History of supercritical fluid chromatography: Instrumental development

Journal of Bioscience and Bioengineering VOL. 115 No. 6, 590e599, 2013 www.elsevier.com/locate/jbiosc

REVIEW

History of supercritical fluid chromatography: Instrumental development Muneo Saito* JASCO Corporation, 2967-5 Ishikawa-cho, Hachioji, Tokyo 192-8537, Japan Received 12 September 2012; accepted 5 December 2012 Available online 11 January 2013

In the early days of supercritical fluid chromatography (SFC), it was categorized as high-pressure or dense gas chromatography (HPGC or DGC) and low boiling point hydrocarbons were used as supercritical mobile phase. Various liquids and gases were examined, however, by the late 1970s, carbon dioxide (CO2) became the most preferred fluid because it has low critical temperature (31.1
C) and relatively low critical pressure (7.38 MPa); in addition, it is non-toxic, nonflammable and inexpensive. A prototype of a modern packed-column SFC instrument appeared in the late 1970s. However, in the 1980s, as open tubular capillary columns appeared and there was keen competition with packed columns. And packed-column SFC at once became less popular, but it regained popularity in the early 1990s. The history of SFC was of “the rise and fall.” Advances in chiral stationary phase took place in the early 1990s made packed-column SFC truly useful chiral separation method and SFC is now regarded as an inevitable separation tool both in analytical and preparative separation. Ó 2012, The Society for Biotechnology, Japan. All rights reserved. [Key words: Supercritical fluid; Chromatography; Open tubular capillary column; Packed column; Preparative supercritical fluid chromatography; Chiral separation]

What is a supercritical fluid? It is a highly compressed gas that has a density similar to that of a liquid. Fig. 1 shows the phase diagram of a pure substance. At the triple point (TP) the three phases (gas, liquid, and solid) of the substance coexist in thermodynamic equilibrium. As the temperature goes high, the substance coexists in two phases, i.e., gas and liquid. At the critical point (CP) and in the region the temperature and the pressure are above the critical temperature and pressure, the substance exists in a single gaseous phase. The substance in this region is defined as in the supercritical state where the density is liquid-like while the viscosity is gas-like, and the diffusivity is in between those of a liquid and a gas as shown in Table 1 (1). It is expected that a supercritical fluid, which has the higher diffusivity and the lower viscosity than a liquid solvent, will function much better than a liquid solvent as an extractant and a mobile phase in extraction and chromatography. Chromatography that uses a supercritical fluid as the mobile phase, i.e., supercritical fluid chromatography (SFC), was first reported by Klesper et al. (2) as high-pressure gas chromatography (HPGC) in 1962, a little before the advent of high-performance liquid chromatography (HPLC). Although SFC has a history as long as or even a little longer than that of HPLC, it was not so long ago, probably in the latter half of the 1990s, when SFC was recognized as a truly useful separation method. There are a few reasons why it took such a long time. The greatest reason is the advent of HPLC. At the time of the first report on SFC, gas chromatography (GC) was * Tel.: þ81 42 646 4111x204; fax: þ81 42 643 0053. E-mail address: [email protected].

already a well established method and its instrumentation was readily available from several commercial sources and researchers’ interest was shifted to an analytical method that could analyze thermally labile, non-volatile or polar compounds that could not be separated by GC. Liquid chromatography (LC) has the potential to realize these requirements, however, stationary phases and instrumentation available at the time did not allow high-speed and high-efficiency analysis comparable to that of GC. And tremendous efforts were paid to the development of HPLC. Although SFC is not as versatile as LC, it too has good potential. The development of SFC was unfortunately shaded by the rapid development of HPLC that took place in the latter half of the 1960s and the 1970s. There are two important review articles on SFC, one published in 2009 by Taylor (3) and the other in 2011 by Guiochon and Tarafder (4). Taylor (3) overviewed various techniques in SFC and put them into a compact and comprehensive article. Guiochon and Tarafder (4) covered every aspect of SFC including theoretical and empirical treatments of physicochemical properties of high temperature and high-pressure fluids, even including thermodynamics and the equations of state. Their article is roughly 77 pages and could be a small monograph. The author recommends the readers to read these review articles for an in-depth understanding of SFC. In this article, the author covers mainly a history of instrumental development that was partially discussed in the above reviews. Fig. 2 shows the number of articles on SFC published each year from 1962 to 2012. In the 1960s, the number is very small and does not chart as well relative to the later years. In the 1970s, the number varies but not more than 30 per year. However, in the 1980s, the number exponentially increases from 15 to over 400 in a decade. In

1389-1723/$ e see front matter Ó 2012, The Society for Biotechnology, Japan. All rights reserved. http://dx.doi.org/10.1016/j.jbiosc.2012.12.008

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HISTORY OF SUPERCRITICAL FLUID CHROMATOGRAPHY

591

900 800 Supercritical Fluid

700

Melting curve

600

Pressure

Pc

500 400

CP

Liquid

300 200 100

rv e

n io at or p a Ev

cu

0 1962 1964 1966 1968 1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012

Solid

Gas

TP FIG. 2. Numbers of publications on supercritical fluid chromatography. Based on a Google Scholar search performed on July 2, 2012.

