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J Mater Sci (2012) 47:2995–3025 DOI 10.

1007/s10853-011-6054-y

REVIEW

Synthesis of nanostructured materials using supercritical CO2: Part I. Physical transformations
D. Sanli • S. E. Bozbag • C. Erkey

Received: 29 April 2011 / Accepted: 13 October 2011 / Published online: 2 December 2011 Ó Springer Science+Business Media, LLC 2011

Abstract Nanostructured materials have been attracting increased attention for a wide variety of applications due to their superior properties compared to their bulk counterparts. Current methods to synthesize nanostructured materials have various drawbacks such as difficulties in control of the nanostructure and morphology, excessive use of solvents, abundant energy consumption, and costly purification steps. Supercritical fluids especially supercritical carbon dioxide (scCO2) is an attractive medium for the synthesis of nanostructured materials due to its favorable properties such as being abundant, inexpensive, non-flammable, non-toxic, and environmentally benign. Furthermore, the thermophysical properties of scCO2 can be adjusted by changing the processing temperature and pressure. The synthesis of nanostructured materials in scCO2 can be classified as physical and chemical transformations. In this article, Part I of our review series, synthesis of nanostructured materials using physical transformations is described where scCO2 functions as a solvent, an anti-solvent or as a solute. The nanostructured materials, which can be synthesized by these techniques include nanoparticles, nanowires, nanofibers, foams, aerogels, and polymer nanocomposites. scCO2 based processes can also be utilized in the intensification of the conventional processes by elimination of some of the costly purification or separation steps. The fundamental aspects of the processes, which would be beneficial for further development of the technologies, are also reviewed.

Introduction Nanostructured materials have been attracting increased attention for many applications due to their superior properties primarily because of their high surface-to-volume ratios. Two general approaches are employed in making nanostructured materials: top-down and bottom-up. Crushing, grinding, milling, and attrition are typical topdown techniques where one starts with a bulk material and obtains a nanostructure by size reduction. With bottom-up methods, one starts with atoms, molecules, or clusters to grow structures with nano-scale features. These are usually techniques such as colloidal dispersion, impregnation, sol– gel, co-precipitation, reverse-micelles and chemical vapor deposition (CVD) as well as re-crystallization. Lithography is a blend of the two since the film growth is bottom-up, whereas the etching process is top-down [1]. It is usually challenging to control the properties such as the average size, size distribution, composition, and morphology of the nanomaterials. Top-down approaches occasionally lead to internal stresses, surface defects, and contaminations. For instance, in the case of nanowires obtained with lithography, the surface imperfections can cause reduced conductivity due to inelastic surface scattering, which in turn would lead to the generation of excessive heat and thus bring extra challenges in design and fabrication [1]. Even though the bottom-up approaches enable the synthesis of nanostructured materials with fewer defects, less impurities and better short/long range ordering, they also have severe limitations originating from a number of reasons such as the instability of the raw materials under working conditions, the utilization of toxic solvents, the requirement of costly separation processes in production lines, and abundant energy consumption [1].

D. Sanli Á S. E. Bozbag Á C. Erkey (&) Department of Chemical and Biological Engineering, Koc ¸ University, 34450 Sariyer, Istanbul, Turkey e-mail: cerkey@ku.edu.tr

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J Mater Sci (2012) 47:2995–3025 Table 1 Comparison of typical physical properties of gases, liquids, and SCFs Fluid properties Density (g cm-3) Diffusivity (m s ) Viscosity (Pa s )
-1 2 -1

The limitations of the conventional top-down and bottom-up approaches can in some cases be overcome by the utilization of supercritical fluids (SCFs). The advantages of SCFs over other solvents or media are primarily due to their physicochemical properties, which are intermediate between a gas and a liquid and are easily adjustable with changes in temperature and pressure. The P–T diagram of a pure compound is given in Fig. 1. The liquid–gas coexistence curve terminates at the critical point the coordinates of which are the critical temperature (Tc) and critical pressure (Pc). A SCF is a fluid that has been compressed and heated above its Tc and Pc. SCFs possess interesting properties such as liquid-like density, gas-like viscosity, and the diffusion coefficients in SCFs are higher than in liquids. The typical values of thermophysical properties of the gas, liquid, and the supercritical state are given in Table 1. Table 2 gives the critical properties of commonly used SCFs. Supercritical carbon dioxide (scCO2) is preferred over other SCFs due to its relatively easily accessible Tc (31.2 °C) and Pc (7.38 MPa). These mild supercritical conditions make CO2 as an attractive medium for a variety of applications especially for processing of thermally labile compounds. scCO2 also has other remarkable advantages such as being abundant, inexpensive, nonflammable, non-toxic, and environmentally benign. Furthermore, like all the other SCFs, mass transfer rates in scCO2 are considerably faster than that of the liquid solvents and scCO2 can penetrate easily to the depths of the highly porous nanostructures. The solvent power of a SCF is a function of its density which increases with pressure at constant temperature. The adjustability of the solubility of a solute (in this case benzoic acid) in CO2 is depicted in Fig. 2a. At constant temperature, the solubility increases with pressure significantly near the Pc and then continues to increase monotonically. Between 9 and 17 MPa, at a particular pressure, the solubility of benzoic acid in scCO2 increases with decreasing temperature due to the decrease of the CO2’s density (thus the solvation

Gas 0.6–2 9 10-3 1–4 9 10 1–3 9 10
-5 -5

SCF 0.2–0.9 2–7 9 10 1–9 9 10
-8 -5

Liquid 0.6–1.6 10-9 10-3

Table 2 Critical properties of some SCFs Fluid Carbon dioxide Ammonia Water Ethane Propane Cyclohexane Methanol Ethanol Isopropanol Acetone Tc (°C) 31.2 132.4 374.1 32.5 96.8 279.9 240.0 243.1 235.6 235.0 Pc (MPa) 7.38 11.29 22.1 4.91 4.26 4.03 7.95 6.39 5.37 4.76 Remarks – Toxic High Tc, corrosive Flammable Flammable High Tc High Tc High Tc High Tc High Tc

Fig. 1 A typical P–T diagram of a pure compound

power). However, above 18 MPa, at a particular pressure, the solubility of benzoic acid increases with increasing temperature. This behavior occurs due to the compensation of the decline of CO2’s solvent power due to decreasing density by the increase in solvent power due to the increase of the vapor pressure of the solute with increasing temperature. As shown in Fig. 2a, the solubility in scCO2 is significantly higher than predicted assuming that benzoic acid and CO2 forms an ideal gas mixture. This is primarily due to the nonideal behavior of the mixture as the density of CO2 approaches liquid like densities. Non-polar compounds have usually high solubility in scCO2 due to the fact that CO2 is a relatively non-polar solvent. However, polar molecules can also be dissolved in scCO2 to a certain extent since scCO2 has a large quadrupole moment. The solvating power of scCO2 can be increased by the addition of modifiers or co-solvents such as ethanol, methanol, and hexane at concentrations ranging from 1 to 20 wt%. scCO2 also displays high permeation rate in many polymers which swell when exposed to scCO2. This is particularly advantageous for the synthesis or processing of polymer nanocomposites as well as for impregnating a wide variety of chemicals into various polymers. Moreover, the degree of CO2 sorption/swelling in polymers, diffusion rates within the substrate, and the partitioning of solutes between the SCF and the swollen polymer can be tuned by density-mediated adjustments of solvent

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J Mater Sci (2012) 47:2995–3025 Fig. 2 a The solubility of benzoic acid in CO2 and the deviation from the ideal behavior (straight lines are the Peng–Robinson equation of state predictions). Adapted from Ref. [2] (Copyright (2011), with permission from Elsevier). b The solubility of CO2 in PET (Reprinted from [3]) (Copyright (2011), with permission from Elsevier). c Depression of PS’s Tg with the increase of the CO2PS system’s equilibrium pressure (Reprinted from [4]) (Copyright (2011), with permission from Elsevier)

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strength via changes in temperature and pressure. Figure 2b illustrates the effects of pressure and temperature on the solubility of CO2 in polyethylene terephthalate (PET). The weight fraction of CO2 in the polymer increases appreciably with increasing pressure and with decreasing temperature (due to the decrease of the density) up to a particular pressure and then increases with increasing temperature. This behavior is observed due to the fact that the CO2 concentration in the polymer at that particular temperature and pressure induces the glass transition from glassy to rubbery state. The glass transition is caused by the plasticization of the polymer due to the sorption of CO2 and the degree of the plasticization increases with increasing temperature which promotes the solubility of CO2 in the polymer with increasing temperature. The extent of the glass transition depression is shown in Fig. 2c. Here, the glass transition temperature (Tg) of poly(styrene) (PS) decreases significantly as the equilibrium pressure of the CO2-PS system increases. scCO2 is completely miscible with gases such as H2, O2, or CO at temperatures above 31.1 °C whereas gases are only sparingly soluble in organic solvents. As a result, significantly higher gas concentrations can be achieved in the scCO2 phase which may be advantageous in processing of nanostructured materials. For example, in reactive

processes which involve such gases, higher concentrations in the fluid phase may result in higher rates of reactions. The mass transfer limitations originating from the slow transfer rates of such gases across the gas–liquid interface may be eliminated. Another important characteristic of scCO2 is its low surface tension. Figure 3a shows the variation of CO2’s surface tension along the saturation envelope which reaches zero at the critical pressure. The interfacial tension between a polymer and CO2 also decreases with increasing pressure as illustrated in Fig. 3b for the case of poly(ethylene glycol) (PEG)-CO2. The interfacial tension declines dramatically within the vicinity of CO2’s critical pressure and then continues to decrease with increasing pressure at 45 °C. Having diffusion coefficients higher than that of liquids, viscosities close to that of gases and low surface tension, CO2 provides better penetration and complete wetting of the substrates which is advantageous for impregnation or extraction applications as compared to conventional solvents. Furthermore, the low interfacial tension induced by the scCO2 makes it the only applicable solvent for processing mesoporous structures with fragile pore morphologies such as aerogels. In the synthesis of nanostructured materials using organic solvents, additional processing steps are generally required

