during thechromatogram to keep the mobile-phase velocity constant (99).Pyo also described a parallel flow path restrictor which was alsotemperature-controllable (100). Vejrosta et al. described andcharacterized a multichannel restrictor (101).

Grover et al. looked at the problem of optimizing SFC whenattempting to achieve adequate resolution with short analysistimes. A numerical model for solute adsorption was used inconjunction with a spatial temperature profile (102). Wenclawiakand Hees compared SFC with optimized HPLC for the separationof 16 PAHs (103).

Smith and Briggs examined the influence of the sample solventchoice and several instrument design features on peak shapes inpacked-column SFC. They found that memory effects caused byadsorption of polar solutes could be eliminated with the appropri-ate use of a modifier (104).

Preparative SFC. Bartle et al. built a large-scale SFC systemand separated fluorene and phenanthrene and a complicatedmixture of milbemycins (105). Brunner and Upnmoor scaled upand studied the SFC separation of tocopherols and prostaglandins.They found that for tocopherols SFC had more capacity than asimilar LC system (106). Cretier et al. compared preparative LCand preparative SFC for separating components in a 25:1 ratio.They found the techniques complementarysLC was easier whenthe minor component eluted first, but SFC was easier when theminor component eluted second (107). Perrut reviewed large-scale SFC, including an analysis of hydrodynamics and adsorp-tion/desorption processes. He concluded that large-scale sepa-rations in pharmaceuticals and fine chemicals will emerge at anincreasing rate in the near future (108). Bevan and Mellishreviewed the considerations necessary to scale-up an SFC separa-tion, including fluid choice, safety, sample introduction, fractioncollection, and mobile-phase recovery (109). Cretier et al. studiedthe competition between solutes in preparative SFC in overloadsituations and the influence on solute peak shape (110). Jus-forgues reviewed large-scale SFC in two reports (111, 112).

Detection. Spectroscopic detection such as mass spectro-metric and infrared absorbance have long been used in SFC, butrelatively few accounts of on-line nuclear magnetic resonance(NMR) detection, potentially one of the most informative detec-tors, have appeared. This may change in coming years. Albertet al. developed a new high-pressure probe for on-line, high-fieldSFC/1H NMR and applied this technique to mixtures of phthalates(113) and acrylates (114). The advantages of HPLC/1H NMRwere described by Albert in a further review (115). The wholeproton spectral range can be observed in SFC/1H NMR with CO2

as mobile phase, without a solvent “window”, unlike HPLC/1HNMR.


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A number of groups continued their work in coupling SFC withFourier transform infrared absorbance (FT-IR) detection. As inprevious reviews, two avenues were explored: direct deposition(solvent elimination) and flow cell detection. Morin describedboth approaches and presented a new, low-volume flow cellintended for 50-µm-i.d., open-tubular SFC columns. Gram-Schmidt reconstruction and spectral subtraction were used toenhance detection despite spectral background changes due todensity programming (116). Kirschner and Taylor compared Xeto CO2 mobile phases in packed-column SFC/flow cell FT-IR(117). Despite xenon’s ability to transmit the full IR spectrum,both mobile phases produced equivalent spectral and library-searching results with standards. However, Xe is a poorer mobilephase for polar analytes and is far more expensive. Jenkins et al.explored multidetector, open-tubular SFC involving FT-IR, inparticular the influence of the flow cell size on chromatographicresolution (118). A 500-nL flow cell was acceptable for 50-µm-i.d. columns, while a 980-nL cell was not. Plant extracts wereexamined using open-tubular SFC/UV/FT-IR/FID. Gurka et al.explored the differences between GC- and SFC/direct-depositionFT-IR (119). Minimum identifiable quantities (MIQs) in the lownanograms were achieved. The greater molecular weight rangeof SFC was clear in a comparison with poly(ethylene glycol)s.Norton and Griffiths reported subnanogram MIQs with SFC/direct-deposition FT-IR of a strong IR absorber (600 pg of caffeine)(120). They also described other performance characteristicssuch as linearity with strong and weak absorbers.

Mass spectrometry is one of the earliest used, and arguablythe most informative, spectroscopic detection methods in SFC.The interface/ion source configurations can generally be dividedinto two groups: low flow rate (up to ∼15 mL/min of expandedCO2) and high flow rate interfaces. The “direct-fluid-introduction”(DFI) interface, where the effluent is admitted directly into anelectron ionization or chemical ionization ion source, is the mostcommon low flow rate interface. It is used for open-tubular andpacked-capillary SFC. The high flow rate interfaces are used formicrobore and standard packed SFC and are generally modifiedversions of interfaces developed for LC/MS. Among those dealingwith low flow rate interfaces, Becker demonstrated a DFI interfacewith improved temperature stability (121). Pinkston and Bowlinginvestigated the use of cryopumping to improve performance inopen-tubular SFC/MS (122). Cryopumping was shown to en-hance signal by a factor of 5 in some cases. Cryopumping waslater used to assist in the identification of high molecular weightcomponents of olestra, a mixture of fatty acid sucrose esters (123).Buecherl et al. built and tested an interface, incorporating a secondrestriction and a stage of pumping between the SFC restrictorand the ion source, for coupling open-tubular SFC to high-resolution MS (124). The additional stage of pumping wasrequired to maintain a sufficient vacuum in the ion source region.Various parameters such as restrictor position and flow rate wereexamined, and an FID was used in parallel. Van Leuken et al.also optimized a DFI interface for the characterization of polymeradditives (125).

Among those working with interfaces capable of handlinghigher flow rates, Via and Taylor used a modified thermosprayinterface and packed-column SFC to examine SFE extracts ofenergetic materials (126). Pressure programming of the CO2

mobile phase resulted in changing background spectra with bothCH4 chemical ionization and CO2-moderated electron attachment

ionization, but the analyte spectra did not change. The versatilityof atmospheric pressure ionization (API) has led to an increasein its use. Thomas et al. used API for open-tubular SFC/MS ofpolycyclic aromatic compounds (127), while Matsumoto usedSFC/API-MS for a more fundamental purpose, the estimation ofhydrogen ion affinities (128). Arpino and Haas reviewed progressand future prospects (focused on API) in SFC/MS interfacing(129). Sadoun et al. explored the utility of electrospray ionization(a form of API) for packed-column SFC/MS (130). The combina-tion showed great promise. However, the authors found that themobile-phase composition affected the response, and some lessvolatile analytes were partially adsorbed near the ionization regionin the initial design. Jedrzejewski and Taylor examined the utilityof the particle beam interface for packed-column SFC/MS. Theyfirst reported improved limits of detection for caffeine but foundthat sensitivity was highly dependent on modifier concentration(131). They later described the use of a “particle-forming solvent”to improve the performance of this interface (132). Limits ofdetection for caffeine were shown to be between 10 and 100 timesbetter than previous reports without the particle-forming solvent(132).

Plasma emission spectrometry and plasma mass spectrometryfor detection after SFC were areas of considerable activity duringthis review period. Long et al. (133) and Uden (134) reviewedplasma-based detection. Luffer and Novotny used a surfatronmicrowave-induced plasma for detection of cyclic boronate deriva-tives of biologically important compounds (135). Sensitivity forboron was 25 pg/s. Wang and Carnahan (136), Arnold et al.(137), and Ducatte and Long (138) examined the effects of varioussupercritical mobile phases on helium microwave-induced plasmaemission detection. Wang and Carnahan focused on the effectsof CO2 and of CO2/methanol on plasma emission (136). Theyfound significant changes in molecular emission bands as themobile-phase composition and pressure changed, but the plasmaeasily tolerated the CO2/methanol mobile phases, and the analyti-cal capacity of the system was not compromised. Arnold et al.found that both CO2 and N2O disturbed the helium plasma of the“plasma emission detector” (137). They demonstrated improvedresults with a concentric dual-flow torch. Ducatte and Long founddepression of the excitation properties of a 150-W He plasma bythe introduction of CO2 mobile phase (138). Higher energy ionictransitions were more strongly affected, a finding consistent withcharge-transfer theory. Therefore, careful analyte line selectionis important when plasma emission detection is used in SFC.Tomlinson et al. discussed the coupling of inductively coupledplasma mass spectrometry with SFC and other separation methodsfor the ultratrace level detection of organometallics (139). Blakeet al. described the use of open-tubular SFC/inductively coupledplasma (ICP) mass spectrometry for the detection of organo-metallic species in environmental samples (140, 141). Theydescribed a new interface for SFC/ICPMS and examined theeffects of various operating parameters on performance, such asrestrictor temperature and mobile-phase flow rate (141).

Almquist et. al. (142) and Dressman and Michael (143)described a heretofore uncommon detector for SFC, electrochemi-cal detection. Almquist et al. demonstrated that their miniaturizedelectrochemical detector was compatible with pressure-pro-grammed elution (142). They used CO2 containing water asmobile phase to separate and detect ferrocene and ferrocenederivatives. The electrochemical cell described by Dressman and


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Michael was used with packed-column SFC and worked well withunmodified, acetonitrile-containing, and methanol-containing CO2

mobile phases (143). The detector compared favorably with aflame ionization detector for electrochemically active analytes.

Investigations using a variety of other less common detectorswere abstracted during this review period. Onuska and Terry(144) and Zegers et al. (145) worked with the photoionizationdetector (PID). Onuska and Terry found that their PID performedwell with microbore and conventional packed-column SFC but wasnot suited for open-tubular SFC due to its large cell volume (144).Zegers et al. found that the PID performed much better whencombined with packed-column SFC using modified CO2 as mobilephase than with HPLC (145). Limits of detection ranged fromtens of picograms to low nanograms. Shirota et al. (146) andJew and Richter (147) used the thermionic ionization detector(TID). The former group of authors formed the methoxime ofbiologically important carbohydrates and used SFC/TID in thenitrogen-selective mode for their characterization (146). Jew andRichter used the TID in quite a different manner (147). Theyoperated it with a N2 atmosphere and obtained electron capturedetector (ECD) behavior. Halogenated compounds were detectedafter SFC with LODs in the low picograms. Yarita et al.demonstrated the use of an actual ECD after packed-column SFCfor the selective detection of chlorinated pesticides (148). Brownet al. evaluated an electrolytic conductivity detector for theselective detection of chlorinated compounds after open-tubularSFC (149). LODs ranged from 0.25 to 5 ng for chlorinatedorganics. Staby et al. investigated perhaps the most commondetector for open-tubular SFC, the FID, as they measuredresponses to ethyl esters of sand eel fish oil (150). Theyjuxtaposed SFC/FID and GC/FID responses and discussed theadvantages and disadvantages which result from some of thechoices the analyst must make with these methods.

Chemiluminescent detection was investigated in three publica-tions abstracted during this review period (151-153). Franciset al. used nitro and nitroso chemiluminescence in the thermalenergy analyzer for the sensitive (tens of picograms) and selectivedetection of these moieties in propellants and explosives (151).Shearer and Skelton evaluated the flameless sulfur chemilumi-nescence detector for sulfur-containing compounds in petroleumproducts (152). The detector had an LOD of 0.3 pg of S/s.Sandmann and Grayeski used peroxyoxalate chemiluminescencewith packed-column SFC (153). The LOD for perylene was ∼20-fold lower than by fluorescence detection and was in the attomolerange.

Lembke et al. used a radioactive flow-through detector forpacked-column SFC (154). They found that pressure or composi-tion gradients did not seem to affect the detector. Demirbukeret al. developed a miniaturized evaporative light-scattering detectorfor the detection of polar lipids and other analytes requiring amodifier in packed-microcolumn SFC (155). They found a regionof relatively uniform response at mobile-phase flow rates below∼16 mL/min (measured after expansion at ambient temperatureand pressure). Hirata and Katoh described a means to regulatecell pressure in the most common detector used for packed-column SFC, UV absorbance detection (156). This eliminatedbaseline drift, even at high sensitivities, and allowed the use ofthe detector as a refractive index detector. The LOD for chrysenewas 10 pg.

(ACHIRAL) SFC APPLICATIONSFats, Oils, and Other Lipids. The advantages of SFC for

the characterization of lipids are clear, and the number ofpublications in this area has grown during this review period.Bartle and Clifford (157, 158), Matsumoto and Taguchi (159),and Hoving (160) have reviewed the SFC separation of variousclasses of lipids.

Blomberg et al. (161) and Blomberg and Demibuker (66) usedargentation SFC for the quantitation of triacylglycerols. Thistechnique, in combination with a miniaturized ELSD, was apowerful tool for studying saturated vs unsaturated lipids (161).Hansen et al. used open-tubular SFC to determine the level ofunaltered triolein remaining during a deep fat frying time study(162). Kaplan et al. studied “normal” cheeses and cheeses highin unsaturated triglycerides using open-tubular SFC with on-lineFT-IR and FID detection (163). Manninen et al. found open-tubular SFC with a very polar, siloxane-based stationary phase(25% cyanopropyl, 50% phenyl) separated natural oils by carbonnumber and degree of unsaturation (164). They also found thatit was difficult to determine fat-soluble vitamins in these oils usingconvention open-tubular SFC because of overloading of thetriglyceride components. Manninen et al. also used this stationaryphase to separate γ- and R-linolenic acid-containing triglycerides(165). Combining two 50-µm-i.d., 10-m-long columns enhancedthe separation of one critical pair by 23%. The SFC/MS charac-terization of olestra, a noncaloric fat replacement, was describedby Pinkston and Bowling (123). Both CI and EI spectra of majorand minor components were obtained using a modified direct fluidintroduction interface.