Sublimation curve

Tc Temperature FIG. 1. Phase diagram of pure substance. TP: triple point; CP: critical point; Pc: critical pressure; and Tc: critical temperature. These parameters are specific to each substance. Reproduced from Saito et al. (47) with permission of John Wiley & Sons, Inc.

the 1990s, the number is somehow saturated at around 500e600. Then, it rapidly increased again in the first decade of the 21st century. EARLY WORKS IN HIGH-PRESSURE GAS CHROMATOGRAPHY (HPGC) OR DENSE GAS CHROMATOGRAPHY (DGC) Works of early pioneers In the early days, presently accepted terminology “supercritical fluid chromatography (SFC)” for the method was not established, and various terms were used such as (ultra) HPGC and dense gas chromatography (DGC). The first report on SFC by Klesper et al. (2) appeared in the Communications to the editor section of Journal of Organic Chemistry in 1962. It is a brief report, less than 2 pages. They indicated thermally labile porphyrin mixtures were separated on polyethylene glycol stationary phase with two mobile phase gases such as dichlorodifluoromethane (Tc ¼ 112
C) and monochlorodifluoromethane (Tc ¼ 96
C) at temperatures of 150e170
C. They also stated “above 1000 psi (7 MPa) with the first and 1400 psi (9.8 MPa) with the second, vaporization increased with increasing gas pressure”, indicating that porphyrins were dissolved in the supercritical mobile phase. In addition, they foresaw the possibility of preparative SFC by stating “the porphyrins could be recovered at the outlet valve.” Sie et al. (5e8) published a series of articles on HPGC in 1966 and 1967. They used supercritical carbon dioxide as the mobile phase and discussed fluidesolid and fluideliquid separation modes. It should be noted that they developed a sophisticated pneumatically

operated injector in order to inject a sample under high-pressure and high-temperature conditions. It is also unique that they used a UV absorption detector with a quartz cell that was equipped with a gaseliquid separator and detection was carried out under atmospheric pressure. Both devices did not survive, however, the author thinks it is worth mentioning these pioneering works. Sophisticated instrumentation developed in the late 1960s In 1968, Klesper’s group reported a new SFC system (9). The system was equipped with a mechanical backpressure regulator that could control the pressure independent of the flow rate. The detector was a filter photometer with a high-pressure flow cell. It should be noted that the detector used in HPLC at that time was a simple single-wavelength photometer with a low-pressure Hg discharge lamp as the light source which emits UV light at 254 nm (10). In 1968, vacuum tubes were still in use and the transition to transistors had just begun. Therefore, the author believes that the system consisted of a sophisticated analog servo system with vacuum tubes. It is remarkable that a prototype of a modern packed-column SFC appeared more than 40 years ago. In 1969, Giddings et al. (11) reported DGC. In the article they stated “One of the most interesting features of ultra-high-pressure gas chromatography would be its convergence with classical liquid chromatography. A liquid is ordinarily about 1000 times denser than a gas; at 1000 atm, however, gas molecules crowd together with a liquid-like density. At such densities intermolecular forces become very large, and are undoubtedly capable of extracting big molecules from the stationary phase. Thus in effect, non-volatile components are made volatile.” The first sentence seems to imply the unified chromatography that was later realized and reported by Ishii et al. (12) in 1988 and more recently by Chester and Pinkston (13). The latter part of the paragraph describes solvation of a solute in a supercritical fluid. This phenomenon was investigated and well elucidated by Kim and Johnston (14) in 1987 and Kajimoto et al. (15) in 1988. Their works will be explained later.

TABLE 1. Properties of gas, liquid and supercritical fluid.a Property

Density Diffusivity Viscosity a

Units

r (g cm3)

Dm (cm2 s1)

h (g cm1 s1)

After Takishima and Masuoka (1).