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nozzles. 21–24]. 4. Then. by using. fluidized beds). size distribution.2998 J Mater Sci (2012) 47:2995–3025 Fig. As CO2 passes over the solid material. with permission from Elsevier) Fig. 5. CO2 is vented from the system by depressurization leaving behind the extract and the extracted material which is free of solvent. The exiting CO2 from the bed is then passed through an expansion valve where the pressure is reduced. the conventional methods mostly yield dilute extracts which necessitates for a concentration step for the products. Control of these properties can be achieved by tuning the thermodynamics and kinetic parameters of the system. i. The properties of scCO2 mentioned above make it attractive as a processing medium for the production of nanostructured materials with controlled properties such as size. First. it extracts the desired compounds from the solid material. free of extract is heated and compressed back to the operating temperature and pressure. The separation is attained due to the decrease of the solubility due to the reduction in pressure. 3 a The variation of CO2’s surface tension with the pressure along the saturation envelope [5] and b the variation of interfacial tension for PEG-CO2 with pressure at 45 °C (reprinted with permission from [6]) (Copyright (2011) American Chemical Society) to remove the organic solvent from the material. At the end of the process. The wide range of nanostructured materials synthesizable via scCO2 based processes are depicted in Fig. and transferred into the vessel. morphology and composition [9–20]. a solid extract phase which is generally almost free of CO2 and a gaseous CO2 phase. the vessel is charged with CO2 which is heated and pressurized above its critical point. via addition of surfactants. [8] (Copyright (2011). 4 A basic SFE cycle. Companies manufacturing materials are faced with an ever increasing solvent problem because of environmental concerns and therefore there is an ongoing trend in industry to replace toxic and hazardous solvents with less toxic or harmless solvents. Then. in the case of extraction. 11.e. Being a non-toxic solvent. CO2 is circulated over the bed using a pump or compressor (1).. nano-reactors or by applying a specific process configuration (i. all the material to be extracted is placed in the high pressure vessel (3). scCO2 based techniques for preparation of nanostructured materials have been reviewed in 2000s [10. The circulation of CO2 is continued until all the desired material is extracted. The gaseous CO2. The present text primarily aims to give a perspective to material scientists and engineers on the matter by focusing on the description and analysis of these techniques.. The text has been divided into two main articles as 123 . scCO2 has already replaced toxic organic solvents in a wide variety of applications and has tremendous potential for use in development of new environmentally friendly processes [7]. A typical supercritical fluid extraction (SFE) process is demonstrated in Fig. Adapted from Ref. An important advantage of scCO2 is that it leaves no residue in the treated medium.e. Additionally. The mixture then separates into two phases.

13–20]. and morphology of the nanostructured materials [13]. production of flavors. as in SAS and laser ablation.J Mater Sci (2012) 47:2995–3025 2999 Fig. RESS rapid expansion from supercritical solutions. synthesis in scCO2. 11. HTS hydrothermal synthesis. as an 123 . Physical processes such as rapid expansion from supercritical solutions (RESS). surface functionalization from supercritical solutions (SFSS) and processes in which scCO2 is used as a reactant are discussed in Part II. The rest of this section describes different scCO2 processes with their physical basis. depressurization rate in SCF based processes influence the final particle size. SFE supercritical fluid extraction the physical and chemical transformations in synthesis of nanostructured materials using scCO2. SFSS surface functionalization from supercritical solutions. anti-solvent. foaming and laser ablation (LA) along with the state-of-art examples are described in Part I. RESOLV rapid expansion of a supercritical solution into a liquid solvent. SAS supercritical anti-solvent. The very high efficiency of scCO2 based extraction processes mostly originates from the superior combination of the liquid and gas like properties of CO2 at the supercritical state [27] together with the favorable characteristics listed in ‘‘Introduction’’. examples from the literature are generally chosen among the studies carried out since 2008 considering the increasing interest in the subject matter since 2008 and also because of the excellent review articles on the topic published before 2008 [10. supercritical fluid extraction (SFE). as in PGSS and foaming [9–11. supercritical anti-solvent (SAS). PGSS particles from gas saturated solutions. Supercritical CO2 as a solvent Supercritical CO2 extraction Extraction of target compounds from solid and liquid matrices is probably the most investigated and wellestablished application of scCO2. nanoreactors (NR). particles from gas saturated solutions (PGSS). depressurization temperature and pressure. NR nanoreactors. 21–23. arrested growth (AG). size distribution. 5 The extent of nanomaterials that can be produced using scCO2. as a solute. SCD supercritical deposition. Synthesis of nanostructured materials using physical transformations Physical processes including the use of scCO2 can be classified according to the role of the CO2 in the process: it can act as a solvent. scCO2 has been used as an extraction medium for a wide range of applications primarily in the food industry such as refining of triglycerides and fatty acids. 25]. as in SFE and RESS. AG arrested growth. In these articles. nanoscale casting. SAIPE supercritical antisolvent-induced polymer epitaxy. and the effects of the above mentioned processing parameters on the final product characteristics. Various operating parameters such as operating temperature and pressure. Methods including chemical transformations such as supercritical deposition (SCD).

Washington Pitt-Des Moines. Washington J. Houston. Japan (500ltx2) Takasago Foods (Mitsubishi Kokoki facility).. In addition. South Africa (200lt) Sumitomo Seiko. Munchmuenster. Table 3 lists some of the commercialized SFE plants together with some extractor sizes and demonstrates the wide acceptance of SFE technology at industrial scale. production of antioxidants. Bremen.. 29].. Reigat. Merebank. Inc. Thus. Germany Raps & Co. the large capillary forces which are generated due to the evaporation of the liquid trapped in the narrow gaps of the device can cause structures to collapse and stick to an adjacent surface. (200lt ? 500lt) SKW Trostberg. Nebraska Hopfenextraktion. Hopewell. Barth. Canada (250ltx4) Color extraction—Red Pepper Mohri Oil Mills. Munchsmunster.and nano-scale structures. Germany (360lt) SKW-Trostberg. Poszzillo. Germany (4000ltx5) Hops Extraction Corp. Wolnzach. Texas Hermsen. medical products. Another large-scale application of SCF extraction is carried out by Aspen Aerogels for the fabrication of aerogel blankets for use as thermal insulators. SFE technology is attracting increasing attention in the pharmaceutical. 1500ltx3) Flavex. Sydney. Japan Hasegawa Koryo. United Breweries.. Inc. selective separation of nicotine from tobacco. Japan (200lt) SKW-Trostberg. Munchmuenster. Among these applications.. MEMS are being developed for a wide variety of applications that requires micro. United Kingdom Nan Fang Flour Mill. France Soda Flavor Co. Germany (200lt) Pauls & White. Italy Hops extraction Pfizer Hops Extraction. production of low fat and low cholesterol foods.. Germany (70lt) Flavors extraction Flavex GmbH. Germany General Foods. Conventional drying methods that are employed to remove the aqueous processing solutions from the device include the replacement of the aqueous solutions with organic solvents such as acetone or hexane and then the heating up of the device to evaporate the organic solvent. Raiser & Co. Virginia Nippon Tobacco. Rehlingen. Kulmbach. Yakima.3000 J Mater Sci (2012) 47:2995–3025 extraction of spices and essential oils. Bremen. the cork extraction is one of the prominent examples that was recently scaled up by NATEX (2500 t/year) [30]. of America. clean. Germany Jacobs Suchard.8lt) Guangxia Toothpaste. Table 3 Examples of commercial supercritical extraction plants scCO2 is also employed for the drying of micro-electro mechanical systems (MEMS). Yakima. Germany SKW-Trostberg. 3500ltx3. Co.. United Kingdom NORAC.. Ltd. The critical steps during the fabrication of MEMS are the processes that release. Japan (200lt ? 300lt ? 300lt) Natal Cane By-Products Ltd. Germany (500ltx3) Shaanxi Jia De Agriculture Eng. the conventional drying methods create the major problem of Coffee decaffeination Kaffee HAG AG. Rehlingen.. and dry the flexible nanostructures which are crucial for device functionality. Pittsburgh. Japan Yasuma (Mitsubishi Kokoki facility). China (500ltx3. Bremen. Haas. and neutraceutical industries. Germany (650lt) Natal Cane By-Products Ltd. However. HVG. even though the SFE processes have rather high equipment costs due to high pressures employed. Japan Flavors/aromas/spices Camilli Albert & Louie. China (500ltx2) Nicotine extraction Tea decaffeination Hops extraction and spices Philip Morris. South Africa (1000lt) Barth & Co. Japan Fuji Flavor. Grasse.I. China (300ltx2) 123 . Japan (5. USA (3000ltx4) Carlton. Merebank. extraction of caffeine from coffee and tea [28.

6 SEM images of microelectronic structures that are dried a with scCO2 b with evaporation of hexane.e. conventional drying using heat to evaporate hexane in b. When scCO2 is employed to extract the organic solvent instead of evaporation. and spring. dry. Additionally. Recently. In a recent study by Zhang et al. formation of residues. which is the commonly used adsorbent for removal of organic compounds from gas streams [40. 41].informaworld.. Jung et al. and c with evaporation of water [35] (Reprinted by permission of Taylor & Francis Group. Additionally. In this study. the organic compounds that are adsorbed inside the porous AC are extracted by the aid of scCO2. Some of the studies on MEMS carried out recently using scCO2 are given in Table 4. Furthermore. Numerous studies were carried out on the reactivation and regeneration of used activated carbon (AC). the effects of reactivation conditions. They also depicted scCO2 extraction to be a non-destructive technique without any decrease of the granule size of the catalyst and sintering of the Pd nanoparticles [47]. Although few. Figure 6 demonstrates the distinction between MEMS structures after drying with scCO2 in a. reported on the preparation of poly-Si cantilevers from p-tetraethylorthosilicate (TEOS) by performing dry etching with HF/H2O in scCO2. In the case of cleaning of the MEMS devices.com) 123 . the pore inducer compounds are mixed with the bulk material and become confined in the matrix. CO2 flow rate. Many advantages of scCO2 over the conventional adsorbent regeneration techniques—mainly steam stripping— have been stated in the literature. scCO2 extraction yields a porous structure. 49]. these techniques are generally insufficient for the complete removal of the process residuals and cause damage to the structures due to the harsh chemical environment. there has also been studies for reactivation of supported metal catalysts with scCO2. pores being formed with the removal of the inducer compounds from the compact solid. the conventional techniques utilize aqueous solutions of harsh chemicals for the photoresist stripping and the removal of organic and inorganic post-etch and post-ash residues usually comprise dipping the device in chemical baths. Use of scCO2 for the cleaning steps of microfabrication offers a potential to eliminate these problems as scCO2 can completely remove the residuals by dissolving them and do not cause any structural deformation [36–40]. on the activity of the reactivated Pd/AC catalyst were investigated. In this process. reactivation of a Pd/AC catalyst for the hydrogenation of benzoic acid was accomplished by extracting the organic compounds that are blocking the pores of the catalyst with scCO2. and time. However. residue-free devices with no stiction [35–39]. scCO2 has received considerable attention in regeneration of catalysts and adsorbents. http://www. This technique is considered to be a promising method as it eliminates the additional drying step of the conventional wet etching and leads to clean.. such as higher recovered adsorption capacity. hydrofluoric acid (HF)] in scCO2. pressure. They also determined that the etch rate increased with the increasing reaction temperature [41]. The authors demonstrated that more than 70% of the fresh catalyst activity was restored.J Mater Sci (2012) 47:2995–3025 3001 microfabrication—stiction—which leads to damaged structures. They successfully obtained cantilevers with high aspect ratios of 1:150 without any residues or stiction problem. Porous grinding wheels were produced using this technique which eliminates some drawbacks of conventional thermal degradation techniques such as swelling. and water in c [31–34]. such as reactivation of Pd/Al2O3 for cyclododecatriene hydrogenation and regeneration of a spent Pd/AC catalyst which is used for hydrogenation of a variety of organic compounds [44–46]. Another important application of scCO2 extraction is the generation of porous structures by supercritical extraction of pore inducers from solid matrices. eliminated residuals such as condensed water in the pores and safer operation environment due to the low desorption temperature and inert CO2 environment [43]. In order to be reused. This technique was first introduced by Erkey’s group in 2004 where biphenyl was used Fig. thus regenerating AC [42]. the etching step has recently been carried out in scCO2 medium by dissolving the etchant [i. such as extraction temperature. the pore size and structures of the wheels could be controlled by changing the particle size of the pore inducers [48. the capillary forces due to the existence of the vapor–liquid interface are eliminated which prevents stiction.