Borch-Jensen et al. (166), Staby and Mollerup (167), Staby etal. (168, 169), and Baiocchi et al. (170) focused on the SFCanalysis of fish oils and lipids of marine origin. Staby et al. foundopen-tubular SFC superior to GC or HPLC for the characterizationof fish oil (168). Shen et al. used a packed capillary column withFID detection to study a variety of oils, including several traditionalChinese medicines (171).

The separation of fatty acids, both free and as alkyl esters,was studied by a number of groups. The work of Sakaki (172)fits well with the results of Smith and Cocks (173). Sakaki foundthat selectivity of the separation of fatty acid methyl esters(FAMEs) on an aminopropyl-bonded silica according to carbonchain length increased with the degree of aminopropyl bonding,while selectivity according to degree of unsaturation decreased(172). Smith and Cocks separated FAMEs on “bare” silicacolumns with ELSD detection (173). They found the separationindependent of chain length but strongly dependent on degreeof unsaturation. Nakajima and Yamamoto patented a means ofremoving free fatty acids from seed oils using packed-column SFCon silica gel (174). Conversely, Nomura et al. studied fatty acidcompositions with a C18-bonded column (175). A very inertcolumn was required since the authors eluted free fatty acids withunmodified CO2. Staby et al. used both open-tubular SFC/FIDand GC/FID to study a fatty acid ethyl ester mixture from sandeel oil (150). They found good agreement within methods andfair agreement between methods.

Pfander et al. (176) and Sakaki et al. (177) discussed theseparation of carotenoids. Pfander et al. reviewed both LC andSFC methods (176), while Sakaki et al. studied retention behavioron nonpolar and polar packed columns (177). They concludedretention on nonpolar packings most closely resembled reversed-


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phase HPLC behavior, while that on more polar columns re-sembled normal-phase behavior. Hui et al. studied spectral shiftsof carotenoids under SFC conditions with respect to their spectrain hexane (178). Changes in pressure and temperature hadgreater effects on the spectral shift of some carotenoids thanothers. Yarita et al. investigated the SFC separation of tocopherolsin vegetable oils (179). They found that the addition of a smallamount of methanol modifier provided a good separation of thetocopherols, including â- and γ-tocopherols.

Miscellaneous Food-Related Samples. Calvey et al. (180)and Block and Calvey (181) explored the utility of SFC and SFEin the study of thermally labile compounds derived from membersof the Allium genus. Low oven and restrictor tip temperatures(50 and 115 °C, respectively) were required to prevent thermaldegradation of allicin, the main thiosulfinate in freshly cut garlic(180). Calvey et al. also characterized compounds extracted frommicrowave susceptor packaging using SFC/MS and SFC/FT-IR(182). These compounds, which could potentially migrate tomicrowaved foods, were primarily aliphatic ketones and alcohols.Chester and Innis used in situ derivatization/extraction followedby SFC/FID to determine maltodextrin in psyllium-based bulklaxatives (183). This determination would not have been possiblewithout the in situ derivatization to render the maltodextrinextractable. Yarita et al. combined packed-column SFC on-linewith GC/FID to fractionate and study citrus essential oils (184).The preliminary fractionation on the silica gel SFC column wasbased primarily on polarity.

Natural Products and Related Samples. The mild elutiontemperatures possible with SFC and the wide range of analytemolecular weights that may be eluted in SFC make it particularlyvaluable for the characterization of natural product extracts. Thecomponents of these extracts often cover a wide molecular weightrange and are thermally labile. Taylor et al. used SFE to extractand a variety of other techniques to characterize Dalea spinosa(185). They performed on-line SFE/SFC of portions of a dissectedseed to determine the distribution of odoriferous compounds.Raynor et al. used SFC to characterize limonoids in bark and seedextracts (186). Morin described the separation of geometricisomers of sesquiterpene and diterpene alcohols by packed-columnSFC (187). The separation was performed on a “bare” silicapacking with methanol-modified CO2. Sewram et al. used themolecular shape selectivity of a liquid crystal-modified polysilox-ane, open-tubular SFC column to separate triterpene acids,including geometric isomers, from Dysoxylum pettigrewianum(188). The separations were not successful on a biphenyl-modified polysiloxane or a poly(ethylene glycol)-coated column.

Coupled SFC/MS and SFC/FT-IR, as well as judiciouslychosen derivatization, are powerful tools for structure elucidationof natural product extracts. Scandola et al. used SFC/MS andSFC/MS/MS to study alkaloids in extracts from the roots ofSecuridaca longipedunculata Fres. (189). The mass spectrometricdata indicated the presence of the ergoline skeleton in some ofthe alkaloids. Johannsen and Brunner used SFC in their studyof the solubilities of the xanthines caffeine, theophylline, andtheobromine in supercritical CO2 (13). The solubilities of thethree differ greatly though their structures are quite similar. Hadj-Mahammed et al. used SFC/FT-IR to study substituted flavones(35). They were separated on a 100% methyl polysiloxane open-tubular column with unmodified CO2. Shim et al. used the uniquederivatization results offered by boronic esters to characterize

ecdysteroids sharing a 20,22-diol structure (190). The bidentatederivative moved the elution time of the products away from thoseof the reactants and of other components. SFC/MS was used byYoung and Games to determine Fusarium mycotoxins in F. roseumculture extracts (191).

Agrochemicals. The determination of agrochemicals is oftena challenging endeavor. Most of the publications abstractedduring this review period take advantage of the rapid analysiscapabilities of packed-column SFC or the reduced sample handlingand trace analysis capabilities associated with on-line SFE/SFCfor the determination of agrochemicals. Mulcahey et al. includedagrochemicals in their review of the use of SFC for environmentalapplications (192). Berger demonstrated the propensity ofpacked-column SFC for rapid analysis with the separation of upto 10 phenylurea herbicides in less than 7 min (193). Berger etal. also used packed-column SFC to separate a variety of carbamatepesticides in 9 min (194). They used in-line UV and NPDdetection and achieved detection limits as low as 110 ppt.Benfenati et al. used packed-column SFC/UV for the rapiddetermination of a herbicide, bromofenoxim (195). They foundthat the LOD (15 pg) and the linear dynamic range of the methodwere better than those achievable with HPLC/UV. The NPD wasused by Zegers et al. to selectively detect 19 organophosphoruspesticides in vegetable extracts (196). These authors evaluatedseven stationary phases for packed-capillary columns with modi-fied CO2 as mobile phase. Yarita et al. used packed-column SFCwith unmodified CO2 and electron capture detection to determinechlorinated pesticides in extracts from carrots (148).

Murugaverl and Voorhees combined the trace analysis capa-bilities of on-line SFE/SFC with on-line solid-phase extractioncleanup to determine pesticides in fats and oils (197). Thisarrangement greatly reduced sample handling. Nam and Kingalso described a “multihyphenated” technique for the character-ization of pesticides in fats and lard (198). They used SFE,followed by on-line packed-column SFC to extract and separatethe pesticide fraction from the coextracted lipids. On-line, open-tubular GC was then used to separate the pesticide fraction. Theyfound the method to be faster and less laborious than conventionalmethods, while still accurate and reproducible. The selectivityand sensitivity of SFC/MS for agrochemical analysis has also beendescribed during this review period. Jablonska et al. investigateda variety of ionization methods for the determination of chlorinatedpesticides by SFC/double-focusing MS (199). Detection limitsin the low-nanogram range were reported regardless of theionization method used. This is somewhat surprising since lowerlimits of detection should be achievable with electron attachmentnegative ionization using the mobile phase as moderating gas.Nelieu et al. compared thermospray LC/MS with electrospraySFC/MS for the determination of atrazine metabolites (200). Theyfound SFC/MS to be more sensitive for the less polar chloro-triazine compounds. Massey and Tandy reviewed the separationand analysis of chiral agrochemicals, including the promise offeredby chiral packed-column SFC (201).

Fossil Fuels, Polycyclic Aromatic Compounds, and Syn-thetic Lubricants. Substantial progress has been made in theapplication of SFC to the characterization of fossil fuels. Threereviews describing this progress in SFC and in other techniquesappeared in one issue of The Journal of High Resolution Chroma-tography. Lundanes and Greibrokk described the separation ofpetroleum and petroleum products into compound classes using


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a variety of techniques, including SFC, in their review (202).Peaden (203) reviewed simulated distillation while Levy (204)presented a variety of applications of SFC and SFE in fossil fuelresearch.

Packed-column SFC has been shown to be quite useful in rapidgroup-type separations of petroleum products. Schubert patenteda method to separate and collect fractions of petroleum-based oilsusing packed-column SFC (205). Li et al. described the use oflong (1 m) packed capillary columns for rapid (10 min) hydro-carbon group-type separations (206). They examined the effectsof packing material pore size and surface area, as well as of columntemperature and pressure. The method appears promising forquality control of diesel fuels. Lynch and Heyward coupledpacked-column SFC with GC for the analysis of petroleumfractions (207). After detection by FID and UV, effluent from theUV detector could be “cut” to the injection port of the GC. Thesystem was shown to be quantitative and reproducible for theautomotive fuel range. A similar system was described by Chenet al. (208). The SFC is useful for rapid group-type analysis, andselected regions can be directed to the GC for quantitativedetermination of individual hydrocarbons.

The use of SFC for simulated distillation is an active area ofresearch. Raynie et al. extended the boiling range of simulateddistillation to over 800 °C using open-tubular SFC (209). Theyfound an n-octylpolysiloxane-coated column minimized the ali-phatic vs aromatic boiling point discrepancy common to chro-matographic methods. Shariff and Bartle evaluated the use ofpacked capillary columns in SFC for simulated distillation (210).They evaluated a variety of columns and minimized the afore-mentioned discrepancy by using three columns. Bartle et al. usedsimulated-distillation SFC in their investigation of progress in theco-refining of coal and petroleum (211). Campbell et al. also usedSFC (with MS detection), along with a variety of other techniques,in the characterization of nondistillable coal liquefaction processstreams (212).

The greater molecular weight range of SFC with respect toGC makes it better suited for determining a wide range of PAHs.Gadzala and Buszewski included SFC in their review of methodsused for PAH determination (213). Mulcahey et al. includedPAHs in their review of the uses of SFC in the environmentalfield (192). Jinno et al. compared the PAH molecular shaperecognition properties of liquid crystal-bonded phases in packed-column SFC and in HPLC (214). They found that selectivity wasenhanced in SFC. Heaton et al. also compared packed-columnSFC to HPLC for the determination of PAHs (215). They achieveda separation of 16 PAHs in 6 min by SFC. Kot et al. developed asimilar, 7-min, packed-column SFC separation of the 16 “priority”PAHs (42). Lee reported the results of an interlaboratory round-robin evaluation of SFC for the determination of aromaticsaccording to ring number (216). The study concluded that SFCpossessed distinct advantages over GC/MS and NMR includingcost, speed, and wide applicability. Hoener et al. used packed-column SFC with fluorescence detection to determine PAHs inwaste gases of a fuel oil boiler (217). The PAHs were extractedfrom foam plugs by off-line SFE. Yao et al. also used SFE followedby SFC to determine PAHs in air particulates from air near a cokeoven and a traffic island (218). The SFE and SFC steps werecombined on-line, however. Recovery of 16 PAHs was ∼90% andRSDs ranged from 1.9 to 6%. Jinno et al. discussed the potentialof on-line SFE/SFC to isolate, purify, and collect fullerenes from

carbon soot (219). Liu et al. also described the separation offullerenes (220). They compared the separation of C60 and C70

fullerenes by SFC and HPLC on “acceptor” bonded phases.Synthetic Polymers and Oligomers. Supercritical fluid

chromatography may be most widely known for its ability toprovide information about relatively low molecular weight poly-mers and oligomers. Polymers that are too low in volatility forGC, and which are difficult to characterize by size exclusionchromatography, are often amenable to SFC. Anton et al. provideda wide-ranging review of the potential of packed-column SFC foranalysis, primarily focusing of applications involving polymers andpolymer additives (221). They found the analysis times to beshorter than with HPLC, and the method development to besimpler.

Perhaps the best example of oligomer characterization by SFCis the characterization of oligomeric surfactants, most commonlyethoxylated alcohols, using open-tubular SFC with flame ionizationdetection. Wang and Fingas (222), Holzbauer and Just (223),and Ye et al. (224) studied various aspects of this separation. Wangand Fingas (222) and Ye et al. (224) verified the distributionsusing HPLC. While Ye et al. advocated the routine use of SFC inthis area, they observed a polar oligomeric series by HPLC thatwas not eluted in SFC (224). They did not use derivatization tomake the polar species more soluble in CO2. Just et al. comparedthe abilities of SFC and matrix-assisted laser desorption/ionizationmass spectrometry (MALDI-MS) for ethoxylated oligomer char-acterization (225). In their hands, SFC worked best for oligomerswith molecular weights up to ∼1000 while MALDI-MS was moreuseful for the higher molecular weight oligomers. Kane et al.demonstrated the use of SFC in the trace analysis of oligomericsurfactants in water (226). Other groups used packed-columnSFC to separate ethylene oxide oligomers. Hagen et al. used apoly(divinylbenzene) packed column and evaporative light-scat-tering detection to achieve baseline resolution of oligomers withup to 44 oligomeric units (227). An open-tubular column with a50% phenyl polysiloxane phase did not perform as well in theirhands. (The reviewers note that well-resolved separations ofsilylated PEGs with molecular weights exceeding 2000 have beenobtained using a 30% biphenyl polysiloxane-coated open-tubularcolumns and an integral restrictor (228).) Guerrero and Roccastudied the separation of ethoxylated alcohols on cyanodecyl-bonded silica packings (229). They used preparatory-scale HPLCand mass spectrometry to explain the coelution of some com-pounds.