Gas 1 atm, 25
C

0.6e2  103 1e4  101 1e3  104

Liquid 1 atm, 25
C

0.6e1.6 0.2e2  105 0.2e3  102

Supercritical fluid Tc, Pc

Tc, 4Pc

0.2e0.5 0.5e4  103 1e3  104

0.4e0.9 0.1e1  103 3e9  104

SAITO

Giddings et al. proposed an extension of the Hildebrand solubility parameter to a supercritical fluid (11). They used various gases including He, N2, CO2 and NH3, and examined retention behavior of various substances such as purines, nucleosides and nucleotides, steroids, sugars, terpenes, amino acids, proteins, carbowaxes, etc. However, CO2 later became the most preferred fluid because it has low critical temperature (31.1
C) and relatively low critical pressure (7.38 MPa), in addition, it is non-toxic, non-flammable and inexpensive. Today, an SFC mobile phase automatically assumes a pure or mixture of CO2 and organic modifiers. SFC instrumentation with pressure programming and fractionation capability In 1970, Jentoft and Gouw (16) reported a new SFC system that allows pressure programming. They separated polycyclic aromatic hydrocarbons and styrene oligomers utilizing pressure programming. In the case of a supercritical mobile phase, the higher the pressure, the stronger the solvating power becomes. Thus, it functions similar to gradient elution in LC. They claimed that their new SFC system offered comparable performance to high resolution LC (note that the terminology “high-performance liquid chromatography” was not yet generally accepted at that time). It is remarkable that they already developed such a sophisticated SFC system as early as in 1970. At that time, HPLC was still in an early developmental stage and there was an argument as to which type of the pump (i.e., a syringe, a reciprocating or a constant-pressure pump) was best suited for the HPLC pump. In 1972, they developed a highpressure fraction collector to fractionate components eluted from an SFC system, proving that SFC can be used for preparative applications (17). In 1977, Klesper and Hartman (18,19) reported a sophisticated preparative SFC (prep-SFC) and fractionation of styrene oligomers. Fractions were analyzed with mass spectrometry, thus, constituting offline SFC-mass spectrometry (MS). In 1978, Randall and Wahrhaftig (20) described a dense gas chromatography (DGC)/ mass spectrometer (MS) Interface. In 1980, a monograph edited by Schneider et al. (21) was published. This book covers developments that took place mainly in Europe in the 1960s and 70s such as plant scale supercritical fluid extraction (SFE) and their applications, physicochemical studies of supercritical fluid including phase equilibria, analytical scale SFE combined with thin layer chromatography (TLC), and SFC. OPEN TUBULAR CAPILLARY COLUMN VERSUS PACKED COLUMN, AND OTHER DEVELOPMENTS

J. BIOSCI. BIOENG., a schematic diagram of a typical GC-like open tubular column SFC system. The SFC system sold well in the beginning mainly in the US, however, within a few years, it was revealed that it had intrinsic technical difficulties. Technical advantages of SFC over other modes of chromatography such as GC and LC are summarized as in Table 2. In SFC, all three parameters (i.e., pressure, temperature and modifier content) can independently or cooperatively control retention, or even a gradient method can be applied to all the parameters. These advantages were too heavily emphasized at that time. Therefore, it often misled chromatographers to think that SFC was a type of super chromatography. However, in the case of open tubular capillary SFC, pressure (or density that is inversely proportional to the pressure under the certain conditions) which is the most important operating parameter, could only be varied by changing the flow velocity due to the limitation of the constant restrictor. This means that the pressure could not be changed independently of the flow velocity. Therefore, one could never obtain the optimum flow velocity at the optimum pressure. In addition, the standard FID detector could not be used with an organic modifier because even a small amount of organic solvent produced too high a background on the baseline, limiting application range. There were a few attempts to use premixed CO2 with an organic solvent in the cylinder to add some polarity to the CO2-based mobile phase in order to elute polar compounds using a UV absorption detector equipped with a micro flow cell. However, this technique did not attract chromatographers because they could not change the modifier content as required or run modifier gradient elutions. Thus, it could not extend the application areas, and open tubular capillary column SFC rapidly diminished in the early 1990’s. Taylor intensively described the history of open tubular capillary column SFC (3). Packed column Before the advent of open tubular capillary column SFC, all SFC research works were performed using packed columns. While open tubular capillary column SFC was GC-like instrument, packed-column SFC was more like LC. In 1982, Gere et al. (24) modified a HewlettePackard (HP) HPLC system to operate as an SFC system by adding a backpressure regulator and other devices. They showed that SFC gave higher efficiency with 3, 5 and 10 mm packing materials especially in high flow velocity region. Packed-column SFC was developed almost independently of open tubular capillary column SFC. Packed-column SFC at once became less popular, especially in the US due to the marketing strategy of open tubular column SFC in the middle of 1980s.