3 MPa.3-tetrafluoro-1-propanol (TFP) scCO2 extraction of toluene scCO2 extraction for reactivation scCO2 drying of aerogels scCO2 drying of starch aerogels scCO2 drying of cellulosic aerogels scCO2 drying of alginate aerogels scCO2 drying of aerogels scCO2 drying of aerogels scCO2 drying of aerogels scCO2 drying of aerogels scCO2 drying of aerogels as the pore inducer and extracted with scCO2 at room temperature and at varying pressures of 8. fluoranthene) Kinetic study for regeneration of granular carbon scCO2 extraction of 2. SiO2. the pore inducer extraction method was extended by Reverchon et al. A year later the same group also investigated the extraction of butyl carbamate as the pore inducer from green grinding wheels and examined the effects of solubility and flow conditions on the extraction rate [49]. anthracene. tetramethylorthosilicate and Vinyltrimethoxysilane 3D-networks of native starch Cellulosic aerogels Nanoporous microspherical alginate aerogels Lead telluride (PbTe) aerogels Titania organogels and titania aerogels Syndiotatic polystyrene aerogels Mesoporous TiO2–SiO2 aerogels Highly crystalline aerogels of isotactic poly(4-methyl-pentene1) (i-P4MP1) scCO2 dry etching of microcantilevers scCO2 dry etching of microcantilevers scCO2 dry etching Application J Mater Sci (2012) 47:2995–3025 References [86] [87] [63] [88] [89] [90] [91] [91] [38] [34] [41] [50] [92] [93] [94] [65] [64] [95] [96] [97] [42] [43] [47] [98] [90] [99] [70] [100] [101] [102] [103] [104] scCO2 reactive drying of metal oxide nanoparticles scCO2 drying. CeO2 scCO2 extraction of PAHs (acenaphthene.3. resulting voidage between 48 and 68% scCO2 drying of carbon and chitin aerogels scCO2 drying of chitosan microspheres with inorganic oxides scCO2 drying of cellulose Supercritical drying of starch gels and reaction of TiO2 precursor with starch in scCO2 Modeling the reactive removal of Cu particles from silicon surface Supercritical drying of ZnO nanoparticles scCO2 drying of poly(L-lactic acid) (PLLA) scaffolds scCO2 drying of poly(L-lactic acid) (PLLA). 7a) along with nanofibrous pore walls 123 .2. phenanthrene. however. and SiN TEOS-doped silicon wafers and poly-Si cantilevers 3D scaffolds for tissue replacement Nanostructured scaffolds Inorganic membranes Porous cellulose from cellulose–NaOH–water solutions Silica-modified cellulosic aerogels Shaped. P-TEOS. This was attributed to the insignificant effects of pressure on the solubility and diffusivity of biphenyl in scCO2 [48]. The extraction rate was demonstrated to be strongly affected by flow rate of CO2. Recently. Al.3002 Table 4 Summary of some of the literature studies involving scCO2 Processed material Interpenetrating networks of Resorcinol formaldehyde (RF) and various metal oxide nanoparticles Agar gels Chitin and carbon aerogels Chitosan polysaccharide and Lewis acidic precursors (Ti.8–15. ultra-light weight aerogels from bacterial cellulose Rare earth elements from their oxides Contaminated soils Bidispersed activated granular carbon Activated carbon Activated carbon Pd/AC catalyst Aerogels from bis[3-(triethoxysilyl)propyl]disulfide. to poly(L-lactic acid) (PLLA) scaffold production for tissue engineering applications [50]. Zn. hydroxyapatite (HA) scaffolds scCO2 extraction of ligands and surfactants scCO2 drying of porous cellulose scCO2 drying of cellulosic aerogels scCO2 drying of cellulosic aerogels scCO2 extraction of Nd and Ce from Nd2O3. was independent of pressure. Sn) Cellulose hydrogels and methanogels Starch TiO2 Cu Poly(3-octylthiophene) (POT) Zinc oxide(ZnO) Poly-Si cantilevers BPSG. By supercritically extracting D-fructose particles placed in PLLAs they managed to generate scaffolds with macropores of about 100–150 lm (Fig.

scCO2 is an efficient purification and sterilization medium for polymeric materials. 56]. and solvent extraction cannot provide sufficient removal of impurities. Although the rate of evaporation can be controlled to some extent by altering the ambient pressure. scCO2 may have also acted as a foaming agent which will be described in ‘‘Foaming.J Mater Sci (2012) 47:2995–3025 3003 which had a great extent of interconnectivity between the macropores (Fig. As a result of this expansion. In supercritical drying of the gels. 54]. Conventional polymer purification techniques such as vacuum. the solid network retains its structure and the pores remain intact without any collapse due to small interfacial forces [28. 7b). In the sol–gel processing of silica-based aerogels. Figure 8 displays clearly the structural differences between the supercritically and ambient dried silica gels. catalysts. 52]. and DMSO/H2O ratio [59].1 and 5 lm by adjusting the operating conditions such as temperature. Conventional ambient drying technique comprises the removal of the pore liquid by evaporation. and causes the ethanol solution to expand. and side reaction products from polymers has been another potent application of scCO2 extraction. Purification of a wide variety of polymers such as poly(methylmethacrylate) (PMMA) [53. Delipidation of bones has been carried out in scCO2 resulting in reduced infection effects and efficient enzymatic deproteination [60. extraction of the ethanol takes place by its diffusion to the bulk CO2-rich phase. poly(lactic acid) PLA microspheres [57]. In the study by Panayiotou et al. we note that it is possible to inactivate some bacterial spores and a number of viruses using scCO2. which will be described later. the interfacial tension owing to the gas–liquid boundary that is formed inside the pores during evaporation leads to collapse of the pores which results in cracked structures and much lower surface areas. scCO2 diffuses into the pore that is filled with ethanol. poly(acrylic acid-co-acrylamide) hydrogel [58] was carried out by scCO2 extraction. However. The hemicellulose microparticles were then purified by extraction of DMSO with scCO2. Consequently. the solution in the pores is discharged to the continuously flowing scCO2 stream. 62]. which results in xerogels with high percentage of reduction in volume. The microparticles were generated by precipitating xylans and mannans from a dimethylsulfoxide (DMSO)/H2O solution with an antisolvent technique (GAS). 7 SEM images of generated PLLA scaffolds at different magnifications (Reprinted from [50]) (Copyright (2011). In this particular study. The mechanical properties of the scCO2-treated polymers depend on the operating conditions and the polymer used. unreacted monomers. poly(lactide-co-glycolide) (PLGA) microspheres [55. with permission from Elsevier) production and purification of hemicellulose microparticles were carried out by utilizing scCO2. [62]. One of the most important applications of scCO2 extraction is the drying of organic and inorganic aerogels. scCO2 has been extensively used in sol– gel processing for the removal of organic solvents from gels. chitin 123 . especially heat-sensitive polymeric materials [51. steam stripping. the organic solvent— generally ethanol—that is also generated during the condensation reactions is confined inside the pores of the solid network which is formed during the gelation step. Besides silica aerogels. and can alter the mechanical structure and physical properties of the polymers. [63].. Simultaneously. The authors obtained particles with a wide range of sizes between 0. Since early 1980s. Fig. supercritical drying method has been widely employed for the production of organic aerogels. Having moderate operating conditions. dissolves in ethanol. the damage to the pore structure at nanoscale cannot be avoided. 61]. Furthermore. pressure. which leads to aerogels as final product.’’ Removal of residual solvents. In a recent study by Haimer et al. the mechanism of extraction from the pores involves two phenomena. Extraction using scCO2 can also be used in biomedical applications such as human bone treatment to obtain new bone substitutes for surgery.

In 2005. According to the nitrogen adsorption and SEM results. The alcogels were similarly dried with scCO2 at 40 °C and 100 bar and the resulting aerogels were found to contain two interpenetrating networks of silica and cellulose [65]. 93000. cellulose integrity. The process fundamentally consists of the extraction of the organic solvent from the droplets of an oil-in-water emulsion and combines the advantages of two different techniques. In a more recent study. In 2010. and silica content were examined. 9 SEM pictures at various magnifications (9200. In 2010. They dried cellulosic alcogels using scCO2 at 40 °C and 100 bar and obtained cellulosic aerogels with densities around 8 mg/cm3. nanoporous microspherical alginate aerogels with high surface area (680 m2/g) and Fig. from left to right) of a scCO2 dried aerogel from bacterial cellulose [64] 123 . silica aerogel microparticles were produced with an in situ emulsion technique and the resulting dispersion (gel–oil) was dried by supercritical extraction. 9 [64]. Production of cellulosic aerogels has also been attracting increased attention since unlike conventional silica aerogels. In a recent study by Alnaief and Smirnova [69]. In another study by the same group. they are biodegradable materials. ultra-lightweight cellulosic aerogels through a sol–gel route. which can be observed from Fig. 9500. silicamodified cellulosic aerogels were synthesized by Litschauer et al. Chattopadhyay and Fig. The precipitation of PLGA microparticles was achieved by the scCO2 extraction of the organic solvent of the oily dispersed phase [68]. Della Prota et al. Mattea and co-workers [67] published an interesting study on the behavior of a drop of dichloromethane in water in contact with scCO2 for analysis of the phenomena that occurs during SEE process. through the sol–gel route and the influence of different parameters on porosity. produced PLGA microparticles with controlled and narrow size distributions (with a mean particle size between 1 and 3 lm) using a continuous SEE process with a countercurrent packed column.and nanoparticles by scCO2 extraction of oil-inwater (o/w) emulsions.and nanoparticles of pharmaceutical polymers-drug nanocomposites which have limited solubilities in water. the aerogels exhibit an open-pore structure that mainly consists of large mesopores and small macropores. synthesized shaped. The main advantage of the technique originates from the correlation between the final particle size and the droplet size distribution in the emulsion which allows for the production of nanomaterials with tunable particle size [67]. 8 Silica gel images obtained by supercritical drying (aerogel) (left) and ambient drying (xerogel) (right) co-workers [66] studied the production of drug (indomethacin and ketoprofen)-polymer (PLGA and Eudragit RS) micro.3004 J Mater Sci (2012) 47:2995–3025 aerogels were obtained by scCO2 extraction with drying temperatures ranging from 40 to 80 °C and pressures ranging from 80 to 300 bar to examine the influence of drying conditions on the porosity of the chitin aerogels. Supercritical emulsion extraction (SEE) is a relatively new technique that has been successfully implemented for the processing of micro. Liebner et al. extraction from emulsions and supercritical fluid extraction.