The success of SFC extends to other surfactants and emulsi-fiers. Artz and Myers described the separation of a number ofemulsifiers by open-tubular SFC/FID (230). Carey and Suttonalso used open-tubular SFC/FID to characterize polyol ester fluidsused as synthetic refrigeration lubricants (231). They coulddeduce the starting carboxylic acids, base polyol structure,reaction scheme, degree of reaction completeness, and additivesfrom the chromatographic data. Wang and Fingas described theSFC separation of sorbitan ester surfactants (232). Open-tubularSFC provided better separations of the higher molecular weightpolyesters than did a previous HPLC method. Macka et al.separated silylated polyglycerols with a degree of polymerizationup to 10 (233). Higher oligoglycerols were eluted but not cleanlyresolved in their method. Ye et al. developed an open-tubularSFC method for the separation of ethoxylated sorbitan esters(234). While the method was superior to GC or gel permeation


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chromatography for these emulsifiers, the authors later found thata separation by gradient elution reversed-phase HPLC wascomparable to the SFC separation (235). However, isocraticelution, and a correspondingly poorer separation, was necessaryfor quantitation by HPLC (235).

Supercritical fluid chromatography has been used to character-ize a variety of other low-molecular weight, nonpolar polymersand polymer additives. Low-molecular weight (up to ∼25 000)polysiloxanes are perhaps best addressed by SFC. Just et al.described the use of SFC/FID and SFC/MS for the determinationof cyclic siloxanes in silicone oils (236) and for the characterizationof methyl and hydroxyl end-capped siloxanes (237). They foundthat matrix-assisted laser desorption MS was a useful comple-mentary technique for higher molecular weight polysiloxanes(237). Takeuchi and Sugihara used packed-column SFC toseparate various functionalized polysiloxanes based upon theorganic functional end group (238). The fractions were furthercharacterized by NMR and GC/MS.

MacKay and Smith used SFC/MS to study additives topolyurethanes (239, 240). They demonstrated the potential ofon-line SFE/SFC/MS for this application. Pasch et al. used SFCin one dimension of a two-dimensional approach to characterizecomplex polymer mixtures (241). “Critical chromatography”(chromatography at the “critical point of adsorption”, at the borderof adsorption and exclusion modes of liquid chromatographywhere separation is governed by the type and number of functionalgroups alone) was used to separate various methacrylate blockcopolymers according to functional group in the first dimension,while SFC was used to separate primarily according to molecularweight in the second dimension (241). Raynor and Bartlereviewed the use of SFC for the characterization of surface-coatingpolymers (242). They described the use of open-tubular SFC withCO2 to separate reactive oligomeric mixtures. More polar oligo-meric mixtures were separated by packed-column SFC usingmodified CO2. Just and Gross conducted a study of vulcanizationusing SFC to separate and identify the reaction products (243).They employed squalene as a model compound and conducted avariety of reactions, simulating various vulcanization processes.

Preparative-scale SFC is useful in fractionating and studyingpolymers. Ute et al. used preparative-scale SFC with CO2/ethanolon silica gel to prepare highly isotactic and highly syndiotacticfractions of poly(methyl methacrylate) with degrees of polymer-ization of 25 and 50 (244). They then used these fractions toexplain some peculiarities in the separation of these materials bygel permeation chromatography. Ute and Hatada later reviewedthe preparative-scale separations of a variety of nonpolar andmoderately polar polymers (245).

Other publications described the use of SFC to study speciesthat could potentially migrate from packaging polymers. Additivesin packaging polymers were separated by Buecherl et al. usingSFC with FID and MS detection (246, 247). They used on-lineSFE to extract the additives from the polymers and found thecombined methods offered considerable time savings. Berg etal. used a novel large-volume-injection technique and open-tubularSFC to achieve detection of additives at concentrations as low as10 ppb (248). They extracted polymers in aqueous acetic acidand isooctane to simulate foods and concentrated the extractsbefore injection. Calvey et al. studied potential migrants frommicrowave susceptor packaging (182). They found aromatic

compounds as well as aliphatic alcohols and ketones in solventextracts of the susceptor packaging.

(Achiral) Pharmaceutical Agents and Biologically Impor-tant Mixtures. Supercritical fluid chromatography is being usedfor the characterization of pharmaceutical agents and biologicallyimportant compounds with increasing frequency. Recent applica-tions in this area were reviewed by Wilson et al. (249) and byGiron (250). The move toward SFC is in part due to theincreasing reliance on packed-column SFC for chiral separations.These applications are reviewed in a separate section on chiralSFC. Many pharmaceutical agents and biologically importantcompounds are relatively polar. These polar analytes can beseparated by packed-column SFC with modified CO2 as mobilephase, with all the advantages this technique brings over HPLC(see above). Fat-soluble vitamins are a natural for SFC. Wysspublished a comprehensive review of the chromatographic andelectrophoretic methods for the determination of retinoids (251).On the basis of the publications he reviewed, he judged SFC/FID insufficiently sensitive when compared to HPLC with UVdetection. However, he did not consider packed-column SFC/FID or packed-column SFC/UV, which should be at least assensitive as HPLC/UV. Ibanez et al. described their use of a“rotatable central composite” experimental design method tooptimize the SFC separation of fat-soluble vitamins using a singlemicropacked column (252) and two coupled columns (253).Hanson studied the retention behavior of steroids in packed-column SFC (254). Retention was influenced not only by polarfunctional groups but also by intramolecular interactions, shield-ing, and shape. He also demonstrated that commercial packed-column SFC equipment could be used for small-scale preparativechromatography of a steroid hormone, cyproterone acetate (255).Preparative-scale SFC was economically viable and environmen-tally friendly. Open-tubular SFC/FID was used by Kim et al. tostudy cholesterol and cholesteryl esters in human serum (256).They achieved an RSD of 2.6% and found that SFC/FID hadadvantages over GC, HPLC, and enzymatic methods. Theyreported a limit of detection of 4-6 pg, which must be in error,since detection limits for the FID are typically in the low-nanogramrange or, at best, in the hundreds of picograms.

Ramsey et al. used the propensity of packed-column SFC foreluting polar analytes, and the selectivity and sensitivity of tandemmass spectrometry, to demonstrate a sensitive assay for ionophoreantibiotics in animal feeds (257). A number of the ionophoreswere, surprisingly, sodium salts. The mass spectrometric dataindicate that these species were eluted as salts, in spite of thefact that the mobile phase was unmodified CO2. Pyo et al.described the use of water-modified CO2 for the SFC separationof polar antibacterial agents (258). Arimoto and Adachi patentedthe use of a surface ionization detector for SFC detection ofmacrolide antibiotics (259).

Berger and Wilson published a series of demonstrations ofthe power of packed-column SFC for the rapid separation ofpsychoactive agents (260-262). They clearly demonstrated thelarge number of degrees of freedom in packed-column SFC byevaluating mobile-phase, pressure, and temperature gradients. Thefirst paper in the series dealt with the separation of phenothiazineantipsychotics (260). They used a tertiary mixture of CO2,methanol, and isopropylamine to separate 10 components in 11min. Isopropylamine was essential for elution of the analytes. Tenantidepressant drugs were separated in less than 6 min (261).


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Stimulants exhibited a wider range of retention behavior than didthe antipsychotic or antidepressant agents (262). Takaichi et al.demonstrated the separation of benzodiazepine tranquilizers bySFC/UV (263).

Simmons et al. described their evaluation of packed-columnSFC/UV for the determination of the antiinflammatory agentphenylbutazone and its major metabolite in human serum and ina commercial tablet (264). The limit of detection of the methodwas 100 ng/mL. Smith et al. determined ranitidine, an antiulceragent, and its polar metabolites in extracts from biological fluidsusing packed-column SFC (265). The separation was performedin under 10 min using a mobile phase of CO2 modified withmethanol/methylamine/water. Bailey et al. evaluated the separa-tion of 10 â-blocker drugs on a variety of packed SFC columns(266). They found that addition of triethylamine to the methanol-modified CO2 mobile phase and the aminopropyl-bonded phaseprovided the best separation. The speed and advantages ofpacked-column SFC for the determination of pharmaceuticalagents were also demonstrated by Strobe et al. in their work withfelodipine, an antihypertensive agent, and a potential degradationproduct (267). The authors used methanol-modified mobile phasewith simultaneous electron capture and UV detection. Theseparation was completed in less than 6 min, which allowed asample throughput 60% greater than that achieved with HPLC,with a 90% decrease in solvent waste. Mount et al. also usedpacked-column SFC with electron capture detection for thedetermination of artemisinin in whole blood (268). They docu-mented a limit of detection of 20 ng in 1 mL of blood.

Lembke and Engelhardt capitalized on the lower viscosity ofthe SFC mobile phase in their determination of the ethyl ester ofphytanic acid extracted from human blood serum (269). Theycoupled three different columns in series (silica, aminopropyl-bonded silica, and C8-bonded silica) to improve the separation, amove they called “selectivity tuning”. Evans and Smith comparedthe performance of GC, HPLC, and SFC for the separation ofhydroxylated dialkyldithiocarbamates with up to three hydroxylgroups, models for drug metabolites (270). SFC comparedfavorably with the other two techniques. Heaton et al. used SFCto monitor extracts of taxicin, which may be used to prepareanticancer drugs, from the English yew tree (271). Theycompared open-tubular SFC with a carbowax phase to packed-column SFC with a cyano column. The cyano packed columnprovided better resolution of taxicins I and II, shorter analysistimes (<10 min), and greater accuracy.

Pinkston et al. evaluated the potential of open-tubular SFC/MS for trace analysis of mebeverine, an antispasmodic agent(272). The drug was determined after extraction from spiked dogplasma. Accuracy and precision were judged acceptable in within-day and between-day comparisons for samples spiked at 6 and 60ng/mL of plasma. Wong et al. encountered one of the obstaclesof commercial open-tubular SFC equipment in their evaluation ofopen-tubular SFC/FID for the determination of new immunosup-pressants extracted from whole blood (273). They used splittinginjection with a small effective injection volume, coupled with thenonselective FID. This resulted in unacceptable selectivity/sensitivity for their assay. A simple, larger volume injectiontechnique, as described earlier (85), would have improved theperformance of the SFC instrument. On the other hand, Waltherand Netscher demonstrated one of the strengths of open-tubularSFC/FID, as compared to GCsthe analysis of reactive and

thermolabile compounds (274). They characterized 63 reactiveor thermally labile intermediates which are useful in the synthesisof natural products. The lower analysis temperatures and lowsurface areas of open-tubular SFC made it the method of choicefor these compounds.

Organometallic Species and Miscellaneous Applications.A number of groups described the SFC separation of a variety ofnonpolar organometallic species. Lin et al. reviewed SFC ofchelated metal ions and of organometallic compounds (275).Fluorinated ligands are very effective for metal ions, since thefluorinated metal chelates are very soluble in CO2. Laintz et al.demonstrated the separation of geometric isomers of Cr and Rhchelates using packed-column SFC (276). Phenyl-bonded phasesand (trifluoroacetyl)acetone chelates yielded the best separations.Both Blake et al. (277) and Bayona and Cai (278) worked withorganotin compounds. Blake et al. evaluated a new interface forSFC/ICPMS using organotin compounds (277). Bayona and Caireviewed extraction, separation, and detection of organotins (278).They described the use of SFC with both nonselective (FID) andselective (atomic emission, flame photometric, mass spectromet-ric) detectors. Wenclawiak and Krah’s goal was to determineorganic and inorganic arsenic species extracted from solidmatrices (279). They compared open-tubular SFC to GC of thethioglycolic acid methyl ester derivatives. They found that, unlikeGC, SFC produced no thermal degradation of the inorganic arsenicderivatives.

Hanson et al. used packed-column SFC to study the reactionproducts from the addition of trimethylaluminum to R,â-unsatur-ated aldehydes (280). They found that the FID was necessaryfor the detection of species with no chromophore. Aqueous formicacid, which is compatible with the FID, was used as mobile-phasemodifier to elute the more polar species. Carey et al. comparedFID to inductively coupled plasma MS detection for the SFC ofchromium chelates and of a thermally labile chromium dimer(281). They found that the limit of detection for the ICPMS couplesystem was 1-2 orders of magnitude better than that of the SFC/FID system for stable analytes, but that the thermally labileorganometallic was not detected with the ICPMS system. Laintzet al. conducted a study of the packed-column SFC of lanthanideâ-diketonates using unmodified and alcohol-modified CO2 (282).They compared six ligands and found advantages with some. One,thenoyltrifluoroacetone, showed thermal degradation during SFCat elevated temperature.

De Geus et al. used packed-capillary SFC to determine trialkyland triaryl phosphates extracted from harbor sediment (283).They used thermionic detection and found detection limits in the0.1-0.2 mg/kg of sediment range.

CHIRAL SFCThere has been great progress in the development and

application of chiral SFC and related techniques. Numerousreports of superior separations, easier and faster method develop-ment, and adoption by industry have been published. Many moresuccesses are being reported, formally and informally, at meetings.The fundamental reasons for these advantages seem to stem fromhigher ordering of the stationary phases under some SFC andSubFC conditions (particularly when compared to GC conditionswith the same stationary phases), solute solvation effects differentfrom that with conventional liquid mobile phases, and of coursethe typical advantages of faster diffusion, faster optimum velocities,


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and much faster column recovery to initial conditions followingprogramming when supercritical or subcritical fluids are usedinstead of conventional liquids. Schurig and co-workers have beendoing chiral SFC for many years. They published two reviewsrecently (284, 285) dealing with their developments of enantiomerseparations using immobilized cyclodextrin stationary phases.Petersson and Markides also reviewed chiral SFC noting its speed,efficiency, low-temperature capability, and wide selection ofdetection options (286).