Research activities on column technology and instrumentation were very active and diverse in the 1980s, and this led to the commercialization of SFC instruments. Open tubular capillary column In 1981, Novotny and Lee’s group introduced open tubular capillary column SFC (22). A typical open tubular capillary column was a 50 mm inner diameter fused silica capillary tube and the internal wall was coated with a polymer such as dimethyl polysiloxane that functioned as the stationary phase. Novotny et al. (23) previously studied retention behavior of packed columns under various conditions, and stated that a packed column could not give high-efficiency at high-linear velocity because of the pressure drop along the column that functions as a negative density gradient. They emphasized that a small pressure drop across an open tubular capillary column would give higher efficiency than a packed column. Later open tubular capillary SFC was patented and exclusively marketed by Lee Scientific. The system consisted of a syringe pump, an injection valve with a split mechanism, a GC-like oven, a wall-coated open tubular column, a fixed restrictor, and a flame ionization detector (FID). Fig. 3 shows

Injection Valve FID

Preheat Coil

CO2 Cylinder

Drive Mechanism

Column

Restrictor

592

Column Oven

Syringe pump FIG. 3. Schematic diagram of typical GC-like open tubular column SFC system. Since the flow rate is very low, a screw-driven syringe pump is used. Backpressure is applied by a restrictor that has a certain flow resistance to keep the system pressure above the critical pressure of the fluid. Pressure was controlled by changing the mobile phase flow rate. Reproduced from Saito et al. (47) with permission of John Wiley & Sons, Inc.

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HISTORY OF SUPERCRITICAL FLUID CHROMATOGRAPHY

TABLE 2. Various modes of chromatography and available control parameters. Parameter/Mode

GC

SFC

LC

Pressure Temperature Modifier

No Yes No

Yes Yes Yes

No Yes Yes

However, it regained popularity when packed columns were found to have a wider application range than open tubular columns (25,26). Fig. 4 shows a schematic diagram of a typical LC-like packed-column SFC system with automated backpressure regulator. It is very similar to an HPLC system. However, a backpressure regulator that keeps the fluid pressure above the critical pressure and an oven that keeps the fluid temperature above the critical temperature are vital devices specific to SFC. Photodiode array UV detector and electronic backpressure regulator In 1985, Sugiyama et al. (27) developed a packedcolumn SFEeSFC hyphenated system, and demonstrated the extraction and chromatography of caffeine from ground coffee beans. The SFE directly coupled to an SFC system allowed an online introduction to an SFC column and the signal was

Sampling syringe

RF

Sample INJ

PU1

Column

Preheat Coil

PU2

CO2 Modifier OVEN

PDA

PT

BR

Collection tube

FIG. 4. Schematic diagram of typical LC-like packed-column SFC system with automated backpressure regulator. PU1: liquefied CO2 delivery reciprocating pump with chilled pump heads; PU2: modifier solvent delivery pump; RF: safety relief valve that prevents over pressure; INJ: injection valve; PDA: photodiode array UV detector; PT: pressure transducer; and BR: backpressure regulator. The pressure transducer monitors the pressure real time and the backpressure regulator compares the set pressure and actual pressure and control the flow resistance of the regulator so that the actual pressure becomes equal to the set pressure.

593

monitored with a photodiode array UV detector (PDA). PDA has soon become the standard detector in packed-column SFC. In a modern SFC system, the most important device may be the backpressure regulator which allows pressure control independent of mobile phase flow rate. Saito et al. (28) developed an electronically controlled backpressure regulator that had a very small internal volume and allowed efficient fractionation without cross contamination between fractions. This type of the backpressure regulator has become the standard device in packed-column SFC. Chiral separation In the 1980s, Okamoto et al. (29,30) developed highly efficient and versatile chiral stationary phases (CSP) and published a series of articles. Later, these CSPs were commercialized by Daicel Corporation, Osaka, Japan, and rapidly spread throughout the world; first used with LC and then extended to SFC. In 1985, Mourier et al. (31) demonstrated a chiral separation of phosphine oxides with supercritical and subcritical carbon dioxide mobile phase. In 1986, Hara et al. (32) demonstrated an SFC chiral separation of dl-amino acid derivatives. In the same year, Perrut and Jusforgues (33) developed a prep-SFC system with a 60-mm i.d. column with carbon dioxide recirculation. They mentioned that a preparative SFC is a sophisticated high-pressure gas equipment and thus expensive (33). Therefore, preparative SFC is suitable for fractionation of high-valued compounds such as chiral drugs, essential oils, etc. Later in the 1990s and 2000s, advances in chiral stationary phase and instrumental development made chiral separations one of the most important and preferred applications in both analytical and preparative SFC (34,35). Cluster theory For the utilization of a supercritical fluid as an extraction solvent or a mobile phase for chromatography, the fluid must have a solvating power. Kajimoto (36) illustrated the behavior of molecules in gas, liquid, and supercritical state in view of the intermolecular potential and the average molecular energy as shown in Fig. 5. At lower temperatures, an energetically lower state is strongly favored as is known in statistical thermodynamics. In the liquid state at low temperatures, therefore, each molecule feels the attractive intermolecular potential and most molecules are trapped in the potential well, the depth of which is usually larger than the average kinetic energy per molecule, moving around only a small region surrounded by adjacent molecules. This is a rough picture of the liquid state. On the other hand, in the gas state, most molecules at high temperatures, where the average kinetic energy is large, can move freely over the attractive potential well to expand the free volume of the system. In the supercritical fluid region near the critical temperature, some molecules may move freely and some may be trapped to form so-called weak clusters since kinetic energies of each molecule are fluctuating around the average value clusters formed when the molecular kinetic energy is smaller than the attractive energy between adjacent molecules. In addition, these clusters are rapidly changing in size and constitution due to molecular collisions. When a solute molecule is thrown into the supercritical fluid, and if the soluteesolvent attractive integration is larger than the solventesolvent interaction, the solute molecule may be surrounded by the solvent molecules which form cluster because attractive potential energy around the solute molecule is larger than the average kinetic energy of the solvent (supercritical) molecules. Clustering around a solute molecule is now considered a major cause of enhanced solubility in supercritical fluids. In 1987, Kim and Johnston (14) experimentally showed that the local concentration of the fluid solvent molecules around a solute molecule, phenol blue, is higher than the bulk concentration by measuring the UV absorption wavelength shift of phenol blue in