solubility of the substance is the limiting factor. So far we overviewed some important applications of scCO2 extraction. D12. however ks is more effective for solubility limited phase. At the start of the extraction process. The effects of the process parameters on the structure of the aerogels were investigated [70]. The diffusion rate can be increased via shortening the diffusion length which can be achieved by reduction of the particle size [9. 76]. diethylformamide (DEF)) by first exchanging DMF and DEF with ethanol followed by extraction with scCO2 at 31 °C and 73 bar. as. 10 [29]. The MOF had a 430 m2/g of accessible surface area which corresponded to a 12-fold increase compared to the conventional solvent removal techniques [75]. Another important application of scCO2 extraction is in the processing of metal-organic frameworks (MOFs) which are functional. ks..12 and 4. which also results in Fig. In order to be extracted. 29]. In the second phase of extraction. It is an important parameter since it affects the efficiency of the extraction process. The results indicated that the MOF sample generated by combining the microwave-assisted solvo-thermal method and sc-CO2 activation had excess and absolute H2 uptake values of 4. which were the largest values among all the Cu3(BTC)2 MOFs [77]. chemical sensing. The solubility can be increased by increasing temperature above the cross-over pressure and/or increasing pressure which increases the supercritical CO2 density. and drug delivery [71–74]. due to the channel collapse upon solvent removal. Operating in a condition where the solute has higher solubility in scCO2 generally results in a shorter extraction time. The mass transfer coefficient. 10 which display a typical trend of extraction yield versus extraction time [9].J Mater Sci (2012) 47:2995–3025 3005 different mean particle diameters (25 lm to few hundred lm) were produced from water-in-oil emulsion. which comprise the most wellknown class of supercritical extraction. 29]. is a geometrydependent parameter and the correlations for obtaining ks for different extraction systems can be obtained from the literature [75. Nelson et al. D12 is a fundamental parameter determining the extraction rate in the diffusion limited phase. ks. The diffusion coefficient doesn’t have any geometry dependency and various correlations including the Funazukuri correlation can be employed to obtain D12 at supercritical conditions [79. the residual molecules (generally solvent from synthesis) are removed by solvent exchange followed by heating the material under vacuum. reported the removal of solvents (dimethylformamide (DMF). In another recent study by Xiang et al. these two parameters play role during the whole extraction process. mass transfer also plays an important role in terms of extraction efficiency [9. In fact. to increase. especially in the solubility limited extraction phase by determining the mass transfer rates of the extracts to scCO2. ion exchange. 10 Typical trend of extraction curves (Reprinted with permission from [78]) (Copyright (2011) American Chemical Society) 123 . diffusion usually becomes the rate-limiting mechanism which leads to longer extraction times. Apart from solubility. particle size reduction can be employed to achieve higher mass transfer coefficients. chemical separations. respectively. These different phases of the overall extraction process can be observed from Fig. and thus increase the process efficiency within the diffusion limited phase as well as within the solubility limited phase that are indicated in Fig. The mass transfer coefficient. selective chemical catalysis. the substance should have an appreciable solubility in scCO2 [9. Removal of solvent and residuals from MOFs by scCO2 extraction is a very efficient technique that overcomes these drawbacks of the conventional techniques and enables the preservation of the microporosity. and thus the solvent strength. Furthermore. 80]. The desired extraction yields should be preferably reached within the solubility phase to achieve an economical extraction process.49 wt% at T = 77 K and P = 18 bar. To have a general knowledge about the underlying phenomena of these processes we will discuss some prominent fundamentals of the supercritical extraction from natural materials. where as D12 is dominant for the diffusion limited phase. Cu3(BTC)2 MOFs were synthesized by four different methods and N2 and H2 uptakes of the synthesized materials were determined. and ultra-high surface area materials being investigated for a wide variety of applications such as hydrogen or methane storage. This reduction also causes the specific interfacial area. low density. 76]. In 2008. The solubility of a substance in scCO2 is basically determined by two factors: the volatility of the substance which is a function of temperature and the solvent strength of the scCO2 which is a function of density [29]. is influenced by the diffusion coefficient. 29]. However. During the synthesis of MOFs. conventional techniques lead to partial or even full loss of porosity [75. On the other hand.

and mold is thus prevented in 123 . The depressurization of the system is started at t = t2. Generally the equations that govern the kinetics of scCO2 extraction process are similar to the typical mass transfer equations which involve two differential solute mass balance equations. which causes a rise in the Reynolds number. the vessel is pressurized with CO2 and the solute starts dissolving as the pressure increases. The relative amount of adsorbed and precipitated solute is governed by the adsorption isotherm. During period I. A process for impregnation of wood using scCO2 was recently commercialized by NATEX. the evolution of the extraction yield with time [27]. because of the lower loading of supercritical CO2 with the extract. Extraction yield can further be increased by increasing the flow rate. For polymers. leather. monomers. In the case of polymers. and aerogels. The impregnation of the solute into the substrate takes place during period II even though there may be some impregnation during period I. Thermodynamic models are needed for the determination of equilibrium conditions and solubility behavior of the solute-supercritical CO2 system and are also important components of the kinetic models which are concerned with the prediction of the dynamics of the process. solutes which can be dissolved in scCO2 can be impregnated or adsorbed onto solid materials such as wood. The solute dissolved in the scCO2 phase inside the pores may at some time precipitate on the internal surface as the solubility decreases with the decreasing pressure. the adsorbed solutes stay on the internal surface. Interested readers are suggested to consult the literature [81–85]. In the case of inorganic and carbonaceous supports with high surface areas.3006 J Mater Sci (2012) 47:2995–3025 increase of the extraction yield [9]. yA the mole fraction of compound A in the CO2–A mixture (fluid phase) the vessel. and thus the mass transfer coefficient. Some of the studies in the literature on nanostructured materials involving SCF extraction carried out since 2008 are listed in Table 4. Simultaneous solution of the differential equations gives the concentration profile for the extracted solute as a function of time. the solute (A) and the substrate is put into Fig. and is applicable for large temperature and pressure ranges [9]. textile fibers. e. Dcm. which eventually increases the extraction yield [9]. The driving force for impregnation is the departure from thermodynamic equilibrium. Another phenomena which takes place in case of polymers during period III is the trapping of the solute inside the polymer matrix as a result of vitrification of the polymer. polymers. or fungicides [30]. During period II. modeling scCO2 extraction involves both thermodynamic modeling and kinetic modeling. semi-empirical equations of state.g. and the derivations from the association laws and/or from the entropies of the components. a thermodynamic equation is needed that takes into account the solubility of materials in scCO2 [27]. which eventually allows for the determination of the effects of different parameters for a desired extraction yield within a desired extraction time. the equilibrium is defined by the sorption isotherm for the solute between the polymer and scCO2 phases. The experimental pressure is reached at t = t1 but the dissolution of the solute may continue. the equilibrium is defined by the adsorption isotherm for the solute between the substrate and scCO2 phase at the system temperature and pressure. on the other hand. the sorption of CO2 into the polymer may also occur as described previously and this accelerates the rate of solute impregnation. The company set up a process consisting of three 17 m3 high pressure vessels in Denmark to impregnate woods with fungicides using scCO2. fungi.. The formation of rot. Additionally. Nanostructured composites by impregnation from SCF solutions In the impregnation process. at the interface of the SCF phase and the bulk solid phase. 11. Peng–Robinson equation of state is the most commonly used equation of state to model the thermodynamics of a binary system of the solute to be extracted and supercritical CO2. The impregnation process is shown in Fig. There have been many attempts to model the scCO2 extraction processes to optimize the process parameters. P pressure of CO2. drugs. Higher flow rates also provide a larger mean concentration gradient. In order to model the phase behavior at the extraction conditions. one for the solvating fluid phase and the other for the treated bulk solid phase. For porous inorganic or carbonaceous substrates. 11 A representation of a basic impregnation process. Such solutes may be dyes. the concentration of the solute in scCO2 phase decreases until equilibrium is reached. three basic types of equations are used in the literature: empirical equations of state. Initially. In general.

PLLA [116] and poly(D.J Mater Sci (2012) 47:2995–3025 3007 Table 5 Summary of some of the impregnation studies since 2008 Substrate Balafilcon A Cellulose acetate Chitosan derivatives Chitosan scaffolds Hilafilcon B Hilafilcon B Methafilcon A Nelfilcon A Omafilcon A PA66 PC PC PE PE PET PET fabric PDLLA Solute Acetazolamide Timolol maleate Vanillin L-Menthol these impregnated woods without using methods based on heavy metals and/or organic solvents [30]. References [119] [122] [118] [123] [120] [121] [121] [121] [121] [124] [125] [126] [127] [126] [128] [129] [130] Flurbiprofen Timolol maleate Dexamethasone Flurbiprofen Flurbiprofen Timolol maleate Flurbiprofen Timolol maleate Flurbiprofen Timolol maleate Flurbiprofen Timolol maleate Dioctyl adipate Alkyldiphenylether Reversacol graphit (R) SAO Poly(dimethysiloxane) SAO Polyglycidyl ether Chitin/chitosan Ibuprofen Aspirin Salicylic acid Naphthalene PLLA Ibuprofen Aspirin Salicylic acid Naphthalene [130] PMMA PMMA PMMA Triflusal Triflusal Triflusal 4-(Trifluoromethyl) salicylic acid [131] [132] [133] PMMA PP PP PP PS PU PVC Polyacrylics Poly(e-caprolactone) SAO Poly(ethylene glycol) Silicon oil SAO Tetraethyl orthosilicate Poly(dimethysiloxane) Glucose oxidase SAO Spiroxazin Timolol maleate [126] [134] [126] [135] [127] [136] [137] [138] [139] 123 . scCO2 can sorb inside a polymer matrix causing it to swell and also decreases the polymer’s Tg and thus easing the impregnation of CO2 soluble solutes inside matrices [108]. The work carried out in Smirnova’s group focused on the impregnation of drugs such ketoprofen.L-lactide-co-glycolide) [117] along with a number of chitosan derivatives [118] were impregnated with drugs using scCO2. An important number of low molecular weight anti-inflammatory. Rapid expansion of supercritical solutions (RESS) As previously mentioned. and Omafilcon A [121] were impregnated with hydrophilic and/or hydrophobic drugs such as acetazolamide. timolol maleate. Nelfilcon A. Along similar lines. Hilafilcon B [120]. As previously mentioned. scCO2 dying may eliminate the environmental problems in the traditional textile industry where polymer fibers are usually subjected to toxic aqueous dye solutions containing surfactants which need to be treated properly after use. It was shown the partitioning of dye between the polymer and the CO2 medium is the primary phenomenon that controls the dying process [109]. The commercial SCLs including Balafilcon A [119]. Substrates other than aerogels including biodegradable polyesters such as poly(D. 111]. Methafilcon A. production of nanostructured materials using classical techniques has serious limitations. Therefore. the process consists of the dissolution of the drug in CO2 and its subsequent adsorption onto the aerogels. to guarantee a rapid and uniformly dyed product. 113]. A summary of some of the impregnation studies given in Table 5 reveals that significant effort is exhausted in impregnation era. and griseofulvin on aerogels from scCO2 [112.L-lactic acid). [110] demonstrated that the choice of the proper working conditions is a compromise between a high value of the partition coefficient and an acceptable level of the dye solubility in the dyeing bath. Dying process therefore basically consists of the impregnation of the dye material in polymeric fibers using scCO2 as previously described. and anti-HIV drugs are soluble in scCO2 [114. Studies on the impregnation of soft contact lenses (SCLs) with a variety of drugs are attracting increased attention. 107]. miconazole. anti-cancer. flurbiprofen. the diffusion rates of dyes may be faster in the presence scCO2 [3. scCO2 impregnation is particularly advantageous in loading drugs into carriers since CO2 does not leave any residue on the treated medium unlike organic solvents. 115]. Furthermore. Interested readers can refer to the excellent review of Kjellow and Henriksen [105] on wood impregnation with biocides using SCFs. Banchero et al. Polymer dying using scCO2 has been under investigation for 20 years [106.

