Emerging Separation Techniques in Supercritical Fluid Chromatography

Abstract

Supercritical fluid chromatography (SFC) has unique separative characteristics distinguished from those of HPLC and gas chromatography. At present, SFC is widely used and there are many applications in various biological, medical, and pharmaceutical fields. In this review, we focus on recently developed novel techniques related to SFC separation including: new column stationary phases, microfluidics, two-dimensional separation, and gas–liquid separation. In addition, we discuss the application of SFC using a water-containing modifier to biological molecules such as amino acids, peptides, and small proteins that had been challenging analytes.

1. Introduction

Supercritical fluid chromatography (SFC) is regarded as one of the typical chromatographic techniques along with HPLC and gas chromatography (GC). Among the three types of chromatography, the feature of SFC is that of using a supercritical fluid as a mobile phase. A substance at a temperature and pressure above its critical point becomes a supercritical fluid that shows different physicochemical characteristics from both liquids and gases. In general, the density of a supercritical fluid is similar to a liquid, while the viscosity is similar to that of a gas. The diffusivity of a supercritical fluid shows intermediate properties between liquid and gas. Therefore, SFC can be expected to provide faster separation with higher resolution when compared to HPLC or GC. The critical values of the temperature and pressure are specified in each substance and carbon dioxide is most commonly used in the research and manufacturing dealing with supercritical fluids as carbon dioxide becomes a supercritical fluid under moderate conditions (31.1 °C and 7.38 MPa) compared to other substances. In addition to this property, supercritical carbon dioxide has several advantages as a mobile phase, namely, carbon dioxide is less harmful to the human body, is non-flammable, non-corrosive, and less reactive to other compounds. Moreover, it is easy to obtain high purity as a reagent. Unless otherwise specified, SFC in this review refers to supercritical carbon dioxide chromatography.

Recently, the application of SFC has covered a wide variety of scientific fields such as natural products,¹⁾ bioanalysis,^2–4) pharmaceutics,⁵⁾ food analysis,^6,7) environments,^8,9) forensics,^10,11) energy,¹²⁾ polymers,¹³⁾ cosmetics,^14,15) etc. The rapid increase in the number of SFC articles over the last decade supports the notion that SFC is currently gaining prominent attention (Fig. 1). There are three major scientific fields where SFC is frequently utilized. In the 2010 s, SFC application to natural products occupied about 25% of SFC articles. On the other hand, bioanalysis and pharmaceutics occupied about 20% and 15-20%, respectively.¹⁶⁾ As expected, SFC actually gives effective and fast separation methods when compared to HPLC and GC in these three fields. Moreover, these SFC methods employing SFC-mass spectrometry (SFC-MS) systems enable comprehensive detection of analytes and are often applied to target/non-target analysis such as metabolomics^17–19) or lipidomics.^20–22) This review will provide technical innovations of SFC separation that are the scientific basis for the rapid increase in the number of SFC articles in the 2010 s from the point of view of analytical chemistry.

Fig. 1. Time Course of the Number of SFC Articles Published from 1970 to 2020

To obtain the number of SFC articles, a search was conducted with SciFinder using the set of keywords: supercritical fluid chromatography.

2. Outline of SFC

Almost 60 years have passed since the first SFC system was developed by Klesper et al. in 1962.²³⁾ As we can see from the title of their article, the first SFC system was developed as a high pressure GC which was performed above critical temperatures. In the early stages of the development, SFC was considered to be less useful than HPLC and GC because it was hard to precisely control the backpressure, resulting in the poor robustness of the analytical system. After that, the weakness of the poor robustness was overcome by the invention of mechanical backpressure regulators.²⁴⁾ Moreover, a packed column, filled with bare silica, which was developed as a stationary phase for HPLC, was shown to be applicable to SFC.²⁵⁾ Upon supercritical carbon dioxide silica gel column chromatography, the chromatographic behaviors of hydrophobic compounds were similar to those on normal-phase HPLC. In addition, SFC gave a better separation of chiral compounds when compared with HPLC. The number of SFC users temporarily increased around 1990 by these findings, however, the increase did not last for long.

Technical innovation of detectors equipped with SFC has been involved in the progress of SFC systems. Most detectors for HPLC and GC can also be applied to SFC, although it is necessary to confirm that the detectors can work under high pressure conditions. Presently, UV-visible light detector (UV-VIS), mass spectrometer,²⁶⁾ flame ionization detector (FID), evaporated light scattering detector (ELSD),^27–29) electron-capture detector (ECD),³⁰⁾ corona-charged aerosol detector (CAD)³¹⁾ and electrochemical detector (ED)^32,33) have been reported to work as SFC detectors. Among these detectors, as with HPLC, UV-VIS is a standard detector for the analysis of compounds having UV absorption. ELSD is regarded as a universal detector in SFC for the analysis of compounds without UV absorption. FID is also used as a standard detector in SFC when an open-tubular capillary column is connected. Although these standard detectors are useful, a mass spectrometer is most preferentially used as an SFC detector to construct an SFC-MS system. This is because supercritical carbon dioxide becomes a gas immediately under atmospheric pressure and less energy is charged for the desolvation and sample ionization. Not only single quadrupole MS, but also triple quadrupole MS and time-of-flight MS³⁴⁾ can also be equipped with SFC. The increase in the detector options contributes to the proper use of SFC in the expansion of its application.