594

SAITO

J. BIOSCI. BIOENG.,

FIG. 5. Behavior of molecules in gas, liquid, and supercritical state. Reproduced from Kajimoto (36) with permission of Kagakudojin.

various supercritical fluids such as CO2, CF3Cl, and CHF3. In 1988, Kajimoto et al. (15) obtained the first experimental evidence of solvation by cluster formation via measurements of the UV absorption wavelength shift of 4-(N,N-dimethyl amino)benzonitrile (DMABN) both in a supersonic jet and supercritical CHF3 with various densities. They calculated the change in the number of the fluid molecules around the solute molecule by employing a clustering model based on the Sutherland potential and Langmuir type adsorption. Comparison of the experimental data agreed well with the calculated values. Symposia and workshops held in the 1980s In 1987, Smith organized the first international workshop on SFC at Loughborough University of Technology. Many research groups; Bartle’s, Smith’s, Leyendecker’s, Lee’s, Sandra’s, Game’s, Lane’s and Saito’s groups, gathered from Europe, US and Japan, and had an intensive discussion. Commercial instruments from Lee Scientific (open tubular capillary column SFC) and JASCO (packed-column SFC and analytical SFE) were demonstrated. Contents of the discussion were published as a monograph edited by Smith from Royal Society of Chemistry (37). In 1988, Perrut organized the first International Symposium on Supercritical Fluids (ISSF) that covered a very wide range of research on supercritical fluids, including industrial scale extraction, chromatography, phase equilibria, equations of state, etc., in Nice, France. This symposium was very successful and gathered many researchers in various fields from various countries. The ISSF has been held in every 3 years and the latest one was held in May 2012 in San Francisco. In 1988, Lee and Markides organized the 1988 Workshop on Supercritical Fluid Chromatography in Park City, Utah. They have organized the Workshop/Symposium in Utah a couple of times. The 4th workshop was held in Cincinnati, Ohio, and the 5th one was held in Baltimore, Maryland. Lee and Markides (38) edited a monograph that collected works presented in the series of symposia and workshops in 1990.

DEVELOPMENT OF SFC AS A PRACTICAL TOOL IN ANALYTICAL AND PREPARATIVE CHROMATOGRAPHY Analytical SFC The solvating power of a supercritical fluid mobile phase depends on the density of the fluid. This means that under the isobaric condition, the lower the temperature, the higher the solvating power becomes. Thus, the lower the temperature, the retention becomes shorter which is contrary to normal retention behavior in GC and HPLC. In GC, the higher the vapor pressure, the shorter the retention. This means that the higher the temperature, the shorter the retention. Therefore, if the column temperature is significantly higher than the critical temperature of the mobile phase fluid, the fluid’s solvating power competes with the solute’s vapor pressure. Fig. 6 shows the relationship between the logarithm of capacity factor k0 and the reciprocal of column temperature T (K) (39). At the temperatures of 2.4 (144
C) or

FIG. 6. Relationship between the logarithm of capacity factor k0 and the reciprocal of column temperature T (K). Conditions: column, Capcell Pak CN, 5 mm; mobile phase, CO2, 4 mL/min as liquid; pressure, constant at 20 MPa. Reproduced from Saito et al. (39) with permission of John Wiley & Sons, Inc.