The precipitation of the particles occurs as a result of nucleation. 19]. 15. The knowledge of P–T curve gives information about the necessary pressure at a given temperature for the process [19. In order to attain this condition. According to the classical nucleation theory. Therefore. the scCO2 solution including the dissolved solute is rapidly depressurized via passing through a capillary or an orifice nozzle. PVC polyvinylchloride. The fast release of CO2 as gaseous phase allows for uniform and rapid supersaturation in the solution. PVP polyvinylpyrrolidone. and by condensation. 149]. in re-crystallization process.1-b((1. for the case of milling. the product suffers severely from the solvent contamination and solvent waste streams are generated which require further separation processes. a high degree of super-cooling is attained. PET poly(ethylene terephthalate). Uniformity and intensity of the supersaturation has an effect on both the particle size and the particle size distribution. After the nucleation. which is the growth by collision of particles. The process comprises two basic steps: first the solid material is dissolved in the scCO2 and then the solution is rapidly expanded to a lower pressure leading to the formation of fine particles of the solid material as precipitates [9–20. A schematic of the RESS process is displayed in Fig. 143. Rapid expansion of supercritical solutions (RESS) technique is one of the most frequently investigated highpressure techniques for nanoparticle synthesis. In addition. r is the radius of the cluster. and c is the interfacial tension.   oT ljt ¼ ð 1Þ oP h The Joule–Thompson coefficient. 13. 145. since the rapid expansion induces a significant decrease in the density and solvent power of CO2. 17. 12. PE polyethylene. which triggers the crystallization of the solute [9. PC polycarbonate. which can be derived by minimizing the value of DG given in the above equation [150]. 142–145]. Dl is the chemical potential difference between the cluster and the bulk phase. also known as the Joule–Thompson effect. particles grow by coagulation. PP polypropylene. PLLA poly(L-lactic acid). Therefore. PS polystyrene. 147]. Gibbs free energy of forming a cluster is composed of two competing terms. the precipitation of fine particles free of a residual solvent with micron or submicron features is obtained [9. the total Gibbs free energy of the system according to the classical nucleation theory is given by: DG ¼ ÀnDl þ 4pr 2 c ð 2Þ where n is the number of atoms or molecules in the cluster. In the classical nucleation theory. coagulation. 142. PMMA poly(methylmethacrylate). Figure 13 displays the difference in particle sizes of nabumetone particles clearly before and after the RESS processing. which is related to the interfacial surface tension of the cluster. 16. ljt.4)oxazine) For instance. 146]. is the slope of the isenthalpic lines of the P–T diagram. polymers in particular. 123 . the volumetric term. owing to the extremely high rate of expansion. UHMWPE ultra-high molecular weight polyethylene. which describes the necessary energy to transfer atoms/molecules to the cluster (driving force for the cluster formation).3008 Table 5 continued Substrate Poly(L-lactide-ran-ecaprolactone) Solute D-Limonene J Mater Sci (2012) 47:2995–3025 References [140] Dissolution of solute in scCO2 Depressurization Hinokitiol Hinokitiol Trans-2-hexenal Poly(ethylene terephthalate) Silica gel Tetrafluoroethylene copolymer with vinylidene fluoride Transdermal patches UHMWPE Poly(ethylene glycol) Silicon oil Reversacol graphit (R) SAO Naproxen Dioctyl adipate Alkyldiphenylether [134] CO2 [125] [137] [141] [124] Fig.30 . 12 Schematic representation of the RESS process PA66 polyamide 66.L-lactic acid). and condensation. and the surface term. the necessary condition for cluster growth is to attain a critical nucleus size. are unstable under conventional working conditions [19]. which is the deposition of molecules on the particles surface [13. PDLLA poly(D. The formulation that describes the Joule–Thompson effect is given with the following equation [147].3-3H-anthraceno(2. The driving force for the precipitation processes is the super-saturation of the solution which is the departure of the fluid composition from the saturation composition.30 -trimethylspiro(indoline-20 . a variety of substances. PU polyurethane. Furthermore. SAO 1.

1. The authors achieved uniform encapsulation of the SiO2 and TiO2 powders with 10–100nm thick PLGA layers in the form of both individual and agglomerating particles. with permission from Elsevier) The magnitude of supersaturation. 149. Additionally. The influence of the thermodynamic behavior and solute properties on the homogeneous nucleation in supercritical solutions is also considered in the present models by including the empirical relations or equation of state to account for the equilibrium saturation concentration of the solute in scCO2 [13. diameter and length. 149]. The main problems of RESS process are the aggregation of the particles in the precipitation chamber due to the surface charges and difficulties in control of the particle size. heat and mass transfer equations together with the nucleation and growth models in a coupled fashion.4-lm SiO2 as well as 70-nm TiO2 powders were utilized as core materials and ethanol was employed as co-solvent. 145. All these factors listed above should be considered individually to determine the optimum processing conditions that would lead to the desired product characteristics. an interesting variation of the RESS process was developed. This can be attributed to the extent of supersaturation being higher for a solute with low solubility as compared to one with higher solubility in scCO2. encapsulated SiO2 and TiO2 fine powders with poly(D. nozzle geometry. 151]. solubility of the solute in supercritical CO2. in which the aggregation problem is overcome by addition of the stabilizing agents or surfactants into the liquid. reader may refer to the articles by Tu [16]. 149]. and temperature in the expansion unit. 146. crystalline or amorphous. and thus solely based on the physical and chemical properties of the solute and the specific interactions with CO2. RESOLV consists of spraying the supercritical solution into a liquid.L-lactic-co-glycolic acid) via RESS process. The expansion temperature and pressure are the two key parameters that dominantly affect the particle characteristics. The modeling studies mostly comprise the solution of fluid mechanics. The optimum values for extraction temperature and pressure that would yield the desired properties depend basically on the phase behavior of the solute–CO2 solution. 149]. Davies et al. the effects of some of the other processing parameters have been investigated both experimentally and theoretically. 151]. rapid expansion of a supercritical solution into a liquid solvent (RESOLV) process. RESS technique can also be used to coat fine particles. residence time. whereas with an increase in the pre-expansion pressure smaller particles are obtained due to the inadequate time for particle growth [143. depends on various parameters such as the chemical nature of the material. Kongsombut et al. which prevents the growth of particles in the 123 . An increase in the saturation pressure brings about an enhancement to the supersaturation and the nucleation rates during the expansion period and causes smaller particle formation [149. Solubility in supercritical CO2 is another important factor and solutes with lower solubility in supercritical CO2 form precipitates with smaller mean particle size [145. 149]. Several mathematical models have been developed so far to explain the mechanisms of the RESS process. extraction and pre-expansion temperature and pressure. a rise in the preexpansion temperature usually leads to an increase in particle size [143. 13 SEM images of nabumetone a before and b after RESS process (Reprinted from [148]) (Copyright (2011). pressure. Besides the expansion temperature and pressure. The nozzle diameter and length were demonstrated to have different effects on particle size and the interested ¨ rk [149]. Following this route the particle growth is suppressed and nanoparticles are produced effectively.J Mater Sci (2012) 47:2995–3025 3009 Fig. and Hezave and Esmaeilzadeh [151] in which the micronization of drug particles with the RESS process was investigated. Figure 14 displays the SEM and TEM images of TiO2 particles coated in this study [152]. nature of solute–solvent interaction and phase behavior of the solute–CO2 mixture [15. In this study. Based on this consideration. and thus the particle size distribution and morphology of the resulting particles.

With RESOLV process. The liberation of the supercritical solution into the liquid solution is provided from the bottom of the liquid solution tank to attain homogeneity in the system. and c with PVP as stabilization agent (0. small particle features are obtained due to the lower solubility and shorter residence time of the particles in the expansion chamber. 16 SEM images of the ibuprofen nanoparticles from RESOLV (ibuprofen concentration 0. The use of RESS process necessitates at least some degree of solubility of the materials to be used as solute in CO2 [13]. b without stabilization and after agglomeration. Moreover. a chemical reaction can also Dissolution of solute in scCO 2 Expansion into liquid solvent CO2 Capillary nozzle Fig. RESS-SC). with permission from Elsevier) 123 . one drawback of the RESOLV process is the difficulty in the recovery of the particles from the liquid solution. In addition. 15 [14. 15 Schematic representation of the RESOLV process take place as a consequence of the interaction among the nucleating solid particles and the compounds contained in the liquid phase.3010 Fig. if the compounds are selected to be reactive. many high molecular weight organic compounds and polymers have no or very little Fig. 145]. However. 14 a SEM and b TEM images of PLGA-encapsulated TiO2 particles generated with RESS process (Reprinted with permission from [152]) (Copyright (2011) American Chemical Society) J Mater Sci (2012) 47:2995–3025 precipitator. and thus the particle growth and agglomeration can be impeded. Figure 16 displays the ibuprofen nanoparticles obtained by RESOLV process with and without poly(N-vinyl-2-pyrrolidone) (PVP) as the stabilizing agent [153]. 200 bar) a without stabilization and before agglomeration. 40 °C. However. Another modification to the RESS process is the utilization of a solid co-solvent (RESS with Solid Co-solvent.5 mg/mL) (Reprinted from [153]) (Copyright (2011).25 mg/mL in CO2. which confines the growth mechanisms. The schematic diagram of the RESOLV process is given in Fig. surfactants can be utilized as components of the liquid solution.

