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R E V I E W
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
Springer Science+Business Media, LLC 2011
Abstract Nanostructured materials have been attracting
increased attention for a wide variety of applications due totheir superior properties compared to their bulk counter-
parts. 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 supercrit-
ical carbon dioxide (scCO2) is an attractive medium for the
synthesis of nanostructured materials due to its favorable
properties such as being abundant, inexpensive, non-flam-
mable, non-toxic, and environmentally benign. Further-
more, 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 trans-
formations. 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, aero-
gels, and polymer nanocomposites. scCO2 based processes
can also be utilized in the intensification of the conven-
tional 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-vol-
ume ratios. Two general approaches are employed in
making nanostructured materials: top-down and bottom-up.
Crushing, grinding, milling, and attrition are typical top-
down 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 scat-
tering, 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 approa-
ches 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 pro-
cesses in production lines, and abundant energy con-
sumption [1].
D. Sanli S. E. Bozbag C. Erkey (&)Department of Chemical and Biological Engineering,
Koc University, 34450 Sariyer, Istanbul, Turkey
e-mail: cerkey@ku.edu.tr
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DOI 10.1007/s10853-011-6054-y
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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 advanta-
ges 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 PTdiagram of a
pure compound is given in Fig. 1. The liquidgas co-existence curve terminates at the critical point the coordi-
nates 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 ther-
mally labile compounds. scCO2 also has other remarkable
advantages such as being abundant, inexpensive, non-
flammable, non-toxic, and environmentally benign. Fur-
thermore, 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 solu-
bility 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 CO2s density (thus the solvation
power). However, above 18 MPa, at a particular pressure,
the solubility of benzoic acid increases with increasing
temperature. This behavior occurs due to the compensa-
tion of the decline of CO2s 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 solu-bility 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 solu-
bility 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 scCO2can be increased by the addition of modifiers or co-sol-
vents such as ethanol, methanol, and hexane at concen-
trations 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. More-
over, 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 solventFig. 1 A typical PT diagram of a pure compound
Table 1 Comparison of typical physical properties of gases, liquids,
and SCFs
Fluid properties Gas SCF Liquid
Density (g cm-3) 0.62 9 10-3 0.20.9 0.61.6
Diffusivity (m2 s-1) 14 9 10-5 27 9 10
-8 10-9
Viscosity (Pa s-1) 13 9 10-5 19 9 10-5 10-3
Table 2 Critical properties of some SCFs
Fluid Tc (C) Pc (MPa) Remarks
Carbon dioxide 31.2 7.38
Ammonia 132.4 11.29 Toxic
Water 374.1 22.1 High Tc, corrosive
Ethane 32.5 4.91 Flammable
Propane 96.8 4.26 Flammable
Cyclohexane 279.9 4.03 High Tc
Methanol 240.0 7.95 High Tc
Ethanol 243.1 6.39 High Tc
Isopropanol 235.6 5.37 High Tc
Acetone 235.0 4.76 High Tc
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strength via changes in temperature and pressure. Fig-
ure 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 withdecreasing temperature (due to the decrease of the den-
sity) 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 tran-
sition is caused by the plasticization of the polymer due
to the sorption of CO2 and the degree of the plastici-
zation increases with increasing temperature which pro-
motes 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 transitiontemperature (Tg) of poly(styrene) (PS) decreases signifi-
cantly 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 gasliquid interface
may be eliminated.Another important characteristic of scCO2 is its low
surface tension. Figure 3a shows the variation of CO2s
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 CO2s
critical pressure and then continues to decrease with
increasing pressure at 45 C. Having diffusion coeffi-
cients higher than that of liquids, viscosities close to that
of gases and low surface tension, CO2 provides betterpenetration and complete wetting of the substrates which
is advantageous for impregnation or extraction applica-
tions 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
Fig. 2 a The solubility of
benzoic acid in CO2 and the
deviation from the ideal
behavior (straight lines are the
PengRobinson 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 PSs
Tg with the increase of the CO2-
PS systems equilibrium
pressure (Reprinted from [4])
(Copyright (2011), with
permission from Elsevier)
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to remove the organic solvent from the material. Addition-
ally, in the case of extraction, the conventional methods
mostly yield dilute extracts which necessitates for a con-
centration step for the products. An important advantage of
scCO2 is that it leaves no residue in the treated medium. A
typical supercritical fluid extraction (SFE) process is dem-
onstrated in Fig. 4. First, all the material to be extracted is
placed in the high pressure vessel (3). Then, the vessel is
charged with CO2 which is heated and pressurized above its
critical point. Then, CO2 is circulated over the bed using a
pump or compressor (1). As CO2 passes over the solid
material, it extracts the desired compounds from the solid
material. The exiting CO2 from the bed is then passed
through an expansion valve where the pressure is reduced.
The mixture then separates into two phases; a solid extract
phase which is generally almost free of CO2 and a gaseous
CO2 phase. The separation is attained due to the decrease ofthe solubility due to the reduction in pressure. The gaseous
CO2, free of extract is heated and compressed back to the
operating temperature and pressure, and transferred into the
vessel. The circulation of CO2 is continued until all the
desired material is extracted. At the end of the process, CO2is vented from the system by depressurization leaving behind
the extract and the extracted material which is free of
solvent.
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. Being a non-toxic solvent, scCO2 has
already replaced toxic organic solvents in a wide variety of
applications and has tremendous potential for use in devel-
opment of new environmentally friendly processes [7].
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, size distribution, morphology and composition [920].
Control of these properties can be achieved by tuning the
thermodynamics and kinetic parameters of the system, via
addition of surfactants, by using, i.e., nano-reactors or by
applying a specific process configuration (i.e., nozzles, flu-
idized beds). The wide range of nanostructured materials
synthesizable via scCO2 based processes are depicted in
Fig. 5.
scCO2 based techniques for preparation of nanostruc-
tured materials have been reviewed in 2000s [10, 11,
2124]. The present text primarily aims to give a per-
spective to material scientists and engineers on the matter
by focusing on the description and analysis of these tech-
niques. The text has been divided into two main articles as
Fig. 3 a The variation of CO2s 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)
Fig. 4 A basic SFE cycle. Adapted from Ref. [8] (Copyright (2011),
with permission from Elsevier)
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the physical and chemical transformations in synthesis of
nanostructured materials using scCO2. Physical processes
such as rapid expansion from supercritical solutions
(RESS), particles from gas saturated solutions (PGSS),
supercritical anti-solvent (SAS), supercritical fluid extrac-
tion (SFE), foaming and laser ablation (LA) along with the
state-of-art examples are described in Part I. Methods
including chemical transformations such as supercritical
deposition (SCD), nanoscale casting, arrested growth (AG),
nanoreactors (NR), synthesis in scCO2, surface function-
alization from supercritical solutions (SFSS) and processes
in which scCO2 is used as a reactant are discussed in Part
II. In these articles, examples from the literature are gen-
erally 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, 11, 2123, 25].
