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Introduction of the physico-chemical properties of the supercritical fluids

A pure supercritical fluid (SCF) is any compound at a temperature and pressure above the critical values (above critical point). Above the critical temperature of a compound the pure, gaseous component cannot be liquefied regardless of the pressure applied. The critical pressure is the vapor pressure of the gas at the critical temperature. In the supercritical environment only one phase exists. The fluid, as it is termed, is neither a gas nor a liquid and is best described as intermediate to the two extremes. This phase retains solvent power approximating liquids as well as the transport properties common to gases.

A comparison of typical values for density, viscosity and diffusivity of gases, liquids, and SCFs is presented in Table 1.

Density (kg/m3 )
Viscosity (cP)
Diffusivity (mm2 /s)

Table 1. Comparision of physical and transport properties of gases, liquids, and SCFs.

The critical point (C) is marked at the end of the gas-liquid equilibrium curve, and the shaded area indicates the supercritical fluid region. It can be shown that by using a combination of isobaric changes in temperature with isothermal changes in pressure, it is possible to convert a pure component from a liquid to a gas (and vice versa) via the supercritical region without incurring a phase transition.

The behavior of a fluid in the supercritical state can be described as that of a very mobile liquid. The solubility behavior approaches that of the liquid phase while penetration into a solid matrix is facilitated by the gas-like transport properties. As a consequence, the rates of extraction and phase separation can be significantly faster than for conventional extraction processes. Furthermore, the extraction conditions can be controlled to effect a selected separation. Supercritical fluid extraction is known to be dependent on the density of the fluid that in turn can be manipulated through control of the system pressure and temperature. The dissolving power of a SCF increases with isothermal increase in density or an isopycnic (i.e. constant density) increase in temperature. In practical terms this means a SCF can be used to extract a solute from a feed matrix as in conventional liquid extraction. However, unlike conventional extraction, once the conditions are returned to ambient the quantity of residual solvent in the extracted material is negligible.

The basic principle of SCF extraction is that the solubility of a given compound (solute) in a solvent varies with both temperature and pressure. At ambient conditions (25°C and 1 bar) the solubility of a solute in a gas is usually related directly to the vapor pressure of the solute and is generally negligible. In a SCF, however, solute solubilities of up to 10 orders of magnitude greater than those predicted by ideal gas law behavior have been reported.

The dissolution of solutes in supercritical fluids results from a combination of vapor pressure and solute-solvent interaction effects. The impact of this is that the solubility of a solid solute in a supercritical fluid is not a simple function of pressure.

Although the solubility of volatile solids in SCFs is higher than in an ideal gas, it is often desirable to increase the solubility further in order to reduce the solvent requirement for processing. The solubility of components in SCFs can be enhanced by the addition of a substance referred to as an entrainer, or cosolvent. The volatility of this additional component is usually intermediate to that of the SCF and the solute. The addition of a cosolvent provides a further dimension to the range of solvent properties in a given system by influencing the chemical nature of the fluid.

Cosolvents also provide a mechanism by which the extraction selectivity can be manipulated. The commercial potential of a particular application of SCF technology can be significantly improved through the use of cosolvents. A factor that must be taken into consideration when using cosolvents, however, is that even the presence of small amounts of an additional component to a primary SCF can change the critical properties of the resulting mixture considerably.

Application of supercritical fluid extraction

Supercritical extraction is not widely used yet, but as new technologies are coming there are more and more viewpoints that could justify it, as high purity, residual solvent content, environment protection.

The basic principle of SFE is that when the feed material is contacted with a supercritical fluid than the volatile substances will partition into the supercritical phase. After the dissolution of soluble material the supercritical fluid containing the dissolved substances is removed from the feed material. The extracted component is then completely separated from the SCF by means of a temperature and/or pressure change. The SCF is then may be recompressed to the extraction conditions and recycled.