VOL. 115, 2013 lower, the retention (k0 ) decreases roughly linearly to the reciprocal of the temperature; according to SFC theory. However, at the temperature of 2.4 (144
C) or higher, the retention (k0 ) decreases as well according to GC theory. At 2.4 (144
C) there are maxima that are generated by the competition between the changes of solvating power and the vapor pressure effect. In the case of open tubular capillary SFC, it is often operated in this temperature region, and makes it difficult to predict the retention. Controlling the pressure by changing the flow velocity further complicates the prediction. In open tubular capillary column SFC, the mobile phase is often pure CO2 and a pressure (density) gradient is used. While in the case of packed-column SFC as stated before, it is more LC-like from view points of instrumentation, and it is common practice to add polar modifier to CO2 and perform LC-like modifier gradient. In packed-column SFC, chromatographers started to use organic modifiers in higher percentage; a few to several 10s%. In such cases, both critical temperature and pressure are rapidly elevated as shown in Fig. 7 (40). For example, 5% (30%) methanol in CO2 gives the critical temperature 51
C (135
C) and the critical pressure of 105 bar (168 bar) as shown in the gray box. Therefore, under commonly used chromatographic conditions such as 100e120 bar pressure and 40
C temperature, the mobile phase fluid is not in a supercritical state. Cui and Olesik (41) started to use highconcentration modifiers in liquefied CO2 as early as in 1991. They recognized that their mobile phase was not a supercritical fluid and they called it “enhanced-fluidity mobile phase”. However, this term was not generally accepted by SFC chromatographers and the term supercritical fluid chromatography remains as is regardless of the actual state of the fluid used. It should be noted that in such conditions, the solvating power or retention can hardly be controlled by changing the pressure because the temperature and the pressure are well below the critical values of the binary mixture fluid and the densities do not change much by the pressure. In short, such a mobile phase is a simple mixture of liquefied CO2 gas and an organic solvent, though when the fluid temperature and pressure are a little under the critical values it may be called a subcritical fluid. Advantages of this type of mobile phase are lower viscosity than a liquid mobile phase and easy recovery of the

HISTORY OF SUPERCRITICAL FLUID CHROMATOGRAPHY

595

sample solute by decompression which is very useful when it is used in preparative separation. An LC-like SFC system together with the use of high-concentration modifier and modifier gradient offered great flexibility in analytical work and chromatographers have finally found it as non-experimental ordinary chromatograph. Preparative SFC As discussed previously, Klesper foresaw the possibility of preparative SFC (2), in their pioneering work in the 1960s (9) and 1970s (18,19). Saito and Yamauchi’s group demonstrated the enrichment of tocopherol from wheat germ in 1989 (42) and the fractionation of lemon peel oil in 1990 (43) by semi-preparative SFC using a 20-mm i.d. column. Berger and Perrut (44) reviewed preparative SFC works in 1970s and in the 80s. In 1992, Ute et al. (45) demonstrated isolation of methyl methacrylate (MMA) oligomer, according to the degree of polymerization employing a negative temperature gradient. In 1995, Saito and Yamauchi (46) separated flavanone enantiomers on a 20mm i.d. column with a stacked injection technique using a photodiode array UV/Vis detector (PDA). These works proved that SFC is suitable for analytical and preparative separations; and that the same SFC system could be used for both analytical and semipreparative applications. Chiral separation is now the most successful application in SFC including analytical and preparative separations. Text books and commercialization of packed-column SFC systems in the 1990s Saito et al. (47) published a monograph that describe the practice of SFE and packed-column SFC including preparative SFC in 1994. T.A. Berger published a monograph on packed-column SFC in 1995 (48). In 1998, Klaus and C. Berger (not related to T.A. Berger) (49) published a book on SFC with packed columns. These books encouraged chromatographers to use SFC, thus, packed-column SFC became the main stream of SFC by the late 1990s, and packed-column SFC instrumentation became commercially available from several sources; Hewlett Packard (later Berger Instrument), JASCO, Gilson, Novasep, etc. Standard configuration of a packed-column SFC system The standard configuration of a packed-column SFC

FIG. 7. Relationship between the calculated critical temperature, pressure and mass % of a CO2-methanol mixture. Recalculated using the program by Saito and Nitta (40) with permission of John Wiley & Sons, Inc.

596

SAITO

J. BIOSCI. BIOENG., TABLE 3. Overview of history of development of SFC.

Publication year

Authors (ref. no.)

Application/Event

Mobile phase

Stationary phase

Apparatus/Detector

1962

Klesper et al. (2)

Porphyrin mixtures

1966, 1967

Sie et al. (5e8)

Paraphins

Diclorodifluoroethane monochlorodifluoromethane CO2

1968

Karayannis et al. (9)

Porphyrin mixtures

1969

Giddings et al. (11)

1970

Jentoft and Gouw (16)

Purines, nucleosides and nucleotides, steroids, sugars, terpenes, amino acids, proteins, carbowaxes, etc. PAHs, styrene oligomer

1972

Jentoft and Gouw (17)

Preparative separation of above solutes and fraction collection

CO2

1977

Hartman and Klesper (18,19)

Fractionation of styrene oligomer

n-pentane þ methanol

1981

Novotny et al. (22)

CO2

Open tubular capillary column/dimethyl polysiloxan

1982

Gere et al. (24)

Various chemicals such as drugs, natural products, etc.; separation of styrene oligomers were often demonstrated to show its high resolution PAHs

CO2

ODS

1985

Sugiyama et al. (27)