Much work continues in the development and application ofnew chiral stationary phases for SFC. Cyclodextrin derivativesare receiving considerable atention. Yi et al. prepared andevaluated seven permethyl-substituted â-cyclodextrins (bound topoly(dimethylsiloxane)) for use in SFC and GC, reporting excel-lent separations (287). Yi et al. also prepared four large-rim-tethered permethyl- (or per(methyl/acetyl)-) substituted â-cyclo-dextrin stationary phases and again reported excellent separationsof a variety of enantiomers (288). Petersson et al. investigatedthe chromatographic performance of copolymeric and side arm-substituted â-cyclodextrin/polysiloxane stationary phases. Theyvaried the amount of cyclodextrin present, the way it was attachedto a silicone backbone, and the effect of chemical substitution onthe cyclodextrin (289). Additional developments of cyclodextrin/polysiloxane stationary phases were disclosed by Bradshaw et al.(290, 291).

Schmalzing et al., using immobilized permethyl-â-cyclodextrin,studied the effects of temperature and pressure on chiral retentionand selectivity for four racemic mixtures (292). Schurig et al.separated hexobarbital by SFC, and other chromatographytechniques using Chirasil-DEX (293, 294). This phase containsan octamethylenepermethyl-â-cyclodextrin linked to poly(dimeth-ylsiloxane). Doennecke et al. anchored γ-cyclodextrin to apolysiloxane. They reported that very polar compounds could beeluted at low temperatures using SFC, achieving higher separationfactors than when GC was used (295). Francotte et al. preparedstationary phases of polysiloxane or poly(ethylene glycol) poly-mers containing substituted benzoylcellulose derivatives anddemonstrated separations using GC and SFC (296). Peterssonet al. prepared polymeric stationary phases with alternating blocksof chiral (1R)-trans-N,N′-1,2-cyclohexylenebisbenzamide and achiralblocks of siloxane. They then used these phases to separate anumber of chiral diols by both GC and SFC. SFC producedsuperior resolution most likely from its lower operating temper-ature and stronger solute/stationary-phase interactions (297).Schleimer and Schurig and Schleimer et al. evaluated Chirasil-nickel, a polysiloxane containing an immobilized Ni(II) chiralcomplex, in open-tubular SFC. They used this phase to separatecoordinating solutes by both GC and SFC. Once again, they foundthe low temperatures afforded by SFC provide higher selectivityfor separating enantiomers (298, 299).

Bargmann-Leyder et al. evaluated chiral stationary phasesbased on tyrosine demonstrating separations of enantiomers ofwarfarin and a pharmaceutical substance, ICI 176334 (300).Bargmann-Leyder et al. separated â-blockers on ChyRoSine-A,noting that SFC separations are achieved in little time but thatthe same solutes were poorly resolved using normal-phase liquidchromatography. They then showed using NMR that CO2 actsas a complexing agent for the solutes, changing their chiraldiscrimination (301). Bargman-Leyder et al. separated â-blockersin under 2 min using short columns packed with ChyRoSine-A

(302). Bargmann-Leyder et al. later used molecular modeling todevelop an explanation of how the solvating effect of CO2 inducesconformational changes in propranolol analogs that enhance chiraldiscrinimation (303). Bargmann-Leyder et al. also studied theeffects of spacer length and steric hindrance near the stereogeniccenter of several chiral stationary phases and proposed a newstationary phase which should allow a broad range of applications(304). Wilkins et al. adsorbed an anthrylamine derivative toporous graphitic carbon and used this to separate two antiinflam-matory agents and a series of racemates (305). Lohmann andDappen made chiral stationary phases from â-lactones and reportthat SFC applications are possible (306).

Numerous additional applications have been reported. Theserepresent both promising possibilities and, more importantly,reports of real-world success stories. Themes running throughthese reports echo superior selectivity, shorter analysis times, fastmethod development, economic operation, etc. Siret et al.separated four optical isomers of a calcium channel blocker byLC and SFC. The LC separation required two stationary phasesused together, but under SFC conditions, a single stationary phase(one of those used in the LC experiment) was sufficient (307).Kot et al. performed chiral separations of â-blockers, benzo-diazepines, nonsteroidal antiinflammatory agents, and â-agonistsby both SubFC and SFC. They reported short analysis times inevery case, and often sufficient resolution to allow solute massapproaching column overload and semipreparative collections ofenantiomers (308). Sandra et al. also reported benefits of couplingdifferent chiral columns in series to broaden the scope of possibleapplications (309). Peytavin et al. separated enantiomers of sevenantimalarial agents (310). Almquist et al. used SFC to separate10 benzodiazepine racemates and temazepam derivatives (311).Petersson et al. determined the enantiomeric purity of (S)-carboranylalanine using open-tubular SFC with a stationary phaseof permethyl-â-cyclodextrin methyloctylsiloxane (312). Bier-manns et al. separated enantiomers of propranolol, atenolol, andmetoprolol by packed-column SFC with sub-part-per-million detec-tion of propranolol (313). Wilson separated enantiomers ofibuprofen in under 7 min, and flurbiprofen in under 4 min usingpacked-column SFC (314). Juvancz et al. used open-tubularcolumns coated with Chirasil-Dex to separate racemates of severalamines, amino acids, amino alcohols, carboxylic acids, coumarines,diols, and imides (315). Whatley preparatively separated racemicglibenclamide analogs by SFC on chiral stationary phases andnoted advantages of SFC over HPLC (316).

Lynam and Nicolas compared Chiracel OD columns from thesame lot in an LC instrument (using hexane plus modifiers) andan SFC instrument (using CO2 and similar modifiers) for theseparation of repeated injections of trans-stilbene oxide and(carbobenzyloxy)phenylalaninol. They reported that, for similaranalysis times, the Chiralcel OD column gave superior resolutionwhen used with the SFC system, plus had the added benefit offaster equilibration following solvent changes (317). Blum et al.used a Whelk-O 1 column to separate a variety of enantiomericpairs, noting superior results in SubFC compared to LC. Theysuccessfully performed preparative separations on a 1-in.-diametercolumn of the same stationary phase (318). Stringham et al.reported advantages of speed and ease of methods developmentfor SFC and SubFC compared to LC. They developed methodsfor four intermediates from a synthetic process of an antiviral drug


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candidate. They were not able to develop HPLC methods for twoof the compounds, and a third was marginal (319).

Walther et al. used (S)-trolox methyl ether to derivatize chiralalcohols and then separated the derivatives by GC and SFC withachiral columns (320).

Chiral SFC examples and procedures are included, along withHPLC and GC data, in a database described by Koppenhoefer etal. (321-323).

Unwarranted generalities proclaiming success are just asdangerous to a new technique as unwarranted generalitiesproclaiming failure. Although we have seen many reports ofdifferent chiral recognition mechanisms and superior chiralseparations using SFC, this is not always so for every application.Anton et al. showed two cases where subcritical fluid chroma-tography gave poorer resolution than HPLC. In the first, CO2

was shown to interact with phenylalaninol, reducing resolution.In the second, a secondary amine was shown by NMR not tointeract with CO2 but still was resolved more poorly with SubFCthan with HPLC (324). Smith et al. showed examples where atemperature reduction improved chiral resolution for enantiomersof a Chromakalim analog in both SFC and HPLC separations onChiracel-OD, while another analog had opposite temperaturedependency with both separation techniques (325). However, atcomparable resolution the SFC conditions eluted the solutes inless than half the time required for the HPLC separations. Insteadof sweeping generalities, it is perhaps more important at this stagein the development of chiral SFC to fully realize that CO2 ofteninteracts differently with solutes than conventional liquids. Chiralselectivity is almost always different and frequently, but not always,better in SFC than in HPLC. A borderline or failed separation inHPLC has a real chance for success in SFC, and vice versa. Onegenerality that will always be true, however, is that when chiralselectivity is roughly equal with the two techniques, SFC tech-niques will always be much faster than HPLC on comparablecolumns.

SUPERCRITICAL FLUID EXTRACTIONMore emphasis has been placed on analytical sample prepara-

tion over the past few years, partly due to the advancements inSFE. Though process-scale SFE, physical-chemical studies, andanalytical uses of supercritical fluids cannot be completelydivorced, this portion of our review is focused on analytical SFE.References to these ancillary uses of the technology are includedonly when they are directly applicable to analytical samplepreparation. However, a bibliographic guide to SFE coveringphysical and thermodynamic data, phase equilibria, and SFEprocesses and applications from 1980 through 1993 may be ofstrong interest (326). Because SFE does not generally provideadditional information about a sample compared with otherextraction procedures, the advantages of speed, efficiency, organicsolvent minimization, and cost per extraction must be significantbefore general analysts will move away from their “tried-and-true”extraction methods. While SFE is rapidly gaining acceptance inthe analytical community, factors such as regulatory approval,standardization of commercial instrumentation configurations, anda more general understanding of the extraction process arenecessary for a more complete acceptance of SFE, or other newerextraction technologies, in general analytical laboratories. Forexample, carbon dioxide either alone at high pressure or com-bined with modifier at moderate pressure may work for a given

applicationsuntil there is some consensus regarding which ispreferred, SFE will be viewed as confusing to those contemplatingentering this exciting and promising field.

While there has been a wealth of information uncovered aboutthe fundamentals of SFE, the most rapid area of growth is theapplication of the technique to analytical problems. The noveltyof the on-line combination of SFE with other analytical methodolo-gies is also losing favor to the exploration of the applicability ofSFE. The balance of this review will reflect this trend.

SFE Theory and Fundamental Measurements. Becausesolvating power, as well as physical properties like viscosity anddiffusivity, can be easily varied in a supercritical fluid, SFE isunique in its ability to be useful to study the extraction processin general. King and Catchpole reviewed physicochemical data,including phase equilibria and mass-transfer parameters, used inthe design of SFE (327). Solute solubility in the extracting fluidis an obvious prerequisite to SFE that can be modeled inpredicting SFE processes. A neural network approach to predict-ing solubility providing data based on analyte molecular structurewas reported (328, 329). Another method for predicting solutesolubility is based on determining the solubility parameter andhydrophobic interactions from easily obtained constants (330).Veress developed a mathematical model for dynamic SFE usingthe diffusion layer theory (331). The model predicted the timerequired to extract a predetermined amount of analyte, in thiscase cannabinoids from marijuana and hashish.

SFE Instrumentation, Techniques, and Performance.Methodologies for the performance of SFE are still being definedas more information is uncovered regarding the factors thatinfluence the technique. Because supercritical fluid solventstrength can be varied simply by changing temperature and/orpressure, these factors, and their influences on extraction, leadto variety of approaches to SFE. A collaborative study, using blindreplicate design with balanced replicates, was performed for theSFE/IR determination of petroleum hydrocarbons (332). Thestudy showed that a carefully documented procedure can providequality results. Bayona reviewed state-of-the-art SFE, includingcommon approaches to method development (333). Gere andDerrico presented an approach to method development in SFE(334). Taylor reviewed strategies for performing SFE (335). Hediscussed occasions where extraction of the matrix, while leavingthe analyte of interest behind (i.e., inverse SFE), may be preferred.Study of the influence of flow rate can be used to characterizethe extraction behavior (336). Extractions limited by solutesolubility show a flow rate dependence, while those limited byanalyte desorption from the matrix and/or diffusion through thematrix are not. Clifford et al. modeled the kinetics of dynamicSFE by evaluating the effect of the matrix on retarding rapidextraction of analyte material (337). Wet matrices are generallydried prior to SFE, and Burford et al. surveyed a number of dryingagents (338). They found that magnesium sulfate, molecularsieves, and Hydromatrix diatomaceous earth successfully boundexcess moisture in most cases. Fang and Chau noted thepossibility of contaminating the laboratory atmosphere duringdynamic SFE and advocated venting the expanded fluid into afumehood or through an adsorbent (339). Via and Taylorreviewed the use of SFE to address processing problems like thefractionation of polymers and soil remediation (340).

New commercial instrumentation for SFE was developed andpatented during this reporting period (341-344). These instru-


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ments feature on-line addition of solvent modifiers and somedegree of automation. Jarvis et al. used robotics to modifycommercial instrumentation to achieve the automation necessaryfor around-the-clock SFE determination of pesticides in environ-mental samples (345). Brewer and Kraus described the develop-ment of an SFE apparatus for the direct extraction of organicsfrom water (346). They presented results for the extraction ofpentachlorophenol at concentrations as low as 0.1 ppm.

Restrictors to maintain operating pressure while allowingdynamic flow have often caused problems in SFE. One reportdescribed the construction of a robust stainless-steel-clad fused-silica restrictor (347). Meanwhile, another restrictor nozzle wasevaluated for use in the SFE of rubber additives, fullerenes, andsoil constituents (348). Yang et al. developed a mathematicalequation to calculate the fluid flow rate through linear restrictors(349).