Some of the advantages and disadvantages of SCFs compared to conventional liquid solvents for separations:


* Dissolving power of the SCF is controlled by pressure and/or temperature
* SCF is easily recoverable from the extract due to its volatility
* Non-toxic solvents leave no harmful residue
* High boiling components are extracted at relatively low temperatures
* Separations not possible by more traditional processes can sometimes be effected
* Thermally labile compounds can be extracted with minimal damage as low temperatures can be employed by the extraction


* Elevated pressure required
* Compression of solvent requires elaborate recycling measures to reduce energy costs
* High capital investment for equipment

Solvents of supercritical fluid extraction

The choice of the SFE solvent is similar to the regular extraction. Principle considerations are the followings.

* Good solving property
* Inert to the product
* Easy separation from the product
* Cheap
* Low PC because of economic reasons

Carbon dioxide is the most commonly used SCF, due primarily to its low critical parameters (31.1°C, 73.8 bar), low cost and non-toxicity. However, several other SCFs have been used in both commercial and development processes. The critical properties of some commonly used SCFs are listed in Table 2.

Critical Temperature (K)
Critical Pressure (bar)
Carbon dioxide
Trifluoromethane (Fluoroform)

Table 2. Critical Conditions for Various Supercritical Solvents

Organic solvents are usually explosive so a SFE unit working with them should be explosion proof and this fact makes the investment more expensive. The organic solvents are mainly used in petrolchemistry.

CFC-s are very good solvents in SFE due to their high density, but the industrial use of chloro-fluoro hydrocarbons are restricted because of their effect on the ozonosphere.

CO2 is the most widely used fluid in SFE.

Beside CO2, water is the other increasingly applied solvent. One of the unique properties of water is that, above its critical point (374°C, 218 atm), it becomes an excellent solvent for organic compounds and a very poor solvent for inorganic salts. This property gives the chance for using the same solvent to extract the inorganic and the organic component respectively.

Industrial applications

The special properties of supercritical fluids bring certain advantages to chemical separation processes. Several applications have been fully developed and commercialized.

Food and flavouring

SFE is applied in food and flavouring industry as the residual solvent could be easily removed from the product no matter whether it is the extract or the extracted matrix. The biggest application is the decaffeinication of tea and coffee. Other important areas are the extraction of essential oils and aroma materials from spices. Brewery industry uses SFE for the extraction of hop. The method is used in extracting some edible oils and producing cholesterine-free egg powder.


The destillation residue of the crude oil is handeled with SFE as a custom large-scale procedure (ROSE Residum Oil Supercritical Extraction). The method is applied in regeneration procedures of used oils and lubricants.

Pharmaceutical industy

Producing of active ingradients from herbal plants for avoiding thermo or chemical degradation. Elimination of residual solvents from the products.

Other plant extractions

Production of denicotined tobacco.

Enviromental protection

Elimination of residual solvents from wastes. Purification of contaminated soil.

Natural raw materials as plants contain a wide range and type of valuable and biologically active compounds and also various extraction methods are applied in industry and are studied at research and development ranging from steam distillation through solvent extractions to pressurized liquid extraction and supercritical fluid extraction. Selection between the methods is in principle based on the technological feasibility, among the suitable methods selection is made upon economics and availability. While simulation based economical calculations are well established is certain cases like distillation or heat exchanger networks, similar simulation methodology is not readily available for plant extractions. There is a significant lack on phase equilibrium data and/or assumption methodology of a complex and very heterogeneous mixture like soluble plant constituent, and furthermore, the mass transfer limitations must be also taken into account. The PhD fellow will develop a suitable method to simulate the various plant extraction methods in ASPEN Hysis, and will perform necessary measurements (e.g. phase equilibrium measurements, characterisation of the solid plant material) and he/she will compare the simulation results with experimental extraction data.