CO2

Silica gel

1985

Mourier et al. (31)

CO2

Pirckle type CSP

1986

Hara et al. (32)

CO2 þ methanol

Homemade CSP

1986

Perrut and Jusforgues (33)

CO2

NA

1987

Saito et al. (28)

CO2

Silica gel

LC-like commercial SFC system/PDA

1987

Kim and Johnston (14)

CO2, CF3Cl, and CHF3

NA

NA

1987 1988

Smith (37) Perrut

NA NA

NA NA

NA NA

1988 1990

NA CO2 þ ethanol

NA Silica gel

1991

Lee and Markides Yamauchi and Saito (43) Cui and Olesik (41)

CO2 þ methanol

Hypercarb PGC

NA LC-like commercial SFC system(JASCO)/PDA HP GC/Isco syringe pump

1992

Ute et al. (45)

CO2

Silica gel

Commercial SFC system/HP GC oven/negative temperature gradient

1995

Saito and Yamauchi (46)

CO2 þ ethanol

Silica gel (20 mm i.d. column)

Commercial semi-prep-SFC system

2001

Wang et al. (61)

CO2 þ methanol

NA

2006

Zheng et al. (80)

Caffeine extraction and separation Chiral separation of phosphine oxides Chiral separation of d-l amino acid derivatives Large scale preparative SFC (60 mm i.d. column) with CO2 recirculation PAHs, experimentally showed outlet mass flow reduction and elucidated the phenomenon theoretically Experimentally showed clustering in supercritical fluids First Workshop on SFC First international symposium on supercritical fluids Workshop on analytical SFC Fractionation of lemon peel oil High-concentration modifier enhanced-fluidity mobile phase Isolation of methyl methacrylate (MMA) oligomer, according to the degree of polymerization Chiral fractionation of flavanone enantiomers on a 20-mm i.d. column with stacked injections Mass-directed fractionation for drug discovery SFC/MS of polypeptides

2005 2006

Xu et al. (81,82)

Estrogen metabolites

CO2 þ (methanol þ trifluoroacetic acid) CO2 þ methanol

2012

Bamba et al. (85)

Metabolite analysis, review

CO2 þ modifier

2-Ethylpyridine bonded silica column Cyanopropyl silica column connected in series with a diol column NA

Homemade semi-prepSFCeMS Commercial SFCeMS

Polyethylene glycol

GC-like very simple homemade system/FID

Diclorodifluoroethane

Silica gel coated with glycerol, squalene Chromosorb/cabowax 20 M

CO2, NH3, etc.

Chromosorb/silicone oil

GC-like relatively simple homemade system/FID GC-like sophisticated homemade system/ photometer GC-like sophisticated homemade system/FID Ultra-high-pressure system, details unknown

CO2

Woelm basic alumina. Porosil/n-pentane polystyrene divinylbenzene Woelm basic alumina. Porosil/n-pentane polystyrene divinylbenzene Porosil

LC-like very sophisticated homemade system/ UV photometer/pressure programming Automated fraction collector added to the above system LC-like homemade very sophisticated system/UV photometer/pressure programming GC-like system with syringe pump/FID

Modified Commercial HPLC system/backpressure regulator LC-like sophisticated system/PDA Modified Varian HPLC system LC-like commercial SFC system(JASCO)/PDA Semi-pilot plan scale preparative SFC