Solute Collection. Collecting or trapping the extractedanalyte following SFE remains an important area for improvement.Factors such as collection temperature, fluid flow rate, analytevolatility, and extraction time all play important roles in efficientanalyte collection. Collection methods can generally be classifiedinto two schemes: collection into liquid solution (i.e., solventtrapping) and collection onto a solid surface, such as a beaker ortest tube, chromatographic interface, or sorbent media (i.e., solidtrapping). Since each vendor of commercial SFE instrumentationuses different variations of these collection methods some levelof confusion will exist for novice users and those outside the field,until analyte collection is thoroughly understood. Bowadt and co-workers compared the two trapping methods for the SFE ofchlorinated materials, using 2,2,4-trimethylpentane as the collect-ing solvent and silica, Florisil, and octadecyl-coated silica as thesorbent traps (350). For nonvolatile polychlorinated biphenyls(PCBs), they saw little difference between the two collectionmethods. When more volatile chlorobenzenes were extracted,the solid-phase methods provided better results under the condi-tions studied, due to the purging of analytes from the collectingsolvent.

Analyte collection directly into organic solvents is the moststraightforward collection method. For subsequent analysis thatrequires solvent dilution, this method eliminates at least one stepfrom the total SFE process. Thompson et al. surveyed ninedifferent collection solvents and four mixed solvents for thecollection efficiency of a polarity test mixture (351). They foundthat quantitative analyte recovery was not always possible withsingle-solvent systems, but recoveries improved with mixed-solvent systems. Subsequently, Thompson and Taylor investi-gated the effects of solvent-trapping collection when mixed fluids(i.e., carbon dioxide entrained with organic cosolvents) were usedfor extraction (352). The mixed collection solvent that providedthe highest recovery when pure carbon dioxide was used gavethe lowest results when modified carbon dioxide was employed.Under the conditions studied, a single collection solvent, hexane,gave the best results with mixed extracting fluids. Wenclawiakand co-workers determined that changes in the extracting pres-sure, fluid flow rate, solvent selection and temperature, andconfiguration of the collection device all played important rolesin the efficient recovery of volatile chlorobenzene and hexachlo-rocyclohexane isomers (353).

When sorbent-trapping methods are used, it is generally easierto allow collection at subambient temperatures than with solvent-

based collection. This leads to two significant, general advan-tages: restrictors can be heated to minimize the possibility ofplugging, and volatile analytes can be more efficiently trapped.Huesers and Kleiboehmer evaluated silica-based traps for thecollection of PAHs (354). They found that high flow rates andorganic modifiers in the carbon dioxide extracting fluid did notsignificantly impact their collection efficiency and claimed thatthe necessity for subsequent sample cleanup is minimized.Postextraction sample cleanup is also minimized using a solid-phase extraction (SPE) cartridge as the collection device (355).The influence of alcohol modifiers and different concentrationsand temperatures on the collection efficiency of PCB congenerswas studied using stainless-steel beads, octadecyl-modified silica,Florisil, or silica gel for trapping (356). Levy and Houckdemonstrated the cryogenic collection advantage of sorbenttrapping for volatile analytes (357). Ezzell introduced a two-stepcollection procedure where a octadecylsilica-embedded glass fibermembrane was placed in-line prior to solvent trapping (358).Moore and Taylor found that high modifier amounts can lead tocollection losses with solid-phase trapping and advocated a tandemtrapping procedure (359). Trap temperature and fluid flow ratesare also especially important when modifiers are used with solid-phase traps.

Finally, Vejrosta and co-workers developed a novel collectiondevice that combines attractive features of both solvent andsorbent trapping (360-362). In this device, the restrictor capillaryis placed into a cryogenic trapping capillary. The extractioneffluent sprays into a flow of condensed modifier solvent (i.e., amoving liquid layer) for collection.

Extracting Fluids. Carbon dioxide and carbon dioxide-basedfluids are the predominantly used fluids in SFE. In addition toits favorable physical properties, carbon dioxide is inexpensive,safe, and abundant. The purity issues that previously limited theuse of carbon dioxide for trace analysis have been resolved formost applications. Bernal et al. compared three different gradesof carbon dioxide to show that, when large amounts of extractantsare used, ECD-sensitive compounds can contaminate the extract(363). SFE pumping efficiency is dramatically improved whenliquid carbon dioxide is delivered to the pump. Rather thancooling the pumps to liquefy the carbon dioxide, most commercialinstruments request that carbon dioxide with a helium headpressure be used. While helium is generally considered an inertgas, extraction kinetics can be slowed when helium-entrainedcarbon dioxide is used (364). While the first report of this effectdealt with the extraction rate of cholesterol from dried egg yolk,King et al. showed that the solubility of soybean oil dramaticallydecreased when helium and carbon dioxide mixtures are used(365). When carbon dioxide is not feasible, alternative extractingfluids become necessary. Howard et al. demonstrated the use ofFreons as extracting fluids for environmental samples (366).Results matched those obtained for Soxhlet when chlorodifluo-romethane extracted three- and four-ring PAHs from montmoril-lonite clay. Hillmann and Baechmann observed a 15% increasein the extraction efficiency of pesticides when they used trifluo-romethane, rather than carbon dioxide, as the extracting fluid(367). They did not observe any selectivity differences betweenthe two fluids.

While carbon dioxide is the preferred fluid in SFE, it possessesseveral polarity limitations. Solvent polarity is important whenextracting polar solutes and when strong analyte/matrix interac-


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tions are present. Organic cosolvents are frequently added to thecarbon dioxide extracting fluid to alleviate the polarity limitationsof the fluid. Langenfeld et al. compared nine different carbondioxide modifiers for the removal of PCBs from river sedimentand PAHs from air particulate matter (368). They determinedthat acidic/basic modifiers enhanced the extraction of PCBs, whilemodifiers capable of dipole-induced dipole and π-π interactionsenhanced the extraction of PAHs. Tena et al. also studied thenature of the cosolvent, as well as the volume and contact time,on the SFE of PAHs in soil (369).

Another modifier-based approach for the SFE of polar com-pounds is to use a derivatizing agent and allow for the derivati-zation reaction to occur prior to dynamic extraction. Hillmannand Bachmann demonstrated this approach for the on-line SFE-GC determination of phenoxycarboxylic acids (370). The methodallowed quantitative analysis down to low parts-per-billion levels.Chatfield et al. allowed acidic acids to bind onto an anionicexchange resins prior to methylation with methyl iodide (371).

SFE-COUPLED TECHNIQUESDuring the rapid initial development of SFE, the direct

combination of the technique to subsequent analysis (i.e., on-lineSFE) was promoted. Growth of such approaches has appearedto slow as researchers use the simpler, off-line approaches tounderstand the fundamentals of SFE and instrument manufactur-ers work to establish simple SFE methodology for generallaboratory use. However, one significant advantage of the on-line approach is that the entire extract can be readily analyzedwithout intervening sample handling and contamination, signifi-cantly improving method detection limits. Successful developmentof on-line methods will also provide the complete level ofautomation necessary to gain total acceptance in some situations.Generally, SFE is coupled with chromatographic methods, thoughspecific spectroscopic techniques are also being developed.

SFE/Chromatography. The key to combining SFE withchromatographic methods is the interface between the techniques.Francis et al. used a thermally modulated interface approach forthe SFE-GC determination of explosives with detection with athermal energy analyzer (372). Detection in SFE-GC systems wasalso evaluated by Farnsworth et al. who used a two-channel opticaldevice to enhance the selectivity of sulfur detection with a radio-frequency plasma detector (373). Sandra et al. discussed anumber of applications of the SFE-GC approach (374).

Daimon and Hirata studied trapping efficiency and solutefocusing in coupling SFE with open-tubular SFC (86). Theirapproach used a linear SFE restrictor and a capillary collectiontube containing a stationary phase. Subsequently, they expandedtheir system for use with modified extraction fluids (375). Ullstenand Markides placed a solid-phase adsorption device in front oftheir SFE/SFC system for the automated analysis of polar solutesfrom liquids (88). A dual-trapping system was needed to eliminatethe modifier solvent. Greibrokk reviewed applications of SFEcoupled with chromatography (376).

Other SFE-Coupled Techniques. SFE combined with IRis becoming an accepted method for the determination of totalpetroleum hydrocarbons (332). The technique was collaborativelyevaluated in a number of laboratories. Heglund et al. used achalcogenide fiber optic to construct a simple SFE/IR system(377). For petroleum hydrocarbon determination, the lineardynamic range of this approach covered 3 orders of magnitude.

Taylor and Jordan (378) reviewed SFE/IR, including applicationsto the evaluation of textile fiber finishes. Wang and Marshallevaluated SFE coupled with atomic absorption spectrometry forthe determination of metals in the subnanogram to low-picogramrange (379). During extraction, in situ complexation of the metalspecies occurred. Tena et al. achieved continuous derivatizationand monitoring of extracted analytes with a continuous-flowmanifold that included a flow-through sensor connect in-line withthe SFE collector (380). Braumann et al. monitored the SFEprocess in an on-line fashion using proton nuclear magneticresonance spectroscopy (381). These researchers also obtainedtwo-dimensional NMR spectra during the extraction process.

SFE APPLICATIONSThe largest area of growth in the development of SFE has been

the rapid expansion of applications. Environmental and foodanalysis led the way. Because many of the applications of SFEare interrelated (e.g., pesticides and environmental samples orpesticides, foods, and natural products), the reader should peruseall related applications to gain a more comprehensive understand-ing of the application of SFE to their field of interest.

Fossils Fuels and Environmental Samples. The largestapplication for SFE continues to be in the field of environmentalanalysis. A number of reviews have been written during thisreporting period which can give the reader a broad overview (204,382-389). Hawthorne et al. described the factors that influencequantitative SFE from environmental samples (390). Theyproposed increasing extraction rates through the use of alternativefluids like chlorodifluoromethane, organic modifiers, or elevatedtemperatures.

Hydrocarbons. Furton et al. compared SFE at temperaturesup to 350 °C to Soxhlet extraction for the determination ofbiomarkers in geological samples (391). Higher recoveries withimproved precision were obtained with the supercritical method.Hawthorne et al. also found that SFE gave higher extraction yieldsthan Soxhlet extraction (392). They extracted heavy petroleumhydrocarbons from soil and needed static modifier addition andtemperatures to 150 °C to get the best results. Lighter hydro-carbons, in the gasoline and diesel range, required lower tem-peratures for SFE-GC (393). The optimized SFE-GC system usedsplit injection with high SFE flows, thick-film columns, andcryogenic trapping (394). In extracting petroleum hydrocarbonsfrom soil, Yang et al. compared sorbent- and solvent-basedcollection methods and found that both methods give comparableresults, higher than by Soxhlet procedures (395). Water contenthad no effect on the Soxhlet extraction of soil-bound petroleumhydrocarbons but did affect the extraction efficiency of SFE (396).Camel et al. found that, as soils age, aromatic compounds becomemore difficult to extract than phosphonates and phosphates (397).Oostdyk et al. found that aliphatic amines on soils extractedfavorably with supercritical fluids, compared with sonication (398).Factors that influenced amine recovery included the percent claycontent, the soil surface area, and the cation exchange capacityof the soil. Meanwhile, two studies investigated the parametersthat influence the recovery of petroleum hydrocarbons fromcontaminated soils (399, 400).

Interest in nonsoil matrices was also strong. Bowyer and Pleilused SFE to clean and desorb common air sampling sorbents(401). Hansen et al. developed a sorbent trap to collect atmo-spheric aerosols which were then extracted and analyzed with


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SFE-GC/MS (402). Nguyen et al. employed an in situ trimethy-silylation procedure in the on-line SFE-GC/MS determination ofsterols in sewage sludge (403). A research group at the U.S. EPAcombined SFE with the disk approach to solid-phase extractionprior to the GC/MS characterization of phenols and other traceorganic pollutants in water (404, 405). Daneshfar et al. lookedat the effects of pressure, temperature, and modifiers on theextraction efficiency of phenoxy acids from water (406).

Polycyclic Aromatic Hydrocarbons. The extraction of PAHs fromsoils, sediments, and other environmental matrices remains adifficult proposition that is being addressed by a variety ofapproaches. Three independent laboratories participated in a“mini-round-robin” study of the SFE of these samples (407). Themethod, using carbon dioxide with methylene chloride as theextracting fluid, appears rugged, though interlaboratory methodprecisions appeared to be concentration-dependent. Dean et al.compared SFE with Soxhlet and microwave extraction for PAH-contaminated soil (408). They reported that the SFE andmicrowave approaches yield higher levels of PAHs than Soxhletextraction. Lee et al. notes that, although nitrous oxide andFreon-22 are stronger supercritical solvents than carbon dioxide,the efficacy of carbon dioxide for the extraction of PAHs isimproved with a mixed modifier of water, methanol, and methyl-ene chloride (409). As in the previous report, Meyer andKleiboehmer reported SFE as more efficient than Soxhlet proce-dures (410). They also found nitrous oxide or carbon dioxidemodifiers (toluene, in this case) improved SFE efficiency.(Note: Despite these reports of the use of nitrous oxide for SFE,as we warned in our previous review (1), we do not condone theuse of nitrous oxide in most SFC or SFE applications.) Haeufelet al. reported methanol as their preferred modifier (411). Inevaluating the experimental design for SFE of soil-bound PAHs,Barnabas et al. studied extraction pressure, temperature, time,and percent methanol addition and noted a high level of impreci-sion due to the elemental sulfur content of the soils studied (412).Tena et al. also investigated the parameters to optimize PAHextraction (413). They especially noted the influence of PAHmolecular weight on the extraction efficiency. Reimer and Suarezcompared SFE with Soxhlet using methylene chloride modifieraddition in two different modes (414). They reported that 85% ofthe variance of the SFE method was due to the sample matrix, aphenomenon that seems to be prevalent in this type of analysis.