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, as in SFE and RESS; as an
anti-solvent, as in SAS and laser ablation; as a solute, as in
PGSS and foaming [911, 1320].
Various operating parameters such as operating tem-
perature and pressure, depressurization temperature and
pressure, depressurization rate in SCF based processes
influence the final particle size, size distribution, and
morphology of the nanostructured materials [13]. The rest
of this section describes different scCO2 processes with
their physical basis, and the effects of the above mentioned
processing parameters on the final product characteristics.
Supercritical CO2 as a solvent
Supercritical CO2 extraction
Extraction of target compounds from solid and liquid
matrices is probably the most investigated and well-
established application of scCO2. The very high efficiency
of scCO2 based extraction processes mostly originates from
the superior combination of the liquid and gas like prop-
erties of CO2 at the supercritical state [27] together with the
favorable characteristics listed in Introduction. scCO2has 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, production of flavors,
Fig. 5 The extent of nanomaterials that can be produced using
scCO2. RESS rapid expansion from supercritical solutions, PGSS
particles from gas saturated solutions, SAS supercritical anti-solvent,
RESOLV rapid expansion of a supercritical solution into a liquid
solvent, AG arrested growth, NR nanoreactors, HTS hydrothermal
synthesis, SCD supercritical deposition, SAIPE supercritical anti-
solvent-induced polymer epitaxy, SFSS surface functionalization
from supercritical solutions, SFE supercritical fluid extraction
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extraction of spices and essential oils, production of anti-
oxidants, production of low fat and low cholesterol foods,
selective separation of nicotine from tobacco, extraction of
caffeine from coffee and tea [28, 29]. In addition, SFE
technology is attracting increasing attention in the phar-
maceutical, medical products, and neutraceutical indus-
tries. Table 3 lists some of the commercialized SFE plants
together with some extractor sizes and demonstrates thewide acceptance of SFE technology at industrial scale,
even though the SFE processes have rather high equipment
costs due to high pressures employed. Among these
applications, the cork extraction is one of the promi-
nent examples that was recently scaled up by NATEX
(2500 t/year) [30]. Another large-scale application of SCF
extraction is carried out by Aspen Aerogels for the fabri-
cation of aerogel blankets for use as thermal insulators.
scCO2 is also employed for the drying of micro-electro
mechanical systems (MEMS). MEMS are being developed
for a wide variety of applications that requires micro- and
nano-scale structures. The critical steps during the fabri-
cation of MEMS are the processes that release, clean, and
dry the flexible nanostructures which are crucial for device
functionality. Conventional drying methods that are
employed to remove the aqueous processing solutions fromthe 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 sol-
vent. However, the large capillary forces which are gen-
erated due to the evaporation of the liquid trapped in the
narrow gaps of the device can cause structures to col-
lapse and stick to an adjacent surface. Thus, the conven-
tional drying methods create the major problem of
Table 3 Examples of
commercial supercritical
extraction plants
Coffee decaffeination Kaffee HAG AG, Bremen, Germany
General Foods, Houston, TexasHermsen, Bremen, Germany
Jacobs Suchard, Bremen, Germany (360lt)
SKW-Trostberg, Poszzillo, Italy
Hops extraction Pfizer Hops Extraction, Sydney, Nebraska
Hopfenextraktion, HVG, Barth, Raiser & Co. (200lt ? 500lt)
SKW Trostberg, Munchsmunster, Germany (650lt)
Natal Cane By-Products Ltd., Merebank, South Africa (1000lt)
Barth & Co., Wolnzach, Germany (4000ltx5)
Hops Extraction Corp. of America, Yakima, Washington
J.I. Haas, Inc., Yakima, Washington
Pitt-Des Moines, Inc., Pittsburgh, USA (3000ltx4)
Carlton, United Breweries, United Kingdom
NORAC, Canada (250ltx4)
Color extractionRed Pepper Mohri Oil Mills, Japan Fuji Flavor, Japan (200lt ? 300lt ? 300lt)
Natal Cane By-Products Ltd,. Merebank, South Africa (200lt)
Sumitomo Seiko, Japan
Yasuma (Mitsubishi Kokoki facility), Japan
Hasegawa Koryo, Japan (500ltx2)
Takasago Foods (Mitsubishi Kokoki facility), Japan
Flavors/aromas/spices Camilli Albert & Louie, Grasse, France
Soda Flavor Co., Japan (5.8lt)
Guangxia Toothpaste, China (500ltx3, 3500ltx3, 1500ltx3)
Flavex, Rehlingen, Germany (70lt)Flavors extraction Flavex GmbH, Rehlingen, Germany
Raps & Co., Kulmbach, Germany (500ltx3)
Shaanxi Jia De Agriculture Eng. Co., Ltd., China (500ltx2)
Nicotine extraction Philip Morris, Hopewell, Virginia
Nippon Tobacco, Japan (200lt)
Tea decaffeination SKW-Trostberg, Munchmuenster, Germany
Hops extraction and spices SKW-Trostberg, Munchmuenster, Germany (200lt)
Pauls & White, Reigat, United Kingdom
Nan Fang Flour Mill, China (300ltx2)
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microfabricationstictionwhich leads to damaged
structures. When scCO2 is employed to extract the organic
solvent instead of evaporation, the capillary forces due to
the existence of the vaporliquid interface are eliminated
which prevents stiction. Figure 6 demonstrates the dis-
tinction between MEMS structures after drying with scCO2in a, conventional drying using heat to evaporate hexane in
b, and water in c [3134].In the case of cleaning of the MEMS devices, the con-
ventional 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.
However, these techniques are generally insufficient for the
complete removal of the process residuals and cause
damage to the structures due to the harsh chemical envi-
ronment. Use of scCO2 for the cleaning steps of micro-
fabrication offers a potential to eliminate these problems as
scCO2 can completely remove the residuals by dissolving
them and do not cause any structural deformation [3640].Furthermore, the etching step has recently been carried
out in scCO2 medium by dissolving the etchant [i.e.,
hydrofluoric acid (HF)] in scCO2. This technique is con-
sidered to be a promising method as it eliminates the
additional drying step of the conventional wet etching and
leads to clean, dry, residue-free devices with no stiction
[3539]. Recently, Jung et al. reported on the preparation
of poly-Si cantilevers from p-tetraethylorthosilicate
(TEOS) by performing dry etching with HF/H2O in scCO2.