Including detectors, the development of an SFC system has been accomplished by instrumental inventions.³⁵⁾ For 20 years from 1990 to 2010, there has been relatively little progress and few breakthroughs in the development of SFC systems. However, several new generation SFC systems, that carry recent inventions to control fluid dynamics more precisely under high pressure conditions, have been launched by some vendors in the 2010 s. Some of these systems were a hybrid system of SFC and HPLC, so that the analysts could choose a suitable chromatographic mode for the separation of target analytes in their sample. Moreover, an on-line connection of a supercritical fluid extraction unit to a chromatography unit (on-line SFE-SFC) was achieved to increase extraction efficiency and to save analytical time. As such, a series of operations, from sample preparation to analysis, is automatically performed by using just one system. These new generation SFC systems earned a number of new SFC users and led to a rapid increase in SFC article publications.

In parallel to these progresses in SFC instruments, new separation techniques in SFC have been recently developed that enable ultrafast separation, high resolution separation, and separation with a high recovery rate. Representative examples of the new separation techniques include turbulent flow in SFC, microfluidic technology, two-dimensional separation, new stationary phases, and using a gas–liquid separator (Fig. 2). The details of each technique will be introduced and discussed in the following sections. Owing to these techniques, SFC can now cover new analytes of hydrophilic compounds such as amino acids, peptides, and proteins (Fig. 2).

Fig. 2. New Separation Techniques and Applications Introduced in This Review

(Color figure can be accessed in the online version.)

3. Recent Trends in SFC Separation

3.1. New Stationary Phases for SFC

As described above, the polarity of supercritical carbon dioxide is comparable to that of non-polar organic solvents such as hexane. Therefore, analytical columns used in normal-phase HPLC including bare silica, diol, aminopropyl, and cyanopropyl are applicable to SFC for the separation of hydrophobic compounds. In addition to these HPLC columns, different types of columns containing unique stationary phases, which are specially designed for SFC use, have also been developed by vendors.³⁶⁾ In addition, smaller particle columns filled with sub 2-µm particles are also applicable to SFC to obtain better separations in a shorter time.^37,38)

A previous study shows a comparison of the retention behavior of several organic compounds between SFC and normal-phase HPLC using various stationary phases to understand their characteristics.³⁹⁾ In their study, 18 different commercially available stationary phases including: bare silica, diol, triazolyl, hydroxyphenyl, pyridinyl, ethylpryidine, picolylamine, aminoanthracene, diethylamine, phenylethyl, naphthylethyl, pyrenylethyl, pentabromophenyl, pentafluorophenyl, nitrophenylethyl, monomeric C18, polymeric C18, and cholesteryl were evaluated for the separation of 11 organic compounds (cinnamyl alcohol, 4-nitrobenzyl alcohol, toluene, 4-hydroxymethylbenzoic acid, 4-aminobenzyl alcohol, benzene, benzyl alcohol, 1,4-benzendimethanol, 4-tert-butylbenzyl alcohol, 1-naphthalenemethanol, and 2-(benzyloxy)ethanol). From the results obtained, polar stationary phases showed similar retention behavior in normal-phase HPLC as well as SFC. On the other hand, only SFC gave a slightly strong retention in the case of low-polarity stationary phases. Furthermore, π–π and dispersion interactions were emphasized in SFC rather than HPLC. In another study, a new model of SFC retention based on linear solvation energy relationships that considered the ionic interaction and shape features of analytes was proposed.⁴⁰⁾ In their study, 14 achiral columns such as: bare silica, alkylamide, propanediol, cyanopropyl, aminopropyl, with polar-embedded octadecyl, without polar embedded octadecyl, phenyl, pentabromophenyl, pyrenylethyl, cholesteryl, pyridyl, triazole, and phenol were classified based on the proposed models. As a result, through SFC, it was shown that reversed-phase HPLC columns were distinguished from normal-phase HPLC columns. Moreover, normal-phase HPLC columns were classified into two different groups. Cyanopropyl, propanediol, pyridyl, phenol, and aminopropyl columns belong to one group, while bare silica, alkylamide, and triazole columns belong to another group where each group shows different separation characters. These findings may help analysts to choose an appropriate stationary phase in the early stages of SFC method development.