Preparation of enantiopure chemicals is still a hot topic in research although there is already a large chiral market. In principle two routes are possible: the synthetic route and isolation from natural sources, typically from plant biomass. Isolation from natural sources is an interesting route not only to obtain single chiral components, but also to prepare mixtures having certain bioactivities. Enantiomer separation by the synthetic route is performed typically either by chiral catalysis of a reaction with a prochiral substrate or by optical resolution of a racemate. Regardless which method is applied, in most of the cases only enantiomeric mixtures are produced in the first step. This is followed by a further purification process, most typically by several recrystallizations. These are time and solvent intensive steps, resulting in significant amounts of the expensive enantiomers or diastereomers dissolved in the solvent phase, while solvent residues are present in significant amounts in the solid phase. After achieving the enantiopure final product size reduction is also typically required before formulation, in the pharma industry at least. Antisolvent fractionation with supercritical carbon dioxide recently gained attention in the scientific literature. The possibility of further purifying either a mixture of the diastereomeric salts of a compound or an enantiomeric mixture can be investigated by recording the ee1 –ee0 or de1 – de0 diagrams of the compounds, where ee and de are enantiomeric and diastereomeric excess, respectively. Such diagrams are also useful in determining the limits of further purification, similarly to those observed in atmospheric resolutions. It must be noted, that antisolvent fractionation is based on fast oversaturation and immediate precipitation followed by an extraction step. It is worthwhile to systematically study when the kinetic effects, and when the thermodynamics of the system (represented by the melting point phase diagrams) are dominant. The process can be influenced strongly by the solubility of the components (the pure enantiomers and the racemic forms or the diastereomeric salts) in supercritical carbon dioxide.

The research is assumed to lead to a better understanding how the chemical equilibrium, the solubility of the compounds present and the kinetics of the process influence the efficiency of the enantiomeric/diastereomeric enhancement.

Most relevant publications: 

Márton Kőrösi, János Madarász, Tamás Sohajda, Edit Székely, Fast further purification of diastereomeric salts of a nonracemic acid by gas antisolvent fractionation, CHIRALITY: THE PHARMACOLOGICAL BIOLOGICAL AND CHEMICAL CONSEQUENCES OF MOLECULAR ASYMMETRY 29:(10) pp. 610-615. (2017)

Márton Kőrösi, János Madarász, Tamás Sohajda, Edit Székely, A fast, new method to enhance the enantiomeric purity of non-racemic mixtures: self-disproportionation of enantiomers in the gas antisolvent fractionation of chlorine-substituted mandelic acid derivatives, TETRAHEDRON-ASYMMETRY Paper TETASY 59695. (2017)


Objectives: development of supercritical diastereomer crystallization methods competitive in efficiency to the traditional solvent based crystallizations and having lower environmental effects.

Tasks and methodology:

  • Literature survey
  • Screening of promising resolving agents for all racemates (4 to 6). Selection of the two best pairs.
  • Measurement of solubility of the selected racemate(s) in CO2 and in CO2-solvent mixtures.
  • Development of the high pressure diastereomeric salt precipitation processes. (separately for the two pairs)
  • Critical evaluation and simple mathematical modelling of results. 


  • racemate – resolving agent pairs grouped to no salt / no enantioselectivity / poor enantioselectivity / good enantioselectivity groups
  • timeframe of salt formation mapped and analytical methodology developed
  • high pressure diastereomeric salt formation process developed and optimised


Selected publications: 

Amit D Zodge, Petra Bombicz, Edit Székely, György Pokol, János Madarász, Structural, analytical and DSC references to resolution of 2-methoxy-2-phenylacetic acid with chiral 1-cyclohexylethylamines through gas-antisolvent precipitation THERMOCHIMICA ACTA 648: pp. 23-31. (2017)

A Zodge, M Kőrösi, M Tárkányi, J Madarász, I M Szilágyi, T Sohajda, E Székely, Gas Antisolvent Approach for the Precipitation of -Methoxyphenylacetic Acid – (R)-1-Cyclohexylethylamine Diateromeric Salt CHEMICAL AND BIOCHEMICAL ENGINEERING QUARTERLY 31:(3) (2017)