They successfully obtained cantilevers with high aspect
ratios of 1:150 without any residues or stiction problem.
They also determined that the etch rate increased with the
increasing reaction temperature [41]. Some of the studies
on MEMS carried out recently using scCO2 are given in
Table 4.
Additionally, scCO2 has received considerable attention
in regeneration of catalysts and adsorbents. Numerous
studies were carried out on the reactivation and regenera-
tion of used activated carbon (AC), which is the commonly
used adsorbent for removal of organic compounds from gas
streams [40, 41]. In order to be reused, the organic com-
pounds that are adsorbed inside the porous AC are
extracted by the aid of scCO2, thus regenerating AC [42].
Many advantages of scCO2 over the conventional adsor-
bent regeneration techniquesmainly steam stripping
have been stated in the literature, such as higher recovered
adsorption capacity, eliminated residuals such as con-
densed water in the pores and safer operation environmentdue to the low desorption temperature and inert CO2environment [43]. Although few, there has also been
studies for reactivation of supported metal catalysts with
scCO2, such as reactivation of Pd/Al2O3 for cyclododec-
atriene hydrogenation and regeneration of a spent Pd/AC
catalyst which is used for hydrogenation of a variety of
organic compounds [4446]. In a recent study by Zhang
et al., reactivation of a Pd/AC catalyst for the hydrogena-
tion of benzoic acid was accomplished by extracting the
organic compounds that are blocking the pores of the cat-
alyst with scCO2. In this study, the effects of reactivation
conditions, such as extraction temperature, pressure, CO2flow rate, and time, on the activity of the reactivated Pd/AC
catalyst were investigated. The authors demonstrated that
more than 70% of the fresh catalyst activity was restored.
They also depicted scCO2 extraction to be a non-destruc-
tive technique without any decrease of the granule size of
the catalyst and sintering of the Pd nanoparticles [47].
Another important application of scCO2 extraction is the
generation of porous structures by supercritical extraction
of pore inducers from solid matrices. In this process, the
pore inducer compounds are mixed with the bulk material
and become confined in the matrix. scCO2 extraction yields
a porous structure, pores being formed with the removal of
the inducer compounds from the compact solid. Porous
grinding wheels were produced using this technique which
eliminates some drawbacks of conventional thermal deg-
radation techniques such as swelling, formation of residues,
and spring. Additionally, the pore size and structures of the
wheels could be controlled by changing the particle size of
the pore inducers [48, 49]. This technique was first intro-
duced by Erkeys group in 2004 where biphenyl was used
Fig. 6 SEM images of microelectronic structures that are dried a with scCO2 b with evaporation of hexane, and c with evaporation of water [35]
(Reprinted by permission of Taylor & Francis Group, http://www.informaworld.com)
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as the pore inducer and extracted with scCO2 at room
temperature and at varying pressures of 8.815.3 MPa. The
extraction rate was demonstrated to be strongly affected by
flow rate of CO2, however, was independent of pressure.
This was attributed to the insignificant effects of pressure
on the solubility and diffusivity of biphenyl in scCO2 [48].
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]. Recently, the pore
inducer extraction method was extended by Reverchon
et al. to poly(L-lactic acid) (PLLA) scaffold production for
tissue engineering applications [50]. By supercritically
extracting D-fructose particles placed in PLLAs they man-
aged to generate scaffolds with macropores of about
100150 lm (Fig. 7a) along with nanofibrous pore walls
Table 4 Summary of some of the literature studies involving scCO2
Processed material Application References
Interpenetrating networks of Resorcinol formaldehyde (RF)
and various metal oxide nanoparticles
scCO2 reactive drying of metal oxide nanoparticles [86]
Agar gels scCO2 drying, resulting voidage between 48 and 68% [87]
Chitin and carbon aerogels scCO2 drying of carbon and chitin aerogels [63]
Chitosan polysaccharide and Lewis acidic precursors (Ti, Zn,Al, Sn)
scCO2 drying of chitosan microspheres with inorganic oxides [88]
Cellulose hydrogels and methanogels scCO2 drying of cellulose [89]
Starch
TiO2
Supercritical drying of starch gels and reaction of TiO2precursor with starch in scCO2
[90]
Cu Modeling the reactive removal of Cu particles from silicon
surface
[91]
Poly(3-octylthiophene) (POT)
Zinc oxide(ZnO)
Supercritical drying of ZnO nanoparticles [91]
Poly-Si cantilevers scCO2 dry etching of microcantilevers [38]
BPSG, P-TEOS, SiO2, and SiN scCO2 dry etching of microcantilevers [34]
TEOS-doped silicon wafers and poly-Si cantilevers scCO2 dry etching [41]
3D scaffolds for tissue replacement scCO2 drying of poly(L-lactic acid) (PLLA) scaffolds [50]Nanostructured scaffolds scCO2 drying of poly(L-lactic acid) (PLLA), hydroxyapatite
(HA) scaffolds
[92]
Inorganic membranes scCO2 extraction of ligands and surfactants [93]
Porous cellulose from celluloseNaOHwater solutions scCO2 drying of porous cellulose [94]
Silica-modified cellulosic aerogels scCO2 drying of cellulosic aerogels [65]
Shaped, ultra-light weight aerogels from bacterial cellulose scCO2 drying of cellulosic aerogels [64]
Rare earth elements from their oxides scCO2 extraction of Nd and Ce from Nd2O3, CeO2 [95]
Contaminated soils scCO2 extraction of PAHs (acenaphthene, phenanthrene,
anthracene, fluoranthene)
[96]
Bidispersed activated granular carbon Kinetic study for regeneration of granular carbon [97]
Activated carbon scCO2 extraction of 2,2,3,3-tetrafluoro-1-propanol (TFP) [42]
Activated carbon scCO2 extraction of toluene [43]Pd/AC catalyst scCO2 extraction for reactivation [47]
Aerogels from bis[3-(triethoxysilyl)propyl]disulfide,
tetramethylorthosilicate and Vinyltrimethoxysilane
scCO2 drying of aerogels [98]
3D-networks of native starch scCO2 drying of starch aerogels [90]
Cellulosic aerogels scCO2 drying of cellulosic aerogels [99]
Nanoporous microspherical alginate aerogels scCO2 drying of alginate aerogels [70]
Lead telluride (PbTe) aerogels scCO2 drying of aerogels [100]
Titania organogels and titania aerogels scCO2 drying of aerogels [101]
Syndiotatic polystyrene aerogels scCO2 drying of aerogels [102]
Mesoporous TiO2SiO2 aerogels scCO2 drying of aerogels [103]
Highly crystalline aerogels of isotactic poly(4-methyl-pentene-
1) (i-P4MP1)
scCO2 drying of aerogels [104]
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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.