3.2. Turbulent Flow in SFC

There is still a possibility that ultrafast separation can be performed when an open-tubular column is applied to SFC based on the involvement of turbulent flow. Open-tubular columns were first introduced to GC for the analysis of complex petroleum products in 1958.⁴¹⁾ Although either an open-tubular column or a packed column can be used as a stationary phase of SFC, the present SFC system prefers a packed column compared to an open-tubular column. This mainly seems to be because various packed columns suitable to SFC have been developed.

Historically, the benefits of turbulent flow to increase column efficiency have gained much attention in the areas of HPLC and GC.^42,43) Recently, Gritti and colleagues studied turbulent flow to extend their results into SFC.^44–48) They used a standard open-tubular column equipped to an SFC system (the Acquity UPC² system) where the column temperature was maintained in a column oven for GC. High flow rate (up to 4 mL/min) of pure carbon dioxide led to the transition of laminar to turbulent flow that was assessed by the reduction of plate height in the open-tubular column of the standard poly(methylphenylsiloxane) stationary phase. This transition from laminar to turbulent flow was also observed in four different stationary phases: poly (dimethylsiloxane-co-methylphenylsiloxane), Rt-βDEXm (https://www.restek.com/en/products/columns/gc-columns/Fused-Silica-Capillary-Columns/22/), CP-Chirasil Dex CB (https://www.agilent.com/en/product/gc-columns/chiral-gc-columns/cp-chirasil-dex-cb-columns), and polyethylene-glycol based cyclodextrin sol gel. These columns were applied to the separation of chiral compounds. In addition, a mixture of four polycyclic aromatic hydrocarbons (naphthalene, phenanthrene, pyrene and triphenylene) were separated within nine seconds. Their study on the re-evaluation of open-tubular columns has had a great impact on the separation sciences in SFC.

3.3. Microfluidic Technology for SFC

There are persuasive benefits to miniaturize an analytical system. For example, i) it can reduce the amounts of sample and reagent, ii) it can shorten the measurement time, iii) it makes it possible to do on-site analysis anywhere, and so on. The microfluidic technologies of liquid and gas have been studied for a long time, and microfluidic LC and GC were established based on the lab-on-a-chip technology.^49,50) In addition to these types of chromatography, a lab-on-a-chip for SFC has been recently reported.⁵¹⁾ The SFC flow way was made on a glass chip. Exact temperature control and precise backpressure control were achieved by using a low-thermal-mass contact thermostat and two pairs of a backpressure regulator with a pressure gauge, respectively. As an example of an application to technology, the separation of Pirkle’s alcohol (2,2,2-trifluoro-1-(9-anthryl)ethanol) was demonstrated to show that the enantiomers were separated within approximately 20 s on a developed chip packed with enantioselective Chiralpak IB-5 as a stationary phase.

3.4. Gas–Liquid Separation in Preparative SFC

For preparative purposes, SFC is a useful method when compared to other types of chromatography. Since a supercritical fluid can easily percolate into a sample, it is possible to obtain extracts from a sample more efficiently than with a liquid.⁵²⁾ Moreover, because supercritical carbon dioxide becomes a gas under atmospheric pressure, there is almost no need to evaporate solvents from eluents. However, it is difficult to collect the whole eluents on a small scale with a high recovery rate. A marked increase in the volume of eluents from supercritical carbon dioxide to gas sometimes induces contamination or loss of the samples. To avoid these problems, gas–liquid separation techniques based on the mechanism of a cyclone separator, where induced cyclonic rotation of a gas–liquid (or gas–powder) mixture can separate liquid (or powder) from a gas, have been introduced to preparative SFC (Fig. 3). In addition to this device, a unique gas–liquid separator for preparative SFC has been developed.⁵³⁾ These gas–liquid separators connecting to a fraction collector resulted in an efficient collection of the small amounts of eluents into a test tube with high recovery rates.

Fig. 3. Illustration of Gas–Liquid Separation (A) without a Separator, (B) with a Cyclone Separator, and (C) with a Unique Gas–Liquid Separator (LotusStream™)

The outline of LotusStream™ was referenced from technical reports of Shimadzu Corporation (C190-E250) with minor modifications. (Color figure can be accessed in the online version.)

3.5. Two-Dimensional Separation Techniques

Two-dimensional (two-channel) separation techniques are sometimes used in the analysis of complex samples. GC × GC^54–57) and HPLC × HPLC^58–62) are common techniques to achieve high selectivity and resolution. In general, measurement time tends to be longer when multiple analytical columns are connected to each other. As the measurement time of SFC is generally shorter than HPLC, SFC × SFC⁶³⁾ and HPLC × SFC^64,65) were developed for the achiral/chiral separation of pharmaceutics. Because of the complexity of a two-dimensional chromatography system that consists of multiple pumps, switch valves, and interfaces for different mobile phases, the introduction of SFC was challenging but succeeded as an established system.