Fine-particles with features of around 120 nm can be obtained with the RESS-SC process which is significantly smaller than 200 nm particles obtained from RESS process. 142].J Mater Sci (2012) 47:2995–3025 3011 solubility in CO2 [16]. Figure 17 illustrates a schematic representation of RESS-SC process compared to the RESS process [145]. 40 °C) (Reprinted with permission from [154]) (Copyright (2011) American Chemical Society) 123 . such as size. The bioavailability of the drugs can be enhanced by increasing the surface–volume ratio of the particles as a consequence of the reduced particle size. crystal structure. making the RESS process suitable for pharmaceutical applications [12. and c obtained with RESS-SC (196 bar. a Unprocessed. biochemicals. Encapsulation studies also involves with different materials besides pharmaceutical compounds. The solid co-solvent can be removed from the precipitates by sublimation. with permission from Elsevier) RESS process and its modifications (RESOLV and RESS-SC) have been under investigation for pharmaceutical applications. 144. 149. Fig. and Fig. An efficient method is to use a solid co-solvent to enhance the low solubility in scCO2. The employment of a solid co-solvent reduces the particle growth by avoiding the surface-to-surface interaction of particles in the solution. 18 displays the SEM images of griseofulvin nanoparticles obtained with RESS and RESS-SC under the same processing conditions [154]. In order to overcome the low solubility problem of the solute materials in scCO2. 40 °C). Besides. due to the dissolution of particles in the expansion chamber most of these liquid co-solvents are not suitable for the RESS process. specialty chemicals. Additionally. various liquid co-solvents have been utilized to enhance the solubilities. Fig. which leads to an improvement of the dissolution behavior [15. 146]. 17 Schematic representation of a RESS and b RESS-SC processes (Reprinted from [145]) (Copyright (2011). b obtained with RESS (196 bar. encapsulation of the drug particles with specific polymers or compounds is also possible with the RESS process [12. catalysts. some degree of control of the characteristic properties of particles. 18 SEM images of griseofulvin particles. 151]. and morphology is required to optimize the drug formulations. shape. However. There are also several studies in the literature that utilizes RESS process and its modifications for the generation of fineparticles with nanometer size features for applications such as explosives.

ASES Processes Process RESS Substance Benzoic acid Griseofulvin Lidocaine RESAS RESS RESS RESAS RESAS RESS PPRGEL RESS ASES RESS RESOLV RESS RESS PCA RESS RESOLV RESAS RESS PGSS Lidocaine PLGA Cholesterol PLGA Prednisolone Poly(1H. RESOLV. SEDS. GAS.1H-dihydrofluorooctyl methacrylate) Retinyl palmitate Poly(L-lactide) (PLLA) Poly(vinylidene fluoride) Active pharmaceutical ingredients (API) Poly(methyl methacrylate) (PMMA) Poly(lactic acid) (PLA) Polyacrylonitrile (PAN) Indomethacin Ibuprofen Glyceryl monostearate (LumulseÒ GMS-K) Waxy triglyceride (Cutina HR) Silanized TiO2 Caffeine PGSS Glyceryl monostearate (LumulseÒ GMS-K) Waxy triglyceride (CutinaÒ HR) Silanized TiO2 Caffeine Glutathione Ketoprofen PGSS SAS SEDS SEDS PCA SAS SAS-EM SAS Ceramide 3A Cholesterol c-Indomethacin b-carotene Poly(hydroxybutirate-co-hydroxyvalerate) (PHBV) Fe3O4-poly(L-lactide) (Fe3O4-PLLA) Lysozyme b-Carotene Poly-lactic acid (PLA) L-PLA PMMA PMMA/PCL blends SAS ASES Cefdinir Tetracycline hydrochloride (TTC) 150 160–310 [198] [199] 803 \100 400 400–1000 Not specified [175] [195] [196] [173] [197] 100 670 [172] [194] Not specified [193] Not specified [156] Ò Particle size (nm) 100–300 References [178] Liposome Essential oil Ketoprofen Naproxen 173 350–7030 560–820 300 150–300 1500 80 200–7000 55 230 200–400 30–160 56–226 Not specified 300–400 270–730 50–300 300–500 40 Not specified [179] [180] [149] [181] [152] [182] [183] [184] [185] [186] [187] [188] [189] [69] [190] [191] [192] [123] 123 . SAS. DELOS.3012 J Mater Sci (2012) 47:2995–3025 Table 6 Summary of literature studies involving RESS. RESSAS. PGSS. PCA.

2–2.L-lactide)-polyethylene glycol-poly(D.9–6.7–95.1 2.1–4.4–3.7 1.7 25–8000 536 675 [213] [214] [215] [216] [217] 79–105 500–5000 250 50–10000 290–4160 [208] [209] [210] [211] [212] 190 250 Not specified 100–300 [204] [205] [206] [207] 200 172–580 [202] [203] Particle size (nm) Ranging from submicron to 50 lm 100–5000 3013 References [200] [201] 123 .6 2.J Mater Sci (2012) 47:2995–3025 Table 6 continued Process SAS GAS Substance Corn zein Hen egg white lysozyme Dimethylsulfoxide (DMSO) Xylans Mannans SAS-EM PCA Dipyridamole Silica particles Polyethylene glycol Polybutadiene Hydroxy terminated SEDS SAS SAS SAS SAS SAS SAS PCA SAS SEDS SAS SAS SEDS SEDS ASES SAS SEDS SAS RESS RESS RESS RESS RESS SAS ? deposition SAS ? deposition SAS-ER (SAS with emulsion reaction) SAA SAA Puerarin Camptothecin Egg yolk phospholipids N-methyl-pyrrolidone (NMP) Ampicillin Polymer-corn zein Ibuprofen sodium Minocycline Poly(desamino tyrosyl-tyrosine ethyl ester carbonate) [poly(DTE carbonate)] Cetirizine dihydrochloride (CTZ) b-Cyclodextrin (b-CD) poly(D.L-lactide) (PLA-PEGPLA) tri-block co-polymer Atorvastatin hemi-calcium Anti-tyrosinase zeaxanthin 5-fuorouracil-SiO2-poly(L-lactide) (5-Fu-SiO2-PLLA) Puerarin Poly(L-lactide) (PLLA) Cefpodoxime proxetil (CPD) Atorvastatin calcium b-Carotene Poly(3-hydroxybutirate-co-hydroxyvalerate) (PHBV) 5-Fluorouracil (5-FU) Fuorinated tetraphenylporphyrin (TBTPP) Cephalexin Ibuprofen Naproxen Griseofulvin Au Pt Ag2S CdS SiO2 WO3 MoO3 Bovine serum albumin (BSA) Beclomethasone Dipropionate(BDP) 300–5000 200–4700 [167] [177] 248–5560 \100 860–7220 880 Not specified \100 4.9 \100 [226] [225] [220] [221] [222] [151] [223] [145] [224] 100–400 152–863 278–570 [174] [218] [219] 712–4800 68.

there are also some disadvantages such as high ratios of gas to solute in the case of low solubility. 147]. 17. So far. resins. and the composition of the mixture [19. 15. 13. 20. 142. The model comprises the coupled solution of the one-dimensional mass. solvent-free products. Supercritical CO2 as an anti-solvent Particles from gas-saturated solutions (PGSS) Another high pressure technique that is employed in fine particle generation is the particles from gas-saturated solutions (PGSS) process which eliminates large amount of gas usage and solubility limitations of the RESS process as it utilizes scCO2 as a non-solvent [7. energy and momentum equations in the nozzle together with the aerosol general dynamic equation which accounts for the nucleation and growth by condensation and coagulation [13]. CO2 is fed into a solution of the substrate in a solvent or a suspension of the substrate in a solvent [13–15. 147]. 142]. the PGSS process is favorable compared to the RESS process due to the reduced consumption of CO2 and elimination of the necessity of the solubility in CO2 for the material to be micronized [13. Figure 20 displays typical SEM images of theophylline/hydrogenated palm oil (HPO) composite particles before and after PGSS process [155]. Recently. 13–20]. high pressures for supercritical conditions of CO2. concentration of CO2 dissolved in the solution is increased and a gassaturated solution is obtained [14. RESSAS rapid expansion of supercritical solution into aqueous solution and cosmetics [9. and difficulties in separation of very fine particles from large volumes of expanded gas as well as the requirement for large-volume pressurized equipment [9. and fat derivatives [18. The temperature of the solution reduces below the crystallization temperature because of the joint effects of these two cooling mechanisms. and as a consequence. 20]. 147]. 147]. a high degree of super-cooling is obtained owing to the Joule–Thompson effect [17. similar to the RESS process. instead of the solubility of the compounds in CO2 [9. 18]. 18. Table 6 includes brief descriptions of some of these studies that have been carried out since 2008. 19. 142. 147].3014 Table 6 continued Process SAA SAA SAA SAA SAA Substance BSA microspheres charged with Gentamicin sulfate (GS) Lysozyme Cefadroxil Ginkgo flavonoids Hydroxypropyl methylcellulose (HPMC) J Mater Sci (2012) 47:2995–3025 Particle size (nm) 2000 100–4000 Various 200–3000 50–5200 References [168] [227] [228] [229] [230] DELOS depressurization of an expanded liquid organic solution. There are several advantages of the PGSS process— similar to RESS and other supercritical processes—over the conventional processes. Moreover. In addition. melting point. 12. the viscosity. 15. The gas-saturated solution is then rapidly expanded to a somewhat lower pressure (generally ambient) through a nozzle [14. natural products. the PGSS process has been investigated for various compounds such as polymers. 147]. 154]. Figure 19 displays a schematic representation of the PGSS process. 143]. such as narrow particle size distribution. 17. 142. the atomization and precipitation of the target substance is triggered [19. and improvement of the desired properties [16. 17. 19. 19 Schematic representation of the PGSS process In PGSS process. This rapid depressurization evokes the release of CO2 in the gaseous state which requires a certain amount of heat that is to be taken from the solution of the target material [13]. In addition. the size and morphology of the generated particles can be controlled by alteration of the process parameters such as temperature. pressure. 19. A model was developed by Li et al. With the dissolution of CO2 in organic compounds. to explain the particle formation in the PGSS process. 19. 142]. and glass transition temperature in case of polymers are lowered [16. With rising pressure. nozzle diameter. 17. PGSS exploits the large cooling effect over depressurization and the ability of CO2 to dissolve in the organic compounds. 20. PGSS has been used to 123 . Depressurization CO2 Solution/ Suspension of the solute Fig. waxes. 147]. Despite various advantages of RESS over conventional processes.