Rather than using modifiers, Hawthorne and Miller demon-strated that greatly elevated temperatures, 200 °C and higher,proved effective for the extraction of PAHs, chlorinated phenols,and other environmental samples (415). Thermal considerations,i.e., thermal desorption, did not account for the increasedextractability of these materials at these temperatures. Yang etal. found that toluene and diethylamine both provided even greaterefficiency at these elevated temperatures, while methanol wassimilar to pure carbon dioxide (416). Using pure carbon dioxide,Champagne and Bienkowski modeled the SFE of anthracene andpyrene from white quartz sand and soil (417). They determinedthe equilibrium partition coefficients and Freundlich isothermconstants and examined the effect of additional water in the soilphase.

Straightforward uses of SFE showed the seasonal and arealvariations of PAH concentration in street dust (418). Lewis et al.used SFE and a multidimensional LC/GC/MS approach todetermine oxygenated, nitrated, and alkylated PAHs adsorbed

onto urban air particulates (419, 420). They subsequentlyreported that the temporal variations of the PAH correlate closelywith the atmospheric nitrogen oxides and carbon monoxide (421).Stalling et al. patented an SFE and adsorption chromatographymethod for the separation of fullerenes from carbon soot (422).A device to sample indoor PAH and extract them with SFE wasconstructed and evaluated (423). Miao et al. also extractedairborne organic contaminants and found that Florisil was the bestsampling adsorbent (424). Yao et al. determined the PAHs inair particulates near a coke oven with SFE-SFC (218), whileHoener et al. monitored the crude gas of boiler plants with off-line SFE-SFC and fluorescence detection (217). Messer andTaylor extracted aqueous PAHs at the low parts-per-billion levelusing a combination of SPE disks and SFE (425).

Polychlorinated Biphenyls, Dibenzofurans, and Dioxins. Removalof PCBs and other chlorinated compounds from sedimentsrepresents a significant analytical challenge due to the complexityof both the sample and the analyte. Akgerman measured theadsorption isotherms of hexachlorobenzene and pentachloro-phenol on soil and carbon (426). The method subsequentlydeveloped predicted desorption profiles to better understand theSFE process. Langenfeld et al. developed a kinetic model for theextraction of PCDD from soils and sediments after examining SFEat temperatures ranging from 40 to 200 °C (427). Miao et al.used supercritical fluid extraction and cleanup with neat carbondioxide, selective sorbents, and extraction temperatures up to 250°C as a sample preparation method for the determination ofPCDDs and PCBs (428). Larsen and Facchetti reviewed the useof SFE for the analysis of PCDD and PCDF (429). They reportedthat fluids stronger than carbon dioxide, such as nitrous oxideand methanol- or benzene-modified carbon dioxide, are oftenneeded. Sweetman and Watts reported the need for methanol-modified carbon dioxide in developing an SFE method for theremoval of PCBs and chlorobenzenes from soils and sludge-amended soils (430). Tong and Imagawa reported methylenechloride as the optimal modifier for the extraction of PCBs fromsediments (431). The resulting extracts required subsequentcleanup with Florisil and graphitized carbon black. Lee and Peartdid not need carbon dioxide modifiers for the extraction of PCBsfrom sediments, but the method required postextraction samplecleanup and sulfur removal with mercury (432). Bowadt andJohansson extracted PCB congeners from sulfur-containing sedi-ment (433). They evaluated three different trapping adsorbentsand compared their final data to the Soxhlet method. Carbon trapspermitted efficient trapping of a variety of chlorinated compounds,though some dependency on analyte aromaticity and polarity wasnoted (434). Three laboratories performed SFE in an interlabo-ratory comparison of congener-specific PCB analysis (435). Thedata showed that SFE is a very competitive analysis method interms of accuracy and precision. Stachel et al. also found thatSFE compared favorably with Soxhlet extraction for the determi-nation of organochlorine compounds in sediment (436). Johansenet al. developed a method for the determination of planar PCBsin milk and tissue samples, using on-line SFE-LC (437). Analumina sorbent placed in the extraction vessel removed the bulkof the coextracted lipids in the SFE of chlorinated pesticide andPCBs from adipose breast tissue (438). SFE was also used forthe determination of PCBs in lyophilized fish tissue (439). Identityand quantitative determination was accomplished with GC withECD and MS. Lopez-Avila and co-workers directly determined


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PCBs in soil with an off-line SFE-ELISA approach (440). Reactive-modifier systems, such as the addition of BSTFA to the sampleprior to SFE, expedited the extraction of halogenated compounds(441). Kvernheim et al. used different extraction methods(including SFE for nonpolar compounds), purification, and de-rivatization in combination with chlorine-specific GC detection forthe characterization of organohalogen matter in sediments neara bleach plant (442).

Metals and Organometallics. While SFE is generally thoughtof as being applicable to nonpolar organics, there has been a greatdeal of recent research in the application of the technique to metal-containing samples. Lin and co-workers reviewed the applicationof SFE to metal chelates and organometallic compounds (275),while Lin and Wai determined a synergistic effect betweenfluorinated â-diketones and tributyl phosphate for the SFE oflanthanides (443). Meanwhile Laintz and Tachikawa employedtributyl phosphate and thenoyltrifluoroacetone for the SFE oflanthanides in acidic solution (444). Wai investigated a numberof chelating agents and crown ethers for the SFE of trace metalsfrom solid and liquid materials (445). Wang and Marshallestablished the effect of the alkyl chain length on the tetraalkyl-ammonium chelating agent on the SFE of metals from aqueousmedia (446).

Bayona and Cai discussed strategies for the determination oforganotin in aqueous and solid matrices using in situ derivatizationor acid-modified carbon dioxide SFE (278). Alzaga and Bayonaapplied these methods to the SFE of tributyltin and its degradationproducts from seawater (447). In the latter study, they employedsolid-phase extraction disks, followed by in situ Grignard ethyla-tion and SFE of the derivatized disks. Cai and Bayona alsodeveloped a method for the simultaneous speciation of butyl-,phenyl-, and cyclohexyltin compounds (448). Bayona reviewedthis and other work on the determination of organotin compoundsin aquatic sediments (449). A comparison of SFE with animproved tropolone solvent extraction procedure for the deter-mination of butyltin species was made by Chau et al. (450). Acomplexation procedure with SFE was investigated for theextraction of 13 organotin compounds in soils or sediment samples(451). Cai et al. needed only mild SFE conditions, 40 °C and 350atm, to extract butyl- and phenyltin compounds in sedimentsamples after derivatization with hexylmagnesium bromide (452).A more detailed study of the SFE of tributyltin in sedimentrequired the use of methanol-modified carbon dioxide (453). Ionicalkyllead species in sediment and urban dust required methanolmodifier for SFE and postextraction derivatization (454). Li andLi used supercritical Freon extraction and MECC for the deter-mination of alkylead and alkyltin compounds in soil and poly(vinylchloride) plastic (455).

Wai et al. used carbon dioxide with a chelating agent asmodifier for the SFE of organic and inorganic mercury from solidmaterials (456). Wenclawiak and Krah reacted thioglycolic acidmethyl ester with organic and inorganic arsenic compounds priorto SFE and SFC determination (279). Furton et al. used in situchelation from the SFE of uranium from solid matrices (457).Subsequent characterization was by UV absorption spectroscopy.Following the chelation SFE of metals in solid samples, Liu et al.characterized the extracts using GC with atomic emission detec-tion (458).

Miscellaneous Environmental Applications. Kane et al. devel-oped an SFE and SFC method for the analysis of aqueous nonionic

surfactants (226, 459), while Poiger et al. used SFE in the LCdetermination of detergent-derived fluorescent whitening agentsin sewage sludges (460). Louie et al. developed sulfur removalmethods using analytical-scale SFE under pyrolysis conditions oncoal samples (461). Preliminary evidence demonstated that SFErecoveries for explosives can equal those for an 18-hour aceto-nitrile sonication (462).

Pesticides and Herbicides. The extraction of pesticidesand/or herbicides can be a challenging situation due to the typicalsample matrices. Extraction from soils encounters the matrixproblems observed in environmental analysis, and extraction fromanimal tissues may result in a large amount of coextracted lipidmatter. Additionally, many of these agrochemicals or theiranalytes are polar. Brooks and Uden extracted the insecticideabamectin from both sample matrices (463). Soil samples needed2-methoxyethanol modifier, but clean extracts were obtained fromanimal tissues. Argauer et al. dealt with the problem of high lipidlevels in meat samples by extracting carbamates with acetonitrilewhile leaving the lipid matter behind (464). The acetonitrileextract was mixed with diatomaceous earth and extracted by SFEto eliminate coextracted compounds. A mixed-adsorbent systemeliminated fatty acids and sterols from the SFE of carbamates fromtissues such as chicken muscle (465). Snyder et al. alsoinvestigated SFE to remove lipophilic pesticides from chickentissues (466). To extract strychnine from oat grain bait, Kellyand Johnston used two sequential modifiers (467). Methanol-modified carbon dioxide was used during a static extraction stepfollowed by dynamic extraction using chloroform modifier.

Lehotay and Ibrahim extracted pentachloronitrobenzene ana-logs from vegetables using carbon dioxide at 40 °C and 200 atm(468). They used an alumina collection to remove chlorophylland other matrix interferences from the sample. In another study,investigating the presence of 46 different pesticides in fruits andvegetables, Lehotay and Eller used octadecyl-coated silica fortrapping and extract cleanup (469). The same research groupadded Hydromatrix to control the amount of water in the solid,moist vegetable samples (470). Dry ice kept the samples frozenand reduced the degradation or volatilization of several pesticides.Valverde-Garcia et al. added anhydrous magnesium sulfate to thevegetable material prior to the SFE of a very polar pesticide,methamidophos (471). Parks and Maxwell placed a neutralalumina trap in-line during the SFE of pesticides in chicken tissueand did not require subsequent cleanup of the extract (472).Rather than mixing the plant material or extract with an adsorbent,Jimenez et al. lyophilized lettuce leaves prior to the SFE deter-mination of carbendazim (473). On-line SFE-SFC/GC providedaccurate and precise determination of organochlorine pesticides(OCPs) and organophosphorus pesticides (OPPs) from fatty foodsamples like chicken fat, ground beef, and lard (198). Followingextraction, they used packed-column SFC to fractionate thepesticides prior to GC.

Papilloud and Haerdi noted that extracts of atrazine metabolitesfrom soils, sediments, and plants were cleaner with SFE than whenliquid solvents were used, allowing for a more reproducibleanalysis (474, 475). Van der Velde et al. used a multiple linearregression technique to study the effects of parameters on theSFE of triazines from soils (476). Camel et al. evaluated the effectof soil surface area and methanol addition to the SFE of OPP fromsoils (477). They also noted potential difficulties with effectiveanalyte collection. Acid/base interactions are important to the


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binding of pirimicarb to soil, as noted by Alzaga et al. (478). Theyevaluated carbon dioxide, nitrous oxide, chlorodifluoromethane,and a number of carbon dioxide modifiers, with the best resultscoming with pyridine and triethylamine modifiers. Lancas et al.determined norflurazon residues in cotton seeds with an SFEmethod that was improved over existing methods (479). Khanshowed that carbon dioxide with methanol modifier was preferableto either pure carbon dioxide or pure methanol for the extractionof radiolabeled pesticides in soil, plants, and wheat (480). Skopecet al. also found that methanol-modified carbon dioxide wasnecessary for the SFE of OPP from rice (481). Also usingmethanol modifier for the SFE of OCP and OPP, Snyder et al.reported that SFE and sonication methods compare equally forthe recovery of these compounds from four different soils (482).Van der Velde et al. also explored the optimization of extractingOCP from soils (483). High organic content (∼50%) leads to poorrecovery of sulfonylurea herbicides from soils (484). Water andmethanol were added to the soil for this extraction. Reddy andLocke also needed to add water to air-dried soil samples prior toSFE (485). Two studies reported the utility of SFE for degradationstudies. One report studied the breakdown of oxadixyl residuesin food crops (486), while the degradation of s-triazine herbicidesfrom granular activated carbon was investigated by Robertson andLester (487). Additionally, Robertson and Lester extended theirSFE development to include soil matrices and phenylurea herbi-cides (488). They found that the phenylurea herbicides were lesssusceptible to thermal degradation by the SFE technique thanby Soxhlet extraction.

Koskinen et al. used carbon dioxide, methanol, and methanol-modified carbon dioxide to study the binding of atrazine to soils(489), and Cassada et al. determined atrazines in sediments withSFE followed by isotope dilution GC/MS (490). Nam and Kingdeveloped a tool for the rapid screening of pesticides in meat tissueusing SFE and enzyme immunoassay (491). The system featuredpumpless SFE based on the phase change of dry ice as it iswarmed. Lopez-Avila also explored the use of enzyme immu-noassays following SFE of pesticides from soil (492). Del Valleand Nelson compared SFE with a number of liquid extractionmethods for removing atrazine from soil and found that, whilethe methods gave equal efficiencies, SFE was more variable (493).Steinheimer et al. thoroughly explored the SFE of triazines fromsoils (494). They used principal component analysis to correlateeach component in a matrix of dependent variables that includedextraction efficiency. They also noted that the modifiers andconditions used did not promote conversion of chlorotriazines tothe hydroxy or methoxy analogs. Sundaram and Nott constructedan inexpensive, homemade SFE and applied the system to thedetermination of pesticide residues from forest soil and coniferfoliage (495). Tena et al. found that the formation of tetramethyl-ammonium ion pair was needed for the efficient extraction ofsulfonamides from solid supports (496). Lopez-Avila et al. alsoused ion pair formation and derivatization, using tetrabutyl-ammonium hydroxide and methyl iodide during the SFE ofchlorophenoxy acid herbicides from soils (497). Tilio et al. usedSFE to selectively remove interferences from elemental sulfur inthe SFE of chlorinated pesticides from sediment (498). In a ratherunique application of SFE, Paquet and Khan confirmed thatorganophosphates and their metabolites covalently bound toserine residues in protein chains could be released by SFE withoutaltering the protein (499).