Production of cellulosic aerogels has also been attracting
increased attention since unlike conventional silica aero-
gels, they are biodegradable materials. In 2010, Liebner
et al. synthesized shaped, ultra-lightweight cellulosicaerogels through a solgel route. They dried cellulosic
alcogels using scCO2 at 40 C and 100 bar and obtained
cellulosic aerogels with densities around 8 mg/cm3.
According to the nitrogen adsorption and SEM results, the
aerogels exhibit an open-pore structure that mainly consists
of large mesopores and small macropores, which can be
observed from Fig. 9 [64]. In a more recent study, silica-
modified cellulosic aerogels were synthesized by Litschauer
et al. through the solgel route and the influence of different
parameters on porosity, cellulose integrity, and silica con-
tent were examined. The alcogels were similarly dried with
scCO2 at 40 C and 100 bar and the resulting aerogels werefound to contain two interpenetrating networks of silica and
cellulose [65].
Supercritical emulsion extraction (SEE) is a relatively
new technique that has been successfully implemented
for the processing of micro- and nanoparticles of pharma-
ceutical polymers-drug nanocomposites which have lim-
ited solubilities in water. In 2005, Chattopadhyay and
co-workers [66] studied the production of drug (indo-
methacin and ketoprofen)-polymer (PLGA and Eudragit
RS) micro- and nanoparticles by scCO2 extraction of oil-in-
water (o/w) emulsions. 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; extraction from emulsions and
supercritical fluid extraction. The main advantage of thetechnique originates from the correlation between the final
particle size and the droplet size distribution in the emul-
sion which allows for the production of nanomaterials with
tunable particle size [67]. In 2010, Della Prota et al. pro-
duced 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 countercur-
rent packed column. The precipitation of PLGA micro-
particles was achieved by the scCO2 extraction of the
organic solvent of the oily dispersed phase [68]. Mattea and
co-workers [67] published an interesting study on the
behavior of a drop of dichloromethane in water in contactwith scCO2 for analysis of the phenomena that occurs
during SEE process. In a recent study by Alnaief and
Smirnova [69], silica aerogel microparticles were produced
with an in situ emulsion technique and the resulting dis-
persion (geloil) was dried by supercritical extraction. In
another study by the same group, nanoporous microspher-
ical alginate aerogels with high surface area (680 m2/g) and
Fig. 8 Silica gel images
obtained by supercritical drying
(aerogel) (left) and ambient
drying (xerogel) (right)
Fig. 9 SEM pictures at various magnifications (9200, 9500, 93000; from left to right) of a scCO2 dried aerogel from bacterial cellulose [64]
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different mean particle diameters (25 lm to few hundred
lm) were produced from water-in-oil emulsion. The effects
of the process parameters on the structure of the aerogels
were investigated [70].
Another important application of scCO2 extraction is in
the processing of metal-organic frameworks (MOFs) which
are functional, low density, and ultra-high surface area
materials being investigated for a wide variety of appli-cations such as hydrogen or methane storage, chemical
separations, selective chemical catalysis, chemical sensing,
ion exchange, and drug delivery [7174]. During the syn-
thesis of MOFs, the residual molecules (generally solvent
from synthesis) are removed by solvent exchange followed
by heating the material under vacuum. However, due to the
channel collapse upon solvent removal, conventional
techniques lead to partial or even full loss of porosity
[75, 76]. Removal of solvent and residuals from MOFs by
scCO2 extraction is a very efficient technique that over-
comes these drawbacks of the conventional techniques and
enables the preservation of the microporosity. In 2008,Nelson et al. reported the removal of solvents (dimethyl-
formamide (DMF), diethylformamide (DEF)) by first
exchanging DMF and DEF with ethanol followed by
extraction with scCO2 at 31 C and 73 bar. 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]. In another recent study by Xiang
et al., Cu3(BTC)2 MOFs were synthesized by four different
methods and N2 and H2 uptakes of the synthesized mate-
rials were determined. 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 4.12 and 4.49 wt% at
T= 77 K and P = 18 bar, respectively, which were the
largest values among all the Cu3(BTC)2 MOFs [77].
So far we overviewed some important applications of
scCO2 extraction. To have a general knowledge about the
underlying phenomena of these processes we will discuss
some prominent fundamentals of the supercritical extrac-
tion from natural materials, which comprise the most well-
known class of supercritical extraction.
In order to be extracted, the substance should have an
appreciable solubility in scCO2 [9, 29]. The solubility of a
substance in scCO2 is basically determined by two factors:
the volatility of the substance which is a function of tem-
perature and the solvent strength of the scCO2 which is a
function of density [29]. Apart from solubility, mass
transfer also plays an important role in terms of extraction
efficiency [9, 29]. At the start of the extraction process,
solubility of the substance is the limiting factor. The sol-
ubility can be increased by increasing temperature above
the cross-over pressure and/or increasing pressure which
increases the supercritical CO2 density, and thus the
solvent strength. Operating in a condition where the solute
has higher solubility in scCO2 generally results in a shorter
extraction time. In the second phase of extraction, diffusion
usually becomes the rate-limiting mechanism which leads
to longer extraction times. These different phases of the
overall extraction process can be observed from Fig. 10
which display a typical trend of extraction yield versus
extraction time [9]. The desired extraction yields should bepreferably reached within the solubility phase to achieve an
economical extraction process. Furthermore, particle size
reduction can be employed to achieve higher mass transfer
coefficients, and thus increase the process efficiency within
the diffusion limited phase as well as within the solubility
limited phase that are indicated in Fig. 10 [29].
The mass transfer coefficient, ks, is influenced by the
diffusion coefficient, D12. It is an important parameter
since it affects the efficiency of the extraction process,
especially in the solubility limited extraction phase by
determining the mass transfer rates of the extracts to
scCO2. The mass transfer coefficient, ks, is a geometry-dependent parameter and the correlations for obtaining ksfor different extraction systems can be obtained from the
literature [75, 76]. On the other hand, D12 is a fundamental
parameter determining the extraction rate in the diffusion
limited phase. The diffusion coefficient doesnt have any
geometry dependency and various correlations including
the Funazukuri correlation can be employed to obtain D12at supercritical conditions [79, 80]. In fact, these two
parameters play role during the whole extraction process,
however ks is more effective for solubility limited phase,
where as D12 is dominant for the diffusion limited phase.