zirconyl nitrate hydrate. 158]. sodium chloride. The process basically relies on the solubilization of scCO2 in the liquid solution of a solvent and a solid solute and the subsequent atomization of this solution through a nozzle [10. kind of liquid solvent. Wang et al. synthesized particulate hybrid carriers of a glyceryl monostearate (LumulseÒ GMS-K). levoflaxocin hydrochloride [166] were synthesized. Another interesting study was published in 2010 by Della Porta which additionally introduced SAA process as a thermal coagulation technique. and triclabenzadol were produced. chitosan [163]. Garcia-Gonzalez et al.J Mater Sci (2012) 47:2995–3025 3015 Fig. 20]. 18. aluminum sulfate. were more efficiently encapsulated in the lipophilic lipidic matrix than hydrophilic drugs. Supercritical-assisted atomization (SAA) SAA process is a relatively recent process that employs scCO2 as the atomizing medium and has been regarded as a special case of PGSS process [10.3 to 5 lm [167]. glutathione. 123 . such as ketoprofen. many micro. The same year Reverchon and Della Porta [159] published another study that comprises the micronization process of tetracycline and rifampicin antibiotics for drug delivery applications. or keto-profen) with PGSS process.and nanoparticles of various materials such as griseofulvin [160]. and nozzle diameter on the final particle size and distribution were investigated [157]. The generated particles had diameters varying from 0. ampicillin. PMMA and PLLA [165]. yttrium acetate. They studied controlled drug delivery systems based on solid lipid particles. pigment red 60 [161].and nanoparticles are the generation of the primary droplets at the exit of the nozzle by the pneumatic atomization and the fast release of CO2 from the droplets which is termed as the decompressive atomization. They reported various particle morphologies such as smooth hollow spherical particles. This droplet size is mainly determined by the parameters such as viscosity. The major distinction from PGSS process is that SAA can be applied to many solvent and solute systems instead of just organic solvents and melt polymer systems. surface tension. Some of the studies on the PGSS process since 2008 are given in Table 6. and corrugated particles under different process conditions. corticosteroid [164]. Recently. During the following years. nanometric and micrometric powders of zinc acetate. cup particles. They obtained 4. silanized TiO2 and different active agents (caffeine. a waxy triglyceride (CutinaÒ HR). They also investigated the elution profiles and concluded that hydrophobic drugs. such as caffeine and glutathione [156]. The major limitation of the process is that the smallest particle size generated depends on the size of the smallest droplet produced during the atomization process (one droplet-one particle process). 20]. Some of the significant studies employing SAA for nanoparticle processing that have been published since 2008 are given in Table 6. Moreover. glutathione. In 2010. dexamethasone. carbamazepine. The two atomization processes that lead to the final micro. or ketoprofen. and the amount of scCO2 dissolved in the liquid solvent.1 wt% loading of the lipid particles with silanized TiO2 and caffeine. cyclodextrins [162]. The GS loading of BSA from 10 to 50% (w/w) was attained and the spherical particles with the mean particle diameter of 2 ± 1 lm could be generated. The GS release experiments were also conducted for 40% GS loaded BSA particles and a continuous GS release for 10 days was reported [168]. 20 SEM images of theophylline/hydrogenated palm oil (HPO) composite particles obtained a before and b after PGSS expansion (Reprinted from [155]) (Copyright (2011). developed bovine serum albumin (BSA) microparticles with SAA technique using water as the solvent. In the very first study of Reverchon. The influences of some processing parameters such as concentration of the liquid solution. with permission from Elsevier) encapsulate drug particles with polymers [16. The authors developed BSA micropheres charged with gentamicin sulfate (GS) for drug delivery application. operating parameters such as temperature and chemical characteristics of the solute dictates the final material morphology (amorphous or crystalline) [10].2–16. 157.

scCO2 and the solution are separately and continuously fed into a precipitation chamber from the nozzles [14. 18. pressure. 147]. the solubility of the solute of interest in the organic solvent is significantly decreased bringing about the precipitation as fine particles [13. c-Indomethacin (IMC) was processed with SAS process by varying the solvent (acetone. 20]. All of these techniques exploit the same basic operating principal which is the employment of CO2 as an anti-solvent instead of a solvent or a solute [13. the addition rate of CO2 was also shown to play a key role in final product characteristics [13. Figure 21 displays these antisolvent processes. The solute to be precipitated. nucleation and particle growth rate. 158]. 18. and pressure (83–117 bar). size distribution. the mixing between the scCO2 and the solution is faster than the precipitation. 16–20]. allows for the introduction of scCO2 and the solution through a coaxial nozzle [14. 17. 170]. However. 18. In the GAS process. the volume expansion of the solution occurs and the viscosity is reduced [13. 20]. solvent composition. 170]. and thus the aforementioned parameters have negligible effect on the precipitation [13. 147]. which is similar to the SAS technique. 20]. 20. The anti-solvent methods benefit from the ability of CO2 to dissolve in organic liquids. As the solvent power of a liquid is often proportional to its density. 142]. scCO2 is introduced into the solution of solute to be precipitated and the organic solvent [14. particle size. SEDS. concentration (0. solution enhanced dispersion by supercritical fluids (SEDS) system. is dissolved in an organic solvent that can also dissolve CO2 [142]. Other factors that affect the supersaturation ratio. The main factor distinguishing SEDS from SAS is that scCO2 is also used as the dispersing agent as well as anti-solvent [14. 18.5% w/v). The copolymer microparticles were precipitated from a H2O/ethanol solution at 313 K. temperature (35–55 °C). 169. precipitation with a compressed anti-solvent (PCA) system.2–1. which causes the precipitation of a solute initially dissolved in the organic liquid [147]. 169. After the contact of scCO2 with the solution. and as a consequence the density of binary CO2/solvent mixture decreases. The major influence of the design of the nozzle and precipitator and the flow regime in the nozzle originates from their effects on mixing of the solution and scCO2. Garay et al. 21 Schematic representation of the GAS. The aforementioned anti-solvent processes differ in the way the solvent and the anti-solvent are contacted [19. dichloro-methane. 18. chemical and physical properties of the solute and the solvent. which has negligible solubility in CO2. shape and morphology are temperature. The SEDS process. 20. investigated the behavior of an acrylate–methacrylate copolymer (Eudragit L100Ò and Eudragit EPOÒ) in scCO2 and developed microparticles by GAS process. intermolecular interaction between scCO2–solvent and scCO2– solute and the binary and ternary phase behavior of the system [147]. nozzle characteristics. 18]. The particle size and size distribution can also be modulated by the mode of addition of the anti-solvent. revealed that when operating at higher pressures than the critical pressure of the mixture. The Vent Coaxial nozzle Expanded organic solution CO2 Particle formation CO2 Organic Solution Particle formation Vent CO2 Organic Solution Vent GAS Process SEDS Process SAS/ASES/PCA Processes Fig. 15. It has been reported that the aggregation behavior of the particles has an intense influence on process parameters and the particle size distribution of the obtained precipitates [13]. 142. and aerosol solvent extraction system (ASES). 20. supercritical anti-solvent (SAS) process. and SAS/ASES/PCA processes [142] 123 . There have been many studies involving anti-solvent processes since 2008. In the SAS technique.3016 J Mater Sci (2012) 47:2995–3025 Supercritical CO2 as an anti-solvent: GAS/SAS/PCA/SEDS/ASES Supercritical CO2 has also been utilized in gas anti-solvent (GAS) process. Figure 22 displays the SEM images of copolymer microparticles obtained [171]. Reverchon et al. 17. a rapid mass transfer of CO2 into the solution occurs due to the high diffusion rate. The organic solution is dispersed in scCO2 in the PCA method which is also known as the ASES method [14. In addition. batch or semi-continuous [147]. and dimethylsulfoxide).

needle-like particles of the a-polymorph [172]. with permission from Elsevier) authors obtained pure. [173] produced micron and submicron particles of poly-lactic acid (PLA) by SAS-EM technique with sizes ranging from 0.2–0. indomethacin (Indo) was also used as a model drug to produce drug–polymer magnetic composite microparticles [175].0 lm. magnetic mass content. with permission from Elsevier) 123 . In another study. In another study. Figure 23 displays the SEM images of particles obtained with these SAS and SAS-EM processes. Fe3O4-poly(L-lactide) (Fe3O4-PLLA) magnetic microparticles were generated by SEDS process by Chen et al. The SEM images together with the particle size distributions of Fe3O4-PLLA and Indo-Fe3O4-PLLA magnetic microparticles are depicted in Figs. They obtained primary particles of sizes 0. derived fine particles of cefpodoxime proxetil (CPD) by utilizing ASES technique.2 lm. The properties such as their morphology. Fig. and magnetic properties were investigated.4 to 1. Fe3O4-PLLA microparticles with mean size of 803 nm were obtained with good magnetic property. 0. 22 SEM image of EPO precipitated from an EtOH/H2O solution at P = 0.1–0. respectively. 24 SEM images of a raw CPD (95000) and b micronized CPD (950. with permission from Elsevier) and b PLA particles from SAS-EM (Reprinted from [173]) (Copyright (2011).000) with ASES (Reprinted from [174]) (Copyright (2011).J Mater Sci (2012) 47:2995–3025 3017 Fig. Additionally. In 2009. Park et al. Chu et al. with permission from Elsevier) Fig.68 Torr (Reprinted from [171]) (Copyright (2011). By the use of ethyl acetate and acetone as solvents to reduce the degree of agglomeration. surface atom distribution. SEM images of raw and ASES processed CPD particled are given in Fig. 23 SEM images of a IMC particles from SAS (Reprinted from [172]) (Copyright (2011). particle size. Some of the other studies carried out since 2008 that employed anti-solvent processes are given in Table 6. 24. 25 and 26.6-lm-sized secondary particles were also generated [174].