Extracting pesticides from water using SFE requires consid-erations different from that of the solid matrices discussed above.Barnabas et al. used the solid-phase extraction disk approach priorto SFE for the determination of OCP and OPP from water (500,501). They were able to extract the OCP with pure carbon dioxidebut needed a methanol-modifier for the OPP. They also studiedthe effect on OCP recovery of increasing the ionic strength ofthe aqueous sample (502). Wolfe et al. employed this sameapproach and were able to maintain biological activity forsubsequent bioassay of water collected from rice fields (503). Hoand Budde also used the combined SPE disk-SFE approach tomonitor rotenone levels in natural river waters (504). The lowpH necessary for the SPE of some pesticide/sorbent combinationsmay degrade some sensitive pesticides (505). The use of bulksorbents and SFE alleviated the acidification problem. Alzaga etal. studied the stability of freeze-dried water for use as a referencematerial and compared liquid/liquid extraction with SFE (506).

Foods and Fragrances. Continued interest in the applica-tions of SFE within the food industry is strong. While otherpotential application areas for SFE have been slow to develop,the application of SFE for food applications is strong for a varietyof reasons, including the use of SFE for food processing. Becausecarbon dioxide will not leave behind any residues, supercriticalprocessing is finding its role in the food industry and this interestand knowledge base are being directly reapplied in the analyticallaboratory. Of course, the other advantages of SFE are alsoapplicable to foods analysis. While workers in other applicationsareas, such as environmental solids analysis, often elaborate onthe difficulty of their analyzes (e.g., matrix interactions), foodanalysis is also less than straightforward due to factors such assample type (e.g., meats vs vegetables), the presence of interferingmoisture or lipid content, and even the definition of the analyte(e.g., does “fat content” include bound vs unbound lipids, phos-pholipids, etc.).

The primary food applications of SFE include essential oils(including flavor and fragrance compounds) and fats and oils.However, SFE is finding utility in other applications as well. Anumber of applications dealt with food processing issues. Pensa-bene et al. explored the occurrence of N-nitrosamines in hamsprocessed with elastic rubber netting (507). The SFE method ismore sensitive, more precise, and faster than the alternative SPEprocedure. Lembke et al. used SFE and GC to simultaneouslydetermine the hydrocarbon patterns and the presence of irradia-tion markers (i.e., alkylcyclobutanones) in irradiated fatty foods(508). Thiebaud et al. studied the fumes generated during thehigh-temperature frying of beef (509). Following SFE of thesample collection filters, they determined chemical compositionby GC/MS and mutagenic activity with a modified Ames Salmo-nella assay. D’Odorico et al. also used SFE to isolate carcinogensand anticarcinogens from dietary and fecal samples (510).Concentrated products, like spray-dried milk, may accumulatecontaminants. Malik et al. determined residues of the animal drugsulfamethazine spiked into spray-dried milk (511). Holak treatedseafood samples and mixed the sample with cellulose powdercontaining stearic acid prior to the SFE of methylmercury (512).Calvey et al. noted higher recoveries of the thiosulfinate allicinfrom fresh garlic and onion when they used sorbent trappingrather that solvent collection (513). Extractions at greater than36 °C led to thermal decomposition. An on-line SFE-GC/FT-IRprocedure for the analysis of basil reduced the total analysis time


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from more than 1 day to 90 min compared with the previousmethod (514). In addition to the pesticide applications previouslydiscussed, SFE is used for specific investigations of fungicides,insecticides, and other related compounds in foods. Atienza etal. used SFE followed by reversed-phase LC for the determinationof fluvalinate in honey from beehives treated for the preventionof varroatosis (515). Aharonson et al. tested potato, banana, andapple samples for benzimidazole fungicides (516). SFE comparedfavorably to liquid extraction procedures for the determination ofaflatoxins in airborne grain dust samples (517). Heikes presentedthe identification of chlorinated fatty acid adducts from thebleaching of flour (518). Supercritical carbon dioxide extractedthe bleaching adducts, which were subsequently purified via acidhydrolysis/methylation and characterized with GC and electrolyticconductivity detection.

Essential Oils. The miscibility of essential oils with carbondioxide leads to a number of applications of the SFE of essentialoils, and other flavor and fragrance components, in the foodindustry and elsewhere. Walker et al. modeled the kinetics ofthe SFE of organic flavor and fragrance compounds from driedlavender flowers and rosemary leaves (519). Reverchon et al.compared the SFE of lavender essential oil with steam distillation(520). The major differences between the two methods wassignificantly higher levels of linalyl acetate in the SFE extract,attributed to hydrolysis during the steam distillation procedure.In a continuing series of reports, Kollmannsberger and Nitz areinvestigating the flavor composition of supercritical extracts ofspices and report the results for allspice and clove (521, 522).Comparison of the SFE with simultaneous distillation/extraction(SDE) shows less thermal degradation products in the SFE profile.Bartley and Foley also noted that the mild SFE conditions do notconcentrate degradation products when they characterized theflavor volatiles of ginger (523).

Vilegas et al. found that oxygenated sesquiterpenes comprisethe main components of essential oils from the laurel family,regardless of whether the extraction method was SDE or SFE(524). This same type of analysis, using the on-line SFE-GCapproach, was performed by Kallio et al. who optimized theiranalysis for the determination of carvone and limonene in carawayfruits (525). Saffrole and other allylbenzenes, such as eugenol,make up the SFE extract of unbrewed sassafras tea determinedby Heikes (526). To extract aroma volatiles from an extrudedoat ready-to-eat cereal, the sample was exposed to high-pressurecarbon dioxide and then depressurized prior to extraction (527).This method improved recoveries and reduced coextracted lipidinterferences. Following extraction, a two-stage fractionationseparation removed undesired compounds from the essential oilof chamomile (528). Goto et al. developed a mathematical modelfor the extraction of the essential oil from peppermint leaves, basedon the local adsorption equilibrium of the oil on lipid in the leaves(529). The adsorption equilibrium constant determined withexperimental data increased with temperature and decreased withpressure. Blanch et al. developed an off-line SFE-GC method foressential oil analysis where they collected the extracted analytesin the quartz liner of a programmed temperature vaporizer (PTV)injector that they placed in their commercial SFE system (530).These researchers subsequently compared the method to con-ventional off-line and on-line SFE-GC for the characterization ofwine aroma (531). Mau et al. reviewed the aroma and flavorcomponents of cultivated mushrooms and noted SDE, SFE,

headspace techniques, and solvent extractions as the isolationmethodologies currently used (532). The volatiles and semi-volatiles in oilseed could be determined without interferences witha method developed by Snyder and King (533). The extract wasnot contaminated with compounds resulting from lipid degrada-tion, due to the mild SFE conditions.

Yao et al. determined the flavonoid in Gingko biloba leaves withSFE and LC (534), while Verotta and Peterlongo determined thetoxic phenolic components of G. biloba with SFE and GC/MS(535). Poiana et al. desired an essential oil extract from bergamotthat was free of bergapten, a phototoxic compound (536). SFEproduced an oil 6 times lower in bergapten than the conventionalcold-pressed oil. Dugo et al. deterpenated sweet orange andlemon oils by SFE (537). Anklam and Mueller extracted vanillinand ethyl vanillin from flavored sugars and compared the resultsto the values declared on the sample package (538). A sesqui-terpene-rich volatile fraction was obtained in the SFE of guava(539). Smith and Burford extended the SFE of essential oils tomedicinal herbs, such as feverfew, tansy, and chamomile (540).Sagrero-Nieves et al. determined aromadendrene as the majorconstituent of the SFE extract of tamarind (541). Not all analysesof aromas in the food industry dealt with the foods themselves.Nielsen and Jaegerstad found that they could measure the aromacompounds sorbed by plastic packaging materials (542). Themethod was then applied to the determination of the partitioncoefficients between apple aroma and common packaging materialand to the study of limonene sorption in refillable poly(ethyleneterephthalate) bottles.

Fats and Oils. Bartle and Clifford published two extensivereviews on the advantages of using SFE and SFC for lipid analysis(157, 158). In a more specific review, Staby and Mollerupdiscussed solubility data, SFE, and SFC of fish oil (167), Mishraet al. presented SFE and SFC as methods for the direct extractionof oils rich in ω-3 fatty acids and the concentration of the esterifiedforms of these acids (543), and Paschke reviewed the SFE of fatsand oils in food, mineral oils in wastes, and metalworking oils onsteel (544). To study the SFE of lipids in a multiple number offood products simultaneous, King et al. developed an extractorcapable of extracting six samples simultaneously (545). Theybalanced fluid flow between the extraction vessels and alsoexplored the extraction of pesticides from adipose tissue. Sub-sequently, this extractor was used to determine the fat content offoods in a total diet study (546). They found reproducible resultsfor a variety of food types including meats, snack chips, cheese,and peanut butter. Levy and co-workers developed manual andautomated SFE methods for the gravimetric determination of fatsin snack foods and animal feeds (547).

Thermal oxidation of oils, such as canola, can be studied withSFE, as presented by Hansen and Artz (548). Walker et al.investigated the oil content of ground and dried canola and neededa moisture adsorbent during the extraction (549). By using asorbent trap, Snyder and King characterized the volatile andsemivolatile constituents of SFE processed soybean oil (550). Themethod can be used to monitor the extraction and the quality ofthe resulting oil. Snyder used this approach for the characteriza-tion of the volatiles in oxidized canola, corn, soybean, andsunflower oils (551). Peroxide values correlated well with theincreasing concentration of several volatiles in the oxidized oils.Another SFE method for the determination of volatiles in lipidextracts is the method of King et al. for the study of raw beef


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(552). During SFE, they collected noncondensible volatiles onTenax for further characterization and examined the volatiles inthe lipid fraction by direct headspace sampling. Li et al. used amultivariate optimization scheme to develop SFE for the extractionof vitamin E in corn oil (553). Maness et al. determined that SFEand organic solvents produce extracts with the same composition(554). Carboxylic and fatty acids were determined in mushroomsand compared to those reported earlier with other methods (555).The SFE method extracted several acids that had not beenpreviously reported from these sources. Suzuki et al. character-ized the polyunsaturated fatty acids in fish oil by mixing the oilwith aqueous silver nitrate prior to SFE (556). For the charac-terization of fat and cholesterol in beef patties, King et al. examinedthe effect of freeze-drying before and after cooking (557). Freeze-drying enhanced the extraction of both fat and cholesterol. Thelipid and cholesterol contents of meat and beef tallow can bereduced with SFE using carbon dioxide (558).

Carotenoids are also of interest and were determined in sweetpotatoes by Spanos et al. (559). The SFE extract contained upto 94% â-carotene with an isomer composition of approximately14% 13-cis and 11% 9-cis. Birtigh et al. evaluated SFE as a methodto determine whether palm oil extracts were enriched in caroteneor tocopherol for downstream processing (560). They alsodetermined solubility data for R-tocopherol in carbon dioxide.Phospholipids are generally not soluble in carbon dioxide andcannot be extracted without the use of modifiers. Dunford andTemelli studied ethanol as a carbon dioxide modifier for theextraction of phospholipids in canola (561). Lancas et al.optimized the use of supercritical pentane for the extraction ofsoybean oil (562).

SFE is also applicable to the study of fat substitute compoundsand other fat-related materials. One of these materials is SALA-TRIM. Huang et al. characterized these interesterified triacyl-glycerols in foods with SFE and LC and compared with standardfat determination methods (563, 564). LC detection was per-formed by MS and by evaporative light-scattering detection. Artzand Myers characterized selected emulsifiers using SFC and SFE(230). The emulsifiers studied included acetylated monoglycer-ides, lactylated monoglycerides, hexaglycerol distearate, triglyc-erol mono-/dioleate, and decaglycerol decaoleate. Boutte andSwanson used SFC and SFE to characterize fat substitutes of themethyl glucose polyester and sucrose polyester type (565).

Polymers. The inherent diffusivity and adjustable solventstrength advantages of supercritical fluids make them favorablefor the extraction of materials from polymers. The increasedsolvent properties of these fluids can be exploited to extractpolymers. Clifford and co-workers compared theoretical modelsto experimental results for the extraction of additives and othermaterials from polymers (566). They discussed diffusion andsolvation limitations. Diffusivity issues were also important forthe extraction of binders in ceramics (567). Franz et al. usedSFE-SFC to study the migration and release of materials inrecycled plastics for possible use as food packaging materials(568). This coupled approach, SFE-SFC, often combined with MS,found great utility in the evaluation of polymer homologs andadditives. One group demonstrated the approach for bothstructural research work and routine polymer analysis (246).Meanwhile, McKay and Smith developed SFE-SFC/MS for thestudy of organophosphate flame retardants in polyurethane foams(239) and other polyurethane additives (240). Brominated flame

retardants in low-density polyethylene were determined withcarbon dioxide after studying the influences of temperature,pressure, and methanol addition (569). Janda et al. used SFEwith SFC to characterize aromatic amines in rubber and othermaterials (570). Quantitative recovery was obtained from inertmaterials, but acidic matrices yielded poor results. In studyinghigh- and low-density polyethylenes, Juo et al. found that SFEproduced results similar to toluene extraction (571). Werthmannet al. also found that results for extracting additives from rubberwas similar for SFE and conventional solvent extractions (572).The amounts of antioxidants in the SFE extracts were determinedwith LC. De Crosta and Jagnandan patented an SFE method forthe removal of residual additives from elastomers (573). In oneclaim, they removed phthalates and PAHs from rubber articles.Gawdzik and Matynia investigated the efficiency of porouspolymer purification with SFE-GC/MS (574). Venema et al.looked at SFE for the removal of caprolactam and oligomers fromnylon-6 (575).