László Lőrincz, György Bánsághi, Máté Zsemberi, Sandra de Simon Brezmes, Imre Miklós Szilágyi, János Madarász, Tamás Sohajda, Edit Székely, Diastereomeric salt precipitation based resolution of ibuprofen by gas antisolvent method, JOURNAL OF SUPERCRITICAL FLUIDS 118: pp. 48-53. (2016)

Enzymatic reactions often show excellent selectivity, and, in the case of chiral synthesis, excellent enantioselectivity. The natural solvent of enzymatic reactions is water. However, some reactions run very slowly in watery media. The reasons are mainly mass transfer limitations, are derived from reaction kinetics, or solvent-induced direction change of the reaction. Generally, acylation/ester formation reactions are catalyzed by lipases better in nonpolar solvents while hydrolysis is preferred in water. Although a large number of enzymatic reactions perform fast and selectively in organic solvents (or somewhat lower but even selectively at neat conditions), the separation of the solvent, remaining substrate and product is problemtic and limits the industrial applicability of these methods.

Some enzymes, mainly lipases, are active in supercritical carbon dioxide (scCO2). Enzymatic reactions in scCO2 , the most widely studied reactions are lipase catalysed acylation reactions, do not only have a well-known temperature optimum, but the enzyme activity is also dependent on the applied pressure . Obiviously, increasing the molar ratio of the acetate donor also enhances the reaction rate. In most cases vinyl acetate, isopropenil acetate or butyl acetate are applied. 

In the recent years we investigated enzyme catalysed kinetic resolutions in batch, circulated and continuous supercritical reactors, and a systematic development approach was also suggested. The reactions studied were mainly acylation reactions, but also a lactame ring opening reaction was investigated and coupled with extraction based product-substrate separation. 

Selected publications:

Néhány publikáció a témakörben: 

Varga Zsófia, Kmecz Ildikó, Szécsényi Ágnes, Székely Edit, Neat lipase-catalysed kinetic resolution of racemic 1-phenylethanol and a straightforward modelling of the reaction, BIOCATALYSIS AND BIOTRANSFORMATION 56: pp. 1-7. (2017)

Székely E, Utczás M, Simándi B Kinetic enzymatic resolution in scCO2 – Design of continuous reactor based on batch experiments JOURNAL OF SUPERCRITICAL FLUIDS 79: pp. 127-132. (2012)

In the recent years chirality of pharmaceuticals and agrochemical compounds has reached a great importance. Although many of drugs used are optically active, the majority of synthetic drugs are produced as racemates. According to FDA's (Food and Drug Administration, USA) policy statement and also to guidelines of the Japan authorities new optically active drugs should be prepared for marketing in their enantiomerically pure form.

Separation of enantiomers called resolution is not a simple procedure. Physical and physico-chemical properties of enantiomers are the same, different properties can be reached by derivatisation with some optically active compounds. These products are the diastereomers which can be separated by a range of methods. Fractionated crystallisation is the most common industrial process, while chromatographic methods are superior in analytical scale [3]. Although, theoretically almost all racemates may be separated via partial or total diastereomeric salt (complex) formation and crystallisation from a proper solvent, this method has a lot of disadvantages: complete enantiomer separation can not be achieved in one step; a small amount of the wanted form is retained in the mother liquor; a great amount of active resolution agent is needed; the widely used organic solvents cause impurities in the product [4]. These problems can be eliminated if the separation is achieved by supercritical fluid extraction using carbon dioxide (CO2).

The applicability of SFE for resolution of some acids and bases has been proved by the researchers of our laboratory. The project is run with co-operation with the Department of Organic Chemical Technology. The basic idea of the resolution is that after the partial diastereomer formation of the racemate only the free enantiomeric mixture is soluble in supercritical carbon dioxide.
On the left side is shown the flow sheet of the resolution process. This can be divided into three parts: preparation of the sample, extractionand processing the raffinate. In case of different compounds all the part-processes need to be optimised. The following parameters are to describe the result of the resolution: enantiomeric excess (ee), yield (Y), and selectivity (F).