The operating conditions are flexible and can be altered depending on the type of the solvent and the antisolvent utilized [16. on the scale-up of the supercritical anti-solvent processing of the drug molecules [176].3018 J Mater Sci (2012) 47:2995–3025 Fig. 154. 25 SEM image and particle size distribution of Fe3O4-PLLA magnetic microparticles (Reprinted from [175]) (Copyright (2011). the parameters that need to be considered are rate of addition of the anti-solvent. 154. size distribution. They are applicable to various kinds of compounds including polymers since the necessity of the solubility in CO2 is eliminated [19. mainly by Separex. with permission from Elsevier) 123 . and morphology control of the final product by altering the operating parameters [19. temperature. Nonetheless.5-L atomization vessel with 5-kg/h CO2 flow rate for 1–20 g and 10–100 g sample processing and 50-L atomization vessel with 500-kg/h CO2 flow rate for larger amounts of sample processing. They are advantageous compared to the conventional liquid anti-solvent processes due to the complete removal of the anti-solvent from the final product [171]. 20]. and degree of mixing. Additionally. spraying conditions should be examined in addition to the aforementioned process parameters as the nozzle properties and design play a major role in the determination of the final particle properties. 147]. On the other hand. In GAS process. removal of the solvent. For SAS and SEDS processes. 161]. Thus far. 26 SEM image and particle size distribution of Indo-Fe3O4-PLLA magnetic microparticles (Reprinted from [175]) (Copyright (2011). 161]. shape. and insufficient knowledge for industrial scale-up which may limit the development of the processes [13. with permission from Elsevier) Anti-solvent processes have similar advantages as RESS and PGSS processes over conventional techniques. there are also some disadvantages of the anti-solvent processes such as the necessity to remove the residual solvent in some cases. there have been many studies. Fine particles with significantly reduced particle size can be obtained at the required supersaturation conditions [171]. the process fundamentals such as phase behavior become much more complicated than the binary SCF-liquid system since a solute phase is also involved in the processes. They also performed Fig. 19. They allow for particle size. Separex developed and operated atomization vessels for different scales of production such as 0. complexity of the processing equipment.

One can observe that there is a difference between the vitrification times of two samples processed at different temperatures. a similar plasticization phenomenon occurs within the polymer resins as the CO2 is injected into the extruder barrel. The morphology and the pore structure of a semi-crystalline polymer are also affected by CO2 process parameters. high density microcellular foams [26. Subsequently. the sample would have more time for pore growth and in turn would possess bigger average pore size. which decreases the solubility of CO2 in polymer creating the supersaturation. different CO2 concentrations in the polymer) of polystyrene (PS) prepared using scCO2 batch foaming is shown in Fig. the polymer processed at higher temperature (T1) would take more time to reach the vitrification point. In their excellent review. When the pressure is suddenly reduced from the equilibrium state. Furthermore. the nuclei grow to build pores as the pressure decreases. there are serious problems in the industry regarding these chemicals due to environmental regulations. scCO2 with its non-toxic and non-residue leaving nature is an excellent medium for polymers. As previously mentioned. Numerous polymeric foams are currently produced using high pressure CO2 [7].. The process temperature and CO2 concentration in the polymer before the depressurization (which depends on parameters such as CO2 pressure and temperature) are very crucial in controlling the pore growth. the generated nuclei increase as predicted by the classical nucleation theory. The alteration of the crystalline melting temperature of the polymer by pressurized CO2 can lead to the recrystallization and morphological modifications [243]. 237] can be prepared using scCO2 via batch or continuous extrusion foaming processes [232]. The final pore size of the foam can be in the mesoporous range (*30–50 nm) for pure [241] and blend polymers [242] or in macroporous range ([50 nm up to 100’s of lms) [237] depending on polymers. As an example. 235]. However. Since the molar volume of CO2 increases with decreasing pressure. the degree of Tg reduction also depends on CO2 density and polymer properties and can be expressed by Chow’s equation [238].J Mater Sci (2012) 47:2995–3025 3019 microencapsulation studies with a 60-L agitation vessel and a 100-L atomization vessel [176]. temperature. organic solvents or blowing agents are used in foaming. With increasing CO2 concentration. This is shown more clearly in Fig. Fig. the nucleation of CO2 molecules occur due to energetic arrangement caused by the supersaturation. As the scCO2 dissolves in the polymer matrix. imposes nucleation. In continuous extrusion foaming. Jacobs et al. Therefore. The scale-up of the SAA process was conducted by Prometeo Consortium (Lugano. The pore growth continues until the polymer re-vitrifies as a result of the decreasing CO2 concentration inside the polymer [239]. process conditions (pressure. For two polymers which have the same CO2 concentration (Csat). the tunability of the pore sizes at different CO2 saturation times (i. 28. It is thereby not surprising that polymer swelling by CO2 has been a very popular and highly studied subject in SCF research in the last 20 years [231–234]. Foaming Conventionally. CO2 concentration also has role in the pore growth since during the depressurization the time required for the vitrification of the polymer (thus the pore size) is associated with two parameters: the CO2 concentration before the depressurization and the process temperature. a pressure gradient is often used to create nucleation due to easier controllability. time) and depressurization rate. The degree of CO2 sorption in polymer depends on the density of CO2 and CO2–polymer interactions. In batch foaming. [234] show how scCO2 process parameters affect the pore size of the polymers. 27 Schematic representation of the decrease in foaming time at lower temperatures of saturation [234]—Reproduced by permission of The Royal Society of Chemistry 123 . the micronization of beclomethasone dipropionate (BDP) with SAA process was successfully performed at a laboratory scale and the particles obtained had appropriate PSD and morphologies. the polymer is placed inside a high pressure vessel and then CO2 is introduced. Switzerland) that operates according to the Good Manufacture Practices (GMP) standards [177]. the Tg diminishes and the plasticization of the polymer occurs.e. 27 which shows the variation of polymer’s Tg with the CO2 saturation concentration (Csat). A single-phase solution is formed by the mixing of CO2 and polymer via screw rotation and inline mixers. We note that the supersaturation can also be caused by a temperature gradient [240]. and scaffolds for tissue engineering [236. Polymer foams for insulation purposes. On the other hand. the rapid and large pressure drop in the die.

b 1 min. a 1 s. This step is followed by the injection of a supercritical blowing agent such as scCO2 which is poorly soluble in the continuous medium and forms a microemulsion system containing CO2 droplets surrounded by surfactant molecules in the continuous phase (middle illustration in Fig. In the scICP technique. 29 (left-hand side illustration). there is a growing need for the micro. Studies including computer simulations along with experimental probes such X-ray scattering techniques can be beneficial for improving our understanding of the phenomena.3 MPa and 40 °C at different CO2 exposure times. the pressure is decreased gently enabling the CO2 to expand inside the micelles forming nano-sized foam bubbles (right-hand side illustration in Fig. 28 Scanning electron micrographs of PS foamed at 24.and nanostructured membranes. The commonly used techniques for the preparation of these membranes are solvent-induced phase separation (SIPS) and thermally induced phase separation (TIPS). Bubble coalescence also needs to be considered. and heat transfer needs to be solved and they need to be coupled with thermodynamics [245. Furthermore. The first step is the formation of a micellar solution as shown in Fig. and d 25 min (Reprinted with permission from [244]) (Copyright (2011) American Chemical Society) J Mater Sci (2012) 47:2995–3025 Modeling of the bubble growth inside a polymer is very challenging since a number of partial differential equations involving mass. the number of cells per cm3 increases by 2–3 orders of magnitude (from 108–9 to 1012) [247. Although the SIPS technique may provide membranes with acceptable structure and mechanical properties.3020 Fig. A recent report revealed the possibility of synthesizing foams with cell densities up to 1019 with pore sizes down to 100 nm [249] using the supercritical microemulsion expansion (POSME) technique. Subsequent polymerization stabilizes the bubbles by formation of a polymer network around the bubbles. 29). 248]. it necessitates extensive post-treatments for the removal of the solvents. 29). Consequently. 246]. For the foams prepared in this fashion. a nanocellular foam is obtained. Among the two. SIPS process involves the separation of the polymer solution to polymer-rich and polymer-poor phases using liquid–liquid extraction. heterogeneous CO2 nucleation and reduced interfacial tension between CO2 and polymer. Using polymers containing nanoparticles and nanoclays is favorable in foaming because the presence of these nanomaterials enhances foaming through the concurrent restriction of CO2 diffusion. c 5 min. Formation of nanostructured membranes by scCO2induced phase-separation (scICP) technique For pharmaceutical and medical applications. After equilibrium is reached. the liquid non-solvent (for the polymer) used in 123 . The development of the technology is currently being carried out by Bayer to produce polyurethane nanofoams on an industrial scale. solvent residues in the membrane are very problematic for biomedical applications [169]. momentum. A monomer is then added to the continuous phase during or at the end of the expansion sequence.

aerogels. and the solution depressurized. and polymer nanocomposites have been synthesized and processed using various scCO2 techniques. The atoms in source plates fragmentize due to the Coulomb explosion and aggregate to form nanonecklaces (a few tens of lm long) and nanospheres (dp = 500 nm). depressurization rate) dense. and adjustable thermophysical properties during processing. MEMS. and wood. with controlled particle size distribution and morphology. In PGSS process. Recent studies for the membrane preparation using scICP include the polymer blends of starch with poly(Llactic acid) [250] and poly(e-caprolactone). temperature. microcellular. SAA. the liquid polymer does not dissolve appreciably in scCO2 but solvent does. Several nanomaterials such as nanoparticles. Therefore. Simultaneously. CO2 may sorb into the polymer (depending on the polymer type) and may induce foaming (as previously discussed). nanofibers. In the case of RESS. [251] some composites of poly(vinylidene fluoride-co-hexafluoropropylene) [252–254] and chitosan devices [255]. [169]. In RESS process. 257]. enhanced diffusion coefficients. The potency of scCO2 utilization in nanomaterial synthesis and processing emanates from the exceptional properties such as liquid-like density. gas-like viscosity. scCO2 is dissolved in a 123 . Laser ablation in scCO2 Laser ablation is a commonly used technique in nanoparticle fabrication as well as in industrial machining. Using impregnation from scCO2. are promising processing media which can eliminate some of the drawbacks of the conventional methods for nanomaterial synthesis. and GAS/SAS/PCA/ASES/SEDS processes. it is possible to remove the solvent using SFE. natural matter extracts. drugs. Using laser ablation in scCO2. the choice of the process depends mainly on the materials to be processed with specific characteristics. organic and inorganic aerogels and purified polymers can be obtained. low surface tension. PGSS. MOFs. aerogels. With scCO2 extraction of desired substances.J Mater Sci (2012) 47:2995–3025 Fig. reactivated catalysts. In the process. Conclusions SCFs. the materials to be processed are dissolved in scCO2. particulate. and free from solvent traces. They have shown that at low CO2 densities (*200 kg/m3) nanonecklaces were formed whereas nanospheres were formed at higher densities (*800 kg/m3). especially scCO2. dyes. mono-disperse particles. Depending on the polymers or the process parameters (pressure. The formed morphologies can precipitate on supports such as carbon since the particles are not soluble in scCO2 [257]. grinding wheels. Many polymeric membranes were prepared using scICP technique and the reader is referred to the excellent review by Reverchon et al. and fungicides can be incorporated in materials such as polymers. 29 Schematic representation of POSME technique [249]—Reproduced by permission of PCCP Owner Societies 3021 the SIPS technique is replaced by scCO2. which facilitate the effective synthesis of ultra-fine. and bicontinuous membranes can be obtained. The process consists of the immersion of a source plate (Si or Au) in scCO2 and the subsequent exposure of this system to the laser ablation with an excitation wavelength of 532 m. foams. it has been shown that nanoclusters of Si and Au can be deposited on surfaces [256.

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