One industry where supercritical fluid techniques can findparticular utility is the textile industry. Raynor and Bartlereviewed the application of SFC and SFE to the study of surfacecoatings (242), while Drews et al. reviewed specific textile andfiber applications (576). Drews et al. compared a number ofcommercial SFE systems for the characterization of extractableson fibers, yarns, and textiles (577). These researchers establishedthe temperature and pressure effects of the extraction efficiencyand composition. Kirschner et al. developed an on-line SFE-IRmethod for the analysis of fiber finishes, ranging from poly-(dimethylsiloxane) oil to multicomponent finishes containingsurfactants, soaps, antioxidants, and oils (578). Jordan et al. usedthis on-line SFE-IR procedure for the determination of polyester-fiber finishes, such as the percent finish on yarn (579). Sikorskifiled a patent for using SFE to extract pure polymeric componentsfrom textile wastes, such as carpets and disposable diapers (580).

Natural Products and Drugs. A variety of natural products,especially high-value-added products, are processed with super-critical fluids. Since many of these have pharmacological activity,a natural extention of this application is to the field of druganalysis. A French review discussed the SFE of compounds ofplant origin (581). Sargenti and Lancas constructed an SFEsystem for the semipreparative SFE of natural products (582),while Queckenberg and Frahm built a unit for analytical SFE ofthreatened Amaryllidaceae species (583). Taylor et al. employedon-line SFE-SFC for the study of single seeds of a desert botanical(185). Their results indicated that the resin sac may be particu-larly enriched in odoriferous compounds. Henning et al. werealso concerned with the large sample amounts needed forconventional extraction methods and used SFE to study specificmorphological regions from individual plants (584). They appliedSFE to study volatiles associated with alfalfa germplasm tissue.These researchers applied the approach to the study of the effectof stem and leave volatiles on resistance to weevils (585).

Simoes et al. developed a countercurrent column for theseparation of terpenes for the purification of eucalyptus oil (586).Bicchi and co-workers compared SFE with hydrodistillation andsolvent extraction of triterpenes in iris rhizomes (587). Rhizomesof Zingiber zerumbet were extracted by Ahmad et al. (588). Theyplaced a silica column in-line to obtain an extraction of nonpolarcomponents. Terauchi et al. found that the compositions ofsupercritical extracts of conifer woods were similar to the essential


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oils obtained by steam distillation (589). The SFE extracts alsocontained higher levels of high molecular mass compounds andterpenes. Mendes et al. studied the SFE of hydrocarbons from amicroalga (590). The extraction behavior led the researchers tobelieve they were extracting the hydrocarbons outside of the cellwall. They subsequently refined their approach for studying othermicroalgae and plant tissue (591). Needles and seeds of Taxuscuspidata contained taxol, as determined by Chun et al. (592).Heaton et al. combined SFE with SFC and NMR to evaluate thetaxanes in yew needles (271). Miki et al. compared SFE withSoxhlet extraction for the extraction of mangrove and determinedthe antitermite activity of the extracts (593). Acid hydrolysis priorto SFE led to the extraction of diosgenin from a plant tuber (594).Prokopczyk et al. developed SFE as an integral step in the analysisof tobacco-specific N-nitrosamines (595). Terpenoids extractedwith SFE were similar to those obtained by Soxhlet proceduresfor Moraceae species, providing a method for rapid phytochemicalexamination (596). Moria et al. investigated the SFE of oxygen-containing sesquiterpenes (597). Cocks et al. compared the useof SFE for the extraction of biologically active compounds fromthe biomass of microbial fermentations with methanol andmethylene chloride extractions (598).

The extraction of drugs and other materials of medicinal valueis necessary. The specific samples may be the natural productsfrom which they originate, the drug formulation, or the biologicalsystems where they interact. Drug formulations are designed tobind the materials they carry until the drug enters the appropriatebiological system. One formulation type is tablets. Scalia et al.showed that SFE can minimize the number of sample-handlingsteps in the characterization of vitamin tablets (599). The mildextraction conditions allowed extraction of labile materials andwere suitable for quality control applications. They also used SFEfor the extraction of these same vitamins from cosmetic creamsand lotions (600). The degree of sample dispersion influencedthe SFE efficiency. Another group extracted water-soluble vita-mins with a reversed micellar solution (601). They needed SFEwith ethanol-modified carbon dioxide to remove the residualsurfactant from the isolated vitamins. Takaichi et al. employedboth SFE and SFC for the evaluation of benzodiazepine trans-quilizer tablets (263). They reported recoveries that variedaccording to analyte polarity, with the lowest recoveries occurringwith the most polar materials. Lawrence et al. also used SFE toisolate benzodiazepines from solid dosage forms (602). Theselatter researchers claimed that extracts of suitable purity andquantity for MS analysis were obtained, even with low concentra-tion dosage forms.

Dean and Lowdon compared SFE with a USP monographmethod for the analysis of megestrol acetate from tablet formula-tions (603). The researchers observed different recoveries withtwo different commercial SFE systems, presumably due to solutecollection considerations. Howard et al. needed sequential staticand dynamic steps for the effective extraction of felodipine fromsustained-release tablets (604). Messer et al. demonstrated theimportance of trapping considerations for the SFE of a pharma-ceutical in animal feeds (605). In many instances the solute ofinterest is too polar to be effectively extracted by SFE. In thiscase, SFE can successfully be applied to the removal of theformulation matrix to isolate the drug material. Moore and Taylordemonstrated this approach for low concentrations of polarpharmaceuticals in semisolid Neosporin ointments and creams

(606). Messer and Taylor used this inverse SFE approach toinvestigate Zovirax ointment (607).

Extracting drugs and metabolites from tissues, fluids, and otherbiological matrices represents another challenge. Walker et al.reviewed a number of newer extraction methodologies, includingSFE, for the analysis of drugs and environmental pollutants inaquatic species (608). Edder et al. employed polar modifiers withcarbon dioxide to extract morphinic alkaloids (609, 610). Theopiates in urine and other liquids required adsorption onto a solidsupport (609), while hair samples could be extracted directly andthese small samples could be easily accommodated by SFE (610).Liu and Wehmeyer extracted drugs directly from plasma withoutimmobilization onto a solid support; however, the samples weretreated with an antifoaming agent to minimize restrictor plugging(611). Karlsson et al. extracted a corticosteroid from plasma,using a low-density initial extraction to remove interfering water(612). Muellner et al. obtained a German patent for the SFE ofa number of organic compound classes from complex matricessuch as tissue, feces, urine, and serum (613). Metals andorganometallics in biological studies could be determined withSFE and ICPMS (614, 615). Organotins were characterized intuna fish (614), and arsenic compounds in a certified dogfishmuscle were determined (615). Wang and Marshall investigatedSFE to characterize cadmium, zinc, and copper bound to metal-lothionein isolated from rabbit liver (616).

Polychlorinated biphenyls (PCBs) incurred in biological samplescan be extracted with considerations for extracting PCBs fromenvironmental samples, as previously discussed, and biologicalsamples. Alley and Lu separated PCBs from fish tissue andchicken egg containing high levels of fat (617). Florisil cleanupfacilitated separation of PCBs from the lipid material. Lee et al.used alumina in-line during their SFE of PCBs in fish, in additionto Florisil cleanup (618). Hale and Gaylor also extracted PCBsin fish tissue using the in-line alumina approach without subse-quent Florisil cleanup (619). Quantitative extraction of PCBs fromhuman adipose tissue was achieved by van Bavel et al. (620).

Klink et al. compared SFE with carbon dioxide and chlorodi-fluoromethane for the removal of free carboxylic acids and sterolsfrom a plant tissue and a sediment sample (621). Mgrd and co-workers extracted androstenone from boar fat samples. Theyimproved selectivity by mixing alumina with the sample (622).Acosta et al. adjusted SFE conditions to selectively extract fat fromphospholipid biomembranes structures (623). Modified fattyacids, acetogenins, were extracted from seed oil as a potentialsource of these bioactive materials (624). An unrefined woolgrease extract resembled high-grade commercial lanolin in termsof color and odor (625). Selective fractionation could yieldproducts enriched in cholesterol. The effect of organic modifierson the SFE of fungal lipids was determined and the costs ofdeveloping SFE processing were estimated (626).

Miscellaneous Applications. As SFE develops, applicationsthat do not fit into the categories defined above are beingdeveloped. Lin et al. extended their previous work on the SFEof metal compounds to the SFE of uranium- and thorium-containing materials from nitric acid solutions with organophos-phorus reagents (627). Wang et al. extracted mercury withionizable crown ethers (628). Purtell et al. cleaned precision metalparts with SFE and characterized the extracted hydrocarbons,silicones, and fluorocarbons with SFC (629). Dahmen et al.extracted hydrocarbon oils from grinding and metal working waste


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with carbon dioxide (630). Lim and co-workers described theinfluences of fluid properties, phase flow rates, column dimensions,and phase dispersion on both mass-transfer efficiency andhydraulic characteristics of spray and packed-extraction columns(631). Esser and Klockow coupled SFE with thin-layer chroma-tography to detect hydroperoxides in combustion aerosols (632).Taylor reported the monitoring of propellant stability with SFEby studying the aging of single-base propellants (633). A patentdescribed the used of SFE for the remediation of pentachlorophe-nol-containing wood (634).

OTHER SUPERCRITICAL FLUID MEASUREMENTSAND RELATED TECHNIQUES

Other applications of supercritical fluids may be of interest tothe analytical chemist. Huang et al. used an SFE method to cleansilica aerogel particles intended for use as a cosmic dust capturemedium (635). A patent was issued for monitoring contaminantlevels in supercritical fluid streams using a quartz crystal mi-crobalance (636). An aerosol solvent extraction system wasdescribed for the production of microparticles (637).

Microwave extraction systems have been commercialized.Meanwhile, another, similar analytical extraction technique, ac-celerated solvent extraction, was introduced by Dionex (638-642). Both of these extraction methods are fundamentally similarto SFE in that the extraction is conducted at elevated pressure sothat temperatures greater than the atmospheric boiling point ofthe extracting fluid can be used. At these temperatures, propertiesinfluencing analytical extraction, such as diffusion, viscosity, andsolubility, become more favorable. While initially developed forthe environmental field, the application of these new techniquesto other areas will proceed rapidly. In another related method,Huettenhain et al. modified an LC system for extraction (643).Soil, denatured with an inert salt, acted as a stationary phase forthe elution of organic compounds.

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(4) Stadler, M. P. Ph.D. Dissertation, Stanford University (UniversityMicrofilms Int., Order No. DA9302317), Stanford, CA, 1992.

(5) Ziegler, J. W.; Dorsey, J. G.; Chester, T. L.; Innis, D. P. Anal.Chem. 1995, 67, 456-461.

(6) Cortesi, A.; Fermeglia, M.; Kikic, I.; Spicka, B. Lat. Am. Appl.Res. 1992, 22, 125-133.

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5-11.

Thomas L. Chester received his B.S. in chemistry from the FloridaState University in 1971, spent a year at the Baychem Corp. in Charleston,SC, and then began graduate studies at the University of Florida underthe direction of J. D. Winefordner. He received the Ph.D. degree in 1976and joined Procter & Gamble where he is currently Head of theSeparations and Optical Spectroscopy Section, Corporate ResearchDivision, at the Miami Valley Laboratories. He has been active in SFCresearch and application since 1982. His research interests also includeother microcolumn techniques, SFE, and chromatography detectors.

J. David Pinkston came to Procter & Gamble in 1985 after receivinghis Ph.D. from Michigan State University. Before beginning his graduatestudies in 1980, he spent a year working with G. Spiteller at the Universityof Bayreuth in West Germany as a DAAD Fellow. He received his B.S.in chemistry and math in 1979 from Ouachita Baptist University inArkadelphia, AR. He is currently a member of Procter & Gamble’sCorporate Research Division at the Miami Valley Laboratories. Hisresearch interests include the development and application of SFC andSFE and the coupling of microcolumn separation methods with MS.

Douglas E. Raynie is a Senior Scientist in the Corporate ResearchDivision of Procter & Gamble. He received his Ph.D. in analyticalchemistry in 1990 from Brigham Young University. He has an M.S. inanalytical chemistry from South Dakota State University and a B.A. inbiology and chemistry from Augustana (SD) College. He is on theEditorial Advisory Board of the Journal of Microcolumn Separations,responsible for Microcolumn Abstracts, and is President of the Tri-StateSupercritical Fluids Discussion Group. His research interests includeanalytical uses of supercritical fluids, high-resolution chromatographicmethods, and chromatographic and separations theory.


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Supercritical Fluid Chromatography and Extraction 1996

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