It was not suprising, because the effect of the used solvent on the selectivity is already known [I]. On the other hand, sometimes the chiral differentiation is higher in SCFs than in organic solvents. The resolution of cis-chrysanthemic acid by S-(+)-benzylamino-1-butanol resolution agent led to 99 % ee in one step[II], while in water-chloroform liquid-liquid extraction system only 28% is achieved [III].

It was experienced, that the physical properites of the carbon dioxide as pressure and temperature(also density, viscosity etc.) influence the chiral differantiation. It suggests, that the extraction step is more than a simple separationII. For example the higher pressure is better for the resolution of cis- and trans- permetric acids[IV], but has no effect in other cases [V].

The scale up of some supercritical extraction processes are already proved to be possible (ex. see the decoffeination of coffee or tee) and the industrial use has serious adventages: the carbon dioxide is quite cheap and enviromentally benign; it does not contaminate the product, because under atmosferic pressure and room temperature it is a gas; and the soluting strange is easily contorlable by pressure and temperature. The main disadventage is the cost of the equipment, but longer run it may be economical.


Extraction of plants (on the example of spices)

Organic foods require processing without the addition of external material. Supercritical fluid extraction (SFE) using carbon dioxide (CO2) is a particularly suitable isolation method. A natural plant extract, free from chemical alterations brought about by heat and water, and without solvent residues and other artifacts can be obtained by this method. Carbon dioxide is non-toxic, non-explosive, readily available and easily removed from the extracted products.

All products characterized by their internal content are claimed by the market consumers to have a reproducible and stable quality. The ground spice products made in the traditional way are frequently not corresponding to the requirements concerning reproducibility, stability and recently also for microbiological point of view. Technological solutions are sought that insure these properties of the products and satisfy the standards in a more reproducible way.

Beyond the supply and demand relations there are situations in Hungary when sale problems occur because the technology is limited in producing standardized spice products. Consequently the ware is not sold, which means it looses further from its internal content.

For extraction of spices a variety of solvents, including alcohols, acetone and hexane can be used. However, these organic solvents leave adsorbed residues behind and elevated temperatures at the desolventization process can cause chemical modifications of the oleoresins. Governmental regulation of these solvents varies from country to country. The solvent residues must be reduced to very small concentrations, generally in the range of 25-30 ppm or less.

Supercritical fluids are gases with properties between that of a "normal" gas and a liquid. Variation of pressure changes properties of supercritical fluids continuously from more gas-like behavior to more liquid-like behavior. This behavior may lead to new technologies in processing natural materials (extraction and purification), in processes related to the environment (destruction of waste with supercritical water), and in reaction engineering (hydrogenation with mixtures of hydrogen and supercritical carbon dioxide). Applications in biotechnology may appear in downstream processing and enzyme catalyzed reactions.

Supercritical fluids produce practically solvent-free products and avoid deteriorating reactions. Process temperatures are low to very moderate. Solvent handling is favorable because it can be easily and totally removed, it is readily available and cheap, and it is accepted and part of the environment (water, carbon dioxide). Even then, solvent losses are minimal when compared to ordinary men's activities for these substances, since the solvent is recycled.

Situations where supercritical fluids may be useful emerge from the effects which supercritical fluids have on pure compounds and mixtures. Supercritical fluids change compound properties, phase equilibria, chemical equilibria, and related rate processes, as has been discussed in many publications.

The product of a supercritical extraction of a spice is normally not solid. The liquid spice-products are more stable than the classic forms, after a longer storage period they loose their internal content in a slighter degree; The new liquid spice-products have a more reproducible quality. Both for the private user and the food technology the reproducibility means surplus value ; The new liquid spice products contain the characteristic aroma, taste and odour; Substances are in a solution form. During their utilization a smaller quantity is required for reaching the same effect; The standardization of the new liquid spice products means that the composition, the characteristic values are controlled during the producing process , but simultaneously they represent the secret of the technology. In consequence hopefully till for a long time  the falsification, dilution or any other market fraud will be prevented by the manufacturing process.


© BME, Research Group on Supercritical Fluids, 2015