The diffusion rate can be increased via shortening the
diffusion length which can be achieved by reduction of the
particle size [9, 29]. This reduction also causes the specific
interfacial area, as, to increase, which also results in
Fig. 10 Typical trend of extraction curves (Reprinted with permis-
sion from [78]) (Copyright (2011) American Chemical Society)
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increase of the extraction yield [9]. Extraction yield can
further be increased by increasing the flow rate, which
causes a rise in the Reynolds number, and thus the mass
transfer coefficient. Higher flow rates also provide a larger
mean concentration gradient, Dcm, because of the lower
loading of supercritical CO2 with the extract, which
eventually increases the extraction yield [9].
There have been many attempts to model the scCO2extraction processes to optimize the process parameters. In
general, modeling scCO2 extraction involves both ther-
modynamic modeling and kinetic modeling. Thermody-
namic models are needed for the determination of
equilibrium conditions and solubility behavior of the sol-
ute-supercritical CO2 system and are also important com-
ponents of the kinetic models which are concerned with the
prediction of the dynamics of the process, e.g., the evolu-
tion of the extraction yield with time [27]. In order to
model the phase behavior at the extraction conditions, three
basic types of equations are used in the literature: empirical
equations of state, semi-empirical equations of state, andthe derivations from the association laws and/or from the
entropies of the components. PengRobinson 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, and is applicable for large
temperature and pressure ranges [9].
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, one for the solvating fluid phase
and the other for the treated bulk solid phase. Additionally,
at the interface of the SCF phase and the bulk solid phase, a
thermodynamic equation is needed that takes into account
the solubility of materials in scCO2 [27].
Simultaneous solution of the differential equations gives
the concentration profile for the extracted solute as a
function of time, which eventually allows for the deter-
mination of the effects of different parameters for a desired
extraction yield within a desired extraction time. Interested
readers are suggested to consult the literature [8185].
Some of the studies in the literature on nanostructured
materials involving SCF extraction carried out since 2008
are listed in Table 4.
Nanostructured composites by impregnation from SCF
solutions
In the impregnation process, solutes which can be dissolved
in scCO2 can be impregnated or adsorbed onto solid
materials such as wood, leather, textile fibers, polymers, and
aerogels. Such solutes may be dyes, drugs, monomers, or
fungicides [30]. The impregnation process is shown in
Fig. 11. Initially, the solute (A) and the substrate is put into
the vessel. During period I, the vessel is pressurized withCO2 and the solute starts dissolving as the pressure
increases. The experimental pressure is reached at t= t1 but
the dissolution of the solute may continue. The impregna-
tion of the solute into the substrate takes place during period
II even though there may be some impregnation during
period I. The driving force for impregnation is the departure
from thermodynamic equilibrium. For porous inorganic or
carbonaceous substrates, the equilibrium is defined by the
adsorption isotherm for the solute between the substrate and
scCO2 phase at the system temperature and pressure. For
polymers, on the other hand, the equilibrium is defined by
the sorption isotherm for the solute between the polymer
and scCO2 phases. In the case of polymers, the sorption of
CO2 into the polymer may also occur as described previ-
ously and this accelerates the rate of solute impregnation.
During period II, the concentration of the solute in scCO2phase decreases until equilibrium is reached.
The depressurization of the system is started at t= t2. In
the case of inorganic and carbonaceous supports with high
surface areas, the adsorbed solutes stay on the internal
surface. 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 relative amount of adsorbed and precipitated solute is
governed by the adsorption isotherm. 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.
A process for impregnation of wood using scCO2 was
recently commercialized by NATEX. The company set up a
process consisting of three 17 m3 high pressure vessels in
Denmark to impregnate woods with fungicides using scCO2.
The formation of rot, fungi, and mold is thus prevented in
Fig. 11 A representation of a basic impregnation process. P pressure
of CO2, yA the mole fraction of compound A in the CO2A mixture
(fluid phase)
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these impregnated woods without using methods based on
heavy metals and/or organic solvents [30]. Interested readers
can refer to the excellent review of Kjellow and Henriksen
[105] on wood impregnation with biocides using SCFs.
Polymer dying using scCO2 has been under investigation
for 20 years [106, 107]. scCO2 dying may eliminate the
environmental problems in the traditional textile industry
where polymer fibers are usually subjected to toxic aqueousdye solutions containing surfactants which need to be treated
properly after use. As previously mentioned, scCO2 can sorb
inside a polymer matrix causing it to swell and also
decreases the polymers Tg and thus easing the impregnation
of CO2 soluble solutes inside matrices [108]. Dying process
therefore basically consists of the impregnation of the dye
material in polymeric fibers using scCO2 as previously
described. It was shown the partitioning of dye between the
polymer and the CO2 medium is the primary phenomenon
that controls the dying process [109]. Along similar lines,
Banchero et al. [110] demonstrated that the choice of the
proper working conditions is a compromise between a highvalue of the partition coefficient and an acceptable level of
the dye solubility in the dyeing bath, to guarantee a rapid and
uniformly dyed product. Furthermore, the diffusion rates of
dyes may be faster in the presence scCO2 [3, 111].
The work carried out in Smirnovas group focused on the
impregnation of drugs such ketoprofen, miconazole, and
griseofulvin on aerogels from scCO2 [112, 113]. An impor-
tant number of low molecular weight anti-inflammatory,
anti-cancer, and anti-HIV drugs are soluble in scCO2 [114,
115]. Therefore, the process consists of the dissolution of the
drug in CO2 and its subsequent adsorption onto the aerogels.
Substrates other than aerogels including biodegradable
polyesters such as poly(D,L-lactic acid), PLLA [116] and
poly(D,L-lactide-co-glycolide) [117] along with a number of
chitosan derivatives [118] were impregnated with drugs
using scCO2. scCO2 impregnation is particularly advanta-
geous in loading drugs into carriers since CO2 does not leave
any residue on the treated medium unlike organic solvents.
A summary of some of the impregnation studies given in
Table 5 reveals that significant effort is exhausted in
impregnation era. Studies on the impregnation of soft
contact lenses (SCLs) with a variety of drugs are attracting
increased attention. The commercial SCLs including Bal-
afilcon A [119], Hilafilcon B [120], Methafilcon A, Nel-
filcon A, and Omafilcon A [121] were impregnated with
hydrophilic and/or hydrophobic drugs such as acetazola-
mide, timolol maleate, flurbiprofen.