Commercial SFCeMS/MS

Commercial SFCeMS/MS

VOL. 115, 2013 system established in the 1990s comprises of a reciprocating CO2 pump with chilled pump heads, a reciprocating modifier solvent pump, a manual or an automated injection device, a column oven, a UV absorption detector (typically a PDA detector), a backpressure regulator that allows the pressure control independent of the flow rate, and a chromatography data system (CDS) as shown in Fig. 4. Other types of detectors have also been used. Various detection systems Randall wrote a long article in 1982, on dense (supercritical) gas chromatographyemass spectrometry (MS), trying to stimulate research in this area (50). There are many articles on capillary column SFCeMS appeared in the 1980s (51e53). Crowther and Henion (54) reported packedcolumn SFCeMS for polar drug analysis. Those works in the 1980s were reviewed by Kalinoski et al. (55) in 1986 and Sheeley and Reinhold (56) in 1989. However, practical application of packedcolumn SFCeMS started in the 1990s after successful interfacing with atmospheric pressure ionization, i.e., APCI and ESI (57). These works were reviewed by several researchers (58e60). In 2001, Wang et al. (61) reported mass-directed fractionation and isolation by packed-column SFC/MS, and proposed a fractionation method utilizing the matching of mass spectra of the sample compounds and those stored in the library. Zhang et al. (62) developed a similar mass-directed preparative SFC purification system in 2006. Recently, Li and Hsieh (63) reviewed SFCeMS. MS detection is now a very powerful and indispensable method to accurately identify the target compound especially in the pharmaceutical industry (64). In chiral separation, a chiral detector plays an important role as no other detector can differentiate chiral compounds. A chiral detector is an optical detector by nature. There are two types of detectors based on different optical property. One is based on optical rotation (OR) and the other on circular dichroism (CD). An OR detector measures the difference in refractive index of enantiomers, whereas a CD detector measures the difference in optical absorption. A refractive index is subject to the change of temperature and density, thus, it is extremely difficult to obtain a stable baseline in SFC. On the other hand, an absorption-based CD signal is very stable as a UV absorption detector, even in SFC. In addition, the g-factor (CD/UV signal), indicates enantiopurity independent of the peak concentration. Kanomata et al. (65) reported advantages of CD detection in SFC especially when it is employed in preparative SFC. FID has been the standard detector in open tubular capillary SFC. In packed-column SFC, the stationary phase is much stronger than that in open tubular capillary SFC, therefore, the addition of a polar modifier is necessary to elute a sample solute. As discussed before, even a small amount of organic modifier interferes with an FID however, it is still used with packed columns for specific analyses such as analyses of petroleum fuels using pure CO2 as a mobile phase. These methods are published by ASTM as D5186 (66) and D6550 (67). Evaporative light scattering detection (ESLD) is regarded as a pseudo-universal detector in HPLC and SFC. Since it does not require analytes to have UV absorption, it is a preferred detector in SFC in place of a refractive index detector that is not compatible with the high-backpressure required by SFC. Early attempts in using an ESLD in SFC were carried out by Carraud et al. (68), by Nizery et al. (69), and by Hoffmann and Greibrokk (70) in the late 1980s. In 1996, Strode and Taylor (71) reviewed previous works of SFC-ESLD and investigated optimum conditions under various elution modes such as pressure gradient and modifier gradient. To facilitate the readers to overview the half-a-century long history of the development of SFC, publications and events related to SFC are listed in chronological order in Table 3.

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RECENT TRENDS IN SUPERCRITICAL FLUID CHROMATOGRAPHY As discussed in the previous section, standardized SFC systems finally became commercially available from several sources by the late 1990s and were recognized as a truly useful separation instruments. However, the history of SFC was of “the rise and fall”, as Smith (72) wrote in his review article in 1999. Harris (73) wrote a very interesting story in her review article based on interviews with Karen Phinney of NIST and other SFC experts. “When Phinney joined NIST, she said to one of her colleagues, ‘I’m doing SFC’, ‘Oh, science fiction chromatography’ replied the colleague.” This happened in the mid 1990s. As we are in the 21st century and the resources are growing scarce, demands for sustainable chemistry or green chemistry have been getting stronger. CO2-based SFC could significantly reduce the use of organic solvents in the separation process, and also energy in a fractionation and evaporation processes. Therefore, SFC has been expected to contribute greatly to green chemistry. In fact, the Green Chemistry Group (Oakmont, PA, USA), has been promoting the International Conference on Packed-Column SFC every year since 2008. The author’s intention, as indicated by the title, is to review history of supercritical fluid chromatography in view of instrumental developments and he will not go into the details about SFC applications. Nevertheless, the author would like to touch on some of important research works. Since the late 1990s, SFC research has been focused on expansion of application areas associated with development of column technology. CO2-based SFC is normal phase chromatography and as such, polar analytes are difficult to separate by SFC. In order to expand the application areas, there are many attempts to separate such analytes (25,26,74e77). Works done in the 1980s and 1990s were intensively reviewed by Berger (78) in 1997. In the 21st century, advances in column and mobile phase chemistry finally allowed the analysis of biomolecules that were difficult to separate by SFC (79). In addition, advances in tandem mass spectrometry enabled the analysis of a very small amount of biomolecules and extended SFCeMS application range to metabolism research. Taylor’s group successfully analyzed a polypeptide with up to 40-mers using trifluoroacetic acid as additive in a CO2/methanol mobile phase to suppress the deprotonation of the peptide carboxylic acid groups and to protonate the peptide amino groups on a 2-ethylpyridine bonded silica column, which was specifically developed for SFC (80). They Xu et al. (81,82) separated 15 estrogen metabolites by using SFCeMS/MS with a mobile phase of CO2-methanol mixture in gradient mode on a cyanopropyl silica column connected in series with a diol column in 10 min, whereas HPLCeMS/MS required 70 min. Bamba’s group (83e85) performed extensive study on metabolic profiling of various natural products including lipids and polar lipids using SFCeMS/MS. To conclude this article, the author would like to mention that there are a huge number of articles published since the advent of modern SFC, however, he had to mention less than 1% of such articles on a sampling basis. The readers may find that this review article examines many older works from the 1960se1980s. However, it is the intention of author to introduce these pioneering works to the readers which are often omitted in more recent review articles.

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