3.6. The Expansion of Analytes to Hydrophilic Compounds in SFC

As noted above, SFC is comparable to normal-phase HPLC. In many SFC methods, small amounts of co-solvent called modifier/entrainer are mixed with supercritical carbon dioxide to control the polarity of a mobile phase (Fig. 2). Alcohols such as methanol, ethanol, and propanol are generally used as a modifier, however, water has not been used as a modifier, because supercritical carbon dioxide cannot dissolve water. Therefore, for a long time, the major applications in SFC were the separation of hydrophobic compounds.

Recently, it has been reported that a small amount of water in a modifier improves the peak shapes of a chromatogram in the analysis of hydrophilic compounds. Due to this finding, the target analytes in SFC were notably expanded from hydrophobic to hydrophilic compounds including amino acids,^17,66,67) peptides,^66,68,69) chiral compounds,^70–72) and achiral compounds.⁷³⁾ In addition to water, a small amount of diethylamine, triethylamine, or trifluoroacetic acid (TFA) added to a modifier also improved the efficiency, retention time and resolutions of biological molecules including nucleosides,⁷⁴⁾ peptides,^68,69,75,76) and proteins.^77,78)

As a next step, SFC purifications of human bradykinin, bovine insulin, bovine ubiquitin, bovine cytochrome c, and equine apomyoglobin were demonstrated on a preparative scale.⁷⁷⁾ Results of circular dichroism spectra, and mass chromatograms of size-exclusion chromatography-hydrogen-deuterium exchange-mass spectrometry (SEC-HDX-MS) of pre- and post-purified peptides or small proteins, showed the SFC purification of human bradykinin and bovine insulin to be successful. Moreover, refolding of the higher-order structure of post-purified insulin was confirmed by comparison with pre-purified insulin. Although ubiquitin, cytochrome c and apomyoglobin were also purified using the same conditions as bradykinin and insulin, there was conformation that these peptides and proteins were significantly modified during SFC purification and unable to re-fold the original structures. In another study, the SFC purification of recombinant human insulin from Escherichia (E.) coli was reported on a semi-preparative scale.⁷⁸⁾ Although recombinant human insulin is generally purified in three steps (ion exchange, size exclusion, and RP-HPLC), SFC could purify recombinant insulin in just one step and its yield was between 80 and 90%. Methanol containing small amounts of water and TFA was employed as a modifier to maintain the structure and the biological activity of the insulin. All these successful applications suggest that SFC would be a promising analytical and preparative tool for biological molecules such as peptides and proteins (Table 1).

Table 1. Analyses of Amino Acids, Peptides, and Proteins in SFC with Modifiers Containing Water

Scale	Analytes	Mobile phase/modifier	Ref.
Analytical	Peptide APIs*a)	CO2/methanol containing 5% (v/v) water and 0.2% (v/v) ammonium hydroxide	66)
	Amino acids	CO2/methanol containing 5% (v/v) water and 0.4% (v/v) TFA	67)
	Amino acids and polypeptide	CO2/methanol containing 5% (v/v) water and 10 mmol/L ethanesulfonic acid	68)
	Peptide gramicidin	CO2/methanol containing 5% (v/v) water	69)
	Gly-Tyr, Val-Tyr-Val, Leu enkephalin, Met enkephalin, Angiotensin II, Macrocyclic peptides, Longer synthetic peptides (17–41 mer)	CO2/methanol containing 0.1% (v/v) TFA and 0.1% (v/v) ammonia	75)
	Human insulin	CO2/methanol containing 5% (v/v) water and 0.2% (v/v) TFA	78)
Preparative	Human bradykinin, Bovine insulin	CO2/methanol/acetonitrile (3 : 1, v/v) containing 5% (v/v) water and 0.2% (v/v) TFA	77)
	Insulin β chain peptide (15–18), Insulin β chain peptide (15–23), Angiotensin II	CO2/methanol containing 5% (v/v) water and 0.2% (v/v) TFA	76)

*a). APIs: active pharmaceutical ingredient.

4. Conclusion and Perspectives

There is no doubt that SFC is an essential separative technique in various fields. As is well known, the number of SFC users was less than those of HPLC and GC. However, SFC has unique characteristics and could be an alternative method in case of insufficient separation by HPLC and GC. In this review, several novel techniques focusing on the “separation” in both analytical and preparative SFC have been introduced. SFC has the potential to achieve ultrafast separation, and its targets are expanding from hydrophobic to hydrophilic compounds. These techniques are expected to be a trigger for the development of new SFC applications in the near future.

Acknowledgments

This work was supported in part by JSPS KAKENHI Grant Numbers JP19K08989 and JP20K15975.

Conflict of Interest

The authors declare no conflict of interest.

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