Rapid expansion of supercritical solutions (RESS)
As previously mentioned, production of nanostructured
materials using classical techniques has serious limitations.
Table 5 Summary of some of the impregnation studies since 2008
Substrate Solute References
Balafilcon A Acetazolamide
Timolol maleate
[119]
Cellulose acetate Vanillin
L-Menthol
[122]
Chitosan derivatives Flurbiprofen
Timolol maleate
[118]
Chitosan scaffolds Dexamethasone [123]
Hilafilcon B Flurbiprofen [120]
Hilafilcon B Flurbiprofen
Timolol maleate
[121]
Methafilcon A Flurbiprofen
Timolol maleate
[121]
Nelfilcon A Flurbiprofen
Timolol maleate
[121]
Omafilcon A Flurbiprofen
Timolol maleate
[121]
PA66 Dioctyl adipate
Alkyldiphenylether
[124]
PC Reversacol graphit (R) [125]
PC SAO [126]
PE Poly(dimethysiloxane) [127]
PE SAO [126]
PET Polyglycidyl ether [128]
PET fabric Chitin/chitosan [129]
PDLLA Ibuprofen
Aspirin
Salicylic acid
Naphthalene
[130]
PLLA Ibuprofen
Aspirin
Salicylic acid
Naphthalene
[130]
PMMA Triflusal [131]
PMMA Triflusal [132]
PMMA Triflusal
4-(Trifluoromethyl)
salicylic acid
[133]
PMMA SAO [126]
PP Poly(ethylene glycol)
Silicon oil
[134]
PP SAO [126]
PP Tetraethyl
orthosilicate
[135]
PS Poly(dimethysiloxane) [127]
PU Glucose oxidase [136]
PVC SAO [137]
Polyacrylics Spiroxazin [138]
Poly(e-caprolactone) Timolol maleate [139]
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For instance, in re-crystallization process, the product
suffers severely from the solvent contamination and sol-
vent waste streams are generated which require further
separation processes. Furthermore, for the case of milling,
a variety of substances, polymers in particular, are unstable
under conventional working conditions [19].
Rapid expansion of supercritical solutions (RESS)
technique is one of the most frequently investigated high-
pressure techniques for nanoparticle synthesis. The processcomprises two basic steps: first the solid material is dis-
solved 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 [920,
142145]. A schematic of the RESS process is displayed in
Fig. 12.
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. In
order to attain this condition, the scCO2 solution including
the dissolved solute is rapidly depressurized via passing
through a capillary or an orifice nozzle. The fast release ofCO2 as gaseous phase allows for uniform and rapid
supersaturation in the solution, since the rapid expansion
induces a significant decrease in the density and solvent
power of CO2. In addition, owing to the extremely high
rate of expansion, a high degree of super-cooling is
attained, also known as the JouleThompson effect, which
triggers the crystallization of the solute [9, 17, 19].
Therefore, the precipitation of fine particles free of a
residual solvent with micron or submicron features is
obtained [9, 13, 15, 16, 142, 143, 146]. Figure 13 displays
the difference in particle sizes of nabumetone particles
clearly before and after the RESS processing. The formu-lation that describes the JouleThompson effect is given
with the following equation [147].
ljt oT
oP
h
1
The JouleThompson coefficient, ljt, is the slope of the
isenthalpic lines of the PT diagram. The knowledge of
PT curve gives information about the necessary pressure
at a given temperature for the process [19, 147].
Uniformity and intensity of the supersaturation has an
effect on both the particle size and the particle size distri-
bution. The precipitation of the particles occurs as a result ofnucleation, coagulation, and condensation. After the nucle-
ation, particles grow by coagulation, which is the growth by
collision of particles, and by condensation, which is the
deposition of molecules on the particles surface [13, 145,
149]. In the classical nucleation theory, Gibbs free energy of
forming a cluster is composed of two competing terms; the
volumetric term, which describes the necessary energy to
transfer atoms/molecules to the cluster (driving force for the
cluster formation), and the surface term, which is related to
the interfacial surface tension of the cluster. Therefore, the
total Gibbs free energy of the system according to the
classical nucleation theory is given by:
DG nDl 4pr2c 2
where n is the number of atoms or molecules in the cluster,
Dl is the chemical potential difference between the cluster
and the bulk phase, ris the radius of the cluster, and c is the
interfacial tension. According to the classical nucleation
theory, the necessary condition for cluster growth is to attain
a critical nucleus size, which can be derived by minimizing
the value ofDG given in the above equation [150].
CO2
Dissolution of solute
in scCO2 Depressurization
Fig. 12 Schematic representation of the RESS process
Table 5 continued
Substrate Solute References
Poly(L-lactide-ran-e-
caprolactone)
D-Limonene
Hinokitiol
Hinokitiol
Trans-2-hexenal
[140]
Poly(ethylene terephthalate) Poly(ethylene glycol)
Silicon oil
[134]
Silica gel Reversacol graphit (R) [125]
Tetrafluoroethylene copolymer
with vinylidene fluoride
SAO [137]
Transdermal patches Naproxen [141]
UHMWPE Dioctyl adipate
Alkyldiphenylether
[124]
PA66 polyamide 66, PC polycarbonate, PE polyethylene, PET
poly(ethylene terephthalate), PDLLA poly(D,L-lactic acid), PLLA
poly(L-lactic acid), PMMA poly(methylmethacrylate), PP polypro-
pylene, PS polystyrene, PU polyurethane, PVC polyvinylchloride,
PVP polyvinylpyrrolidone, UHMWPE ultra-high molecular weightpolyethylene, SAO 1,30,30-trimethylspiro(indoline-20,3-3H-anthra-
ceno(2,1-b((1,4)oxazine)
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The magnitude of supersaturation, and thus the particle
size distribution and morphology of the resulting particles,
crystalline or amorphous, depends on various parameters
such as the chemical nature of the material; extraction andpre-expansion temperature and pressure; nozzle geometry,
diameter and length; residence time, pressure, and tem-
perature in the expansion unit; solubility of the solute in
supercritical CO2; nature of solutesolvent interaction and
phase behavior of the soluteCO2 mixture [15, 146, 149].
The expansion temperature and pressure are the two key
parameters that dominantly affect the particle characteris-
tics. The optimum values for extraction temperature and
pressure that would yield the desired properties depend
basically on the phase behavior of the soluteCO2 solution,
and thus solely based on the physical and chemical prop-
erties of the solute and the specific interactions with CO2.Besides the expansion temperature and pressure, the effects
of some of the other processing parameters have been
investigated both experimentally and theoretically. 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, 151]. Additionally, a rise in the pre-
expansion temperature usually leads to an increase in
particle size [143, 149, 151], whereas with an increase in
the pre-expansion pressure smaller particles are obtained
due to the inadequate time for particle growth [143, 145,
149]. The nozzle diameter and length were demonstrated tohave different effects on particle size and the interested
reader may refer to the articles by Turk [149], Davies et al.
[16], and Hezave and Esmaeilzadeh [151] in which the
micronization of drug particles with the RESS process was
investigated. 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]. 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. All these factors listed above should be considered
individually to determine the optimum processing condi-
tions that would lead to the desired product characteristics.RESS technique can also be used to coat fine particles.
Kongsombut et al. encapsulated SiO2 and TiO2 fine pow-
ders with poly(D,L-lactic-co-glycolic acid) via RESS pro-
cess. In this study, 1.4-lm SiO2 as well as 70-nm TiO2powders were utilized as core materials and ethanol was
employed as co-solvent. The authors achieved uniform
encapsulation of the SiO2 and TiO2 powders with 10100-
nm thick PLGA layers in the form of both individual and
agglomerating particles. Figure 14 displays the SEM and
TEM images of TiO2 particles coated in this study [152].
Several mathematical models have been developed so
far to explain the mechanisms of the RESS process. Themodeling studies mostly comprise the solution of fluid
mechanics, heat and mass transfer equations together with
the nucleation and growth models in a coupled fashion.
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, 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 particlesize. Based on this consideration, an interesting variation of
the RESS process was developed; rapid expansion of a
supercritical solution into a liquid solvent (RESOLV)
process, in which the aggregation problem is overcome by
addition of the stabilizing agents or surfactants into the
liquid. Following this route the particle growth is sup-
pressed and nanoparticles are produced effectively.
RESOLV consists of spraying the supercritical solution
into a liquid, which prevents the growth of particles in the
Fig. 13 SEM images of nabumetone a before and b after RESS process (Reprinted from [148]) (Copyright (2011), with permission from
Elsevier)
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precipitator. 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. The
schematic diagram of the RESOLV process is given in
Fig. 15 [14, 145]. Moreover, a chemical reaction can also
take place as a consequence of the interaction among the
nucleating solid particles and the compounds contained in
the liquid phase, if the compounds are selected to be reactive.
With RESOLV process, small particle features are obtained
due to the lower solubility and shorter residence time of the
particles in the expansion chamber, which confines the
growth mechanisms. In addition, surfactants can be utilized
as components of the liquid solution, and thus the particle
growth and agglomeration can be impeded. However, one
drawback of the RESOLV process is the difficulty in the
recovery of the particles from the liquid solution. Figure 16
displays the ibuprofen nanoparticles obtained by RESOLV
process with and without poly(N-vinyl-2-pyrrolidone)
(PVP) as the stabilizing agent [153].
Another modification to the RESS process is the utili-
zation of a solid co-solvent (RESS with Solid Co-solvent,
RESS-SC). The use of RESS process necessitates at least
some degree of solubility of the materials to be used as
solute in CO2 [13]. However, many high molecular weight
organic compounds and polymers have no or very little
Fig. 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)
CO2
Dissolution of solute
in scCO2 Expansion into
liquid solvent
Capillary nozzle
Fig. 15 Schematic representation of the RESOLV process
Fig. 16 SEM images of the ibuprofen nanoparticles from RESOLV
(ibuprofen concentration 0.25 mg/mL in CO2, 40 C, 200 bar) a with-
out stabilization and before agglomeration, b without stabilization and
afteragglomeration, and c with PVP as stabilization agent (0.5 mg/mL)
(Reprinted from [153]) (Copyright (2011), with permission from
Elsevier)
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solubility in CO2 [16]. In order to overcome the low sol-
ubility problem of the solute materials in scCO2, various
liquid co-solvents have been utilized to enhance the solu-
bilities. However, due to the dissolution of particles in the
expansion chamber most of these liquid co-solvents are not
suitable for the RESS process. 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 par-ticle growth by avoiding the surface-to-surface interaction
of particles in the solution. The solid co-solvent can be
removed from the precipitates by sublimation. Fine-parti-
cles 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. Figure 17
illustrates a schematic representation of RESS-SC process
compared to the RESS process [145], and Fig. 18 displays
the SEM images of griseofulvin nanoparticles obtained
with RESS and RESS-SC under the same processing con-
ditions [154].
RESS process and its modifications (RESOLV and
RESS-SC) have been under investigation for pharmaceu-
tical applications. The bioavailability of the drugs can be
enhanced by increasing the surfacevolume ratio of the
particles as a consequence of the reduced particle size,
which leads to an improvement of the dissolution behavior
[15, 144, 149, 151]. Additionally, some degree of control
of the characteristic properties of particles, such as size,shape, crystal structure, and morphology is required to
optimize the drug formulations, making the RESS process
suitable for pharmaceutical applications [12, 142]. Besides,
encapsulation of the drug particles with specific polymers
or compounds is also possible with the RESS process [12,
146]. Encapsulation studies also involves with different
materials besides pharmaceutical compounds. There are
also several studies in the literature that utilizes RESS
process and its modifications for the generation of fine-
particles with nanometer size features for applications such
as explosives, catalysts, specialty chemicals, biochemicals,
Fig. 17 Schematic
representation of a RESS and
b RESS-SC processes
(Reprinted from [145])
(Copyright (2011), with
permission from Elsevier)
Fig. 18 SEM images of griseofulvin particles. a Unprocessed, b obtained with RESS (196 bar, 40 C), and c obtained with RESS-SC (196 bar,
40 C) (Reprinted with permission from [154]) (Copyright (2011) American Chemical Society)
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Table 6 Summary of literature studies involving RESS, PGSS, SAS, GAS, PCA, DELOS, RESOLV, RESSAS, SEDS, ASES Processes
Process Substance Particle size (nm) References
RESS Benzoic acid
Griseofulvin
Lidocaine
100300 [178]
RESAS Liposome
Essential oil
173 [179]
RESS Ketoprofen 3507030 [180]
RESS
RESAS
Naproxen 560820 [149]
300
RESAS Lidocaine 150300 [181]
RESS PLGA 1500
80
[152]
PPRGEL Cholesterol 2007000 [182]
RESS PLGA 55 [183]
ASES Prednisolone 230 [184]
RESS Poly(1H,1H-dihydrofluorooctyl methacrylate) 200400 [185]
RESOLV Retinyl palmitate
Poly(L-lactide) (PLLA)
30160 [186]
RESS Poly(vinylidene fluoride) 56226 [187]
RESS Active pharmaceutical ingredients (API) Not specified [188]
PCA Poly(methyl methacrylate) (PMMA) 300400 [189]
RESS Poly(lactic acid) (PLA) 270730 [69]
RESOLV Polyacrylonitrile (PAN) 50300 [190]
RESAS Indomethacin 300500 [191]
RESS Ibuprofen 40 [192]
PGSS Glyceryl monostearate (Lumulse GMS-K)
Waxy triglyceride (Cutina
HR)
Silanized TiO2
Caffeine
Not specified [123]
PGSS Glyceryl monostearate (Lumulse GMS-K)
Waxy triglyceride (Cutina HR)
Silanized TiO2
Caffeine
Glutathione
Ketoprofen
Not specified [156]
PGSS Ceramide 3A
Cholesterol
Not specified [193]
SAS c-Indomethacin 100 [172]
SEDS b-carotene
Poly(hydroxybutirate-co-hydroxyvalerate) (PHBV)
670 [194]
SEDS Fe3O4-poly(L-lactide) (Fe3O4-PLLA) 803 [175]
PCA Lysozyme \100 [195]
SAS b-Carotene 400 [196]
SAS-EM Poly-lactic acid (PLA) 4001000 [173]
SAS L-PLA
PMMA
PMMA/PCL blends
Not specified [197]
SAS Cefdinir 150 [198]
ASES Tetracycline hydrochloride (TTC) 160310 [199]
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Table 6 continued
Process Substance Particle size (nm) References
SAS Corn zein
Hen egg white lysozyme
Ranging from submicron
to 50 lm
[200]
GAS Dimethylsulfoxide (DMSO)
Xylans
Mannans
1005000 [201]
SAS-EM Dipyridamole 200 [202]
PCA Silica particles
Polyethylene glycol
Polybutadiene
Hydroxy terminated
172580 [203]
SEDS Puerarin 190 [204]
SAS Camptothecin 250 [205]
SAS Egg yolk phospholipids Not specified [206]
SAS N-methyl-pyrrolidone (NMP)
Ampicillin
100300 [207]
SAS Polymer-corn zein 79105 [208]
SAS Ibuprofen sodium 5005000 [209]
SAS Minocycline 250 [210]
PCA Poly(desamino tyrosyl-tyrosine ethyl ester carbonate) [poly(DTE
carbonate)]
5010000 [211]
SAS Cetirizine dihydrochloride (CTZ)
b-Cyclodextrin (b-CD)
2904160 [212]
SEDS poly(D,L-lactide)-polyethylene glycol-poly(D,L-lactide) (PLA-PEG-
PLA) tri-block co-polymer
7124800 [213]
SAS Atorvastatin hemi-calcium 68.795.7 [214]
SAS Anti-tyrosinase zeaxanthin 258000 [215]
SEDS 5-fuorouracil-SiO2-poly(L-lactide) (5-Fu-SiO2-PLLA) 536 [216]
SEDS Puerarin
Poly(L-lactide) (PLLA)
675 [217]
ASES Cefpodoxime proxetil (CPD) 100400 [174]
SAS Atorvastatin calcium 152863 [218]
SEDS b-Carotene
Poly(3-hydroxybutirate-co-hydroxyvalerate) (PHBV)
278570 [219]
SAS 5-Fluorouracil (5-FU) 2485560 [220]
RESS Fuorinated tetraphenylporphyrin (TBTPP) \100 [221]
RESS Cephalexin 8607220 [222]
RESS Ibuprofen 880 [151]
RESS Naproxen Not specified [223]
RESS Griseofulvin \100 [145]
SAS ? deposition AuPt
4.96.1 [224]2.43.6
SAS ? deposition Ag2S
CdS
2.14.7 [225]
1.22.9
SAS-ER (SAS with emulsion
reaction)
SiO2
WO3
MoO3
\100 [226]
SAA Bovine serum albumin (BSA) 3005000 [167]
SAA Beclomethasone
Dipropionate(BDP)
2004700 [177]
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and cosmetics [9, 12, 147]. Table 6 includes brief
descriptions of some of these studies that have been carried
out since 2008.
Despite various advantages of RESS over conventional
processes, there are also some disadvantages such as high
ratios of gas to solute in the case of low solubility, high
pressures for supercritical conditions of CO2, and difficulties
in separation of very fine particles from large volumes of
expanded gas as well as the requirement for large-volumepressurized equipment [9, 1320].
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 solu-
tions (PGSS) process which eliminates large amount of gas
usage and solubility limitations of the RESS process as it
utilizesscCO2 as a non-solvent [7, 17, 20, 142]. PGSS exploits
the large cooling effect overdepressurization and the ability ofCO2 to dissolve in the organic compounds, instead of the
solubility of the compounds in CO2 [9, 13, 20, 147].
With the dissolution of CO2 in organic compounds, the
viscosity, melting point, and glass transition temperature in
case of polymers are lowered [16, 18, 20]. Figure 19 dis-
plays a schematic representation of the PGSS process.
In PGSS process, CO2 is fed into a solution of the
substrate in a solvent or a suspension of the substrate in a
solvent [1315, 17, 18]. With rising pressure, concentration
of CO2 dissolved in the solution is increased and a gas-
saturated solution is obtained [14, 15, 143]. The gas-satu-
rated solution is then rapidly expanded to a somewhat
lower pressure (generally ambient) through a nozzle [14,
15, 17, 142]. This rapid depressurization evokes the release
of CO2 in the gaseous state which requires a certain amountof heat that is to be taken from the solution of the target
material [13]. In addition, similar to the RESS process, a
high degree of super-cooling is obtained owing to the
JouleThompson effect [17, 19, 154]. The temperature of
the solution reduces below the crystallization temperature
because of the joint effects of these two cooling mecha-
nisms, and as a consequence, the atomization and precip-
itation of the target substance is triggered [19, 147].
A model was developed by Li et al. to explain the particle
formation in the PGSS process. The model comprises the
coupled solution of the one-dimensional mass, energy and
momentum equations in the nozzle together with the aerosolgeneral dynamic equation which accounts for the nucleation
and growth by condensation and coagulation [13].
There are several advantages of the PGSS process
similar to RESS and other supercritical processesover
the conventional processes, such as narrow particle size
distribution, solvent-free products, and improvement of the
desired properties [16, 19, 142, 147]. Moreover, the size
and morphology of the generated particles can be con-
trolled by alteration of the process parameters such as
temperature, pressure, nozzle diameter, and the composi-
tion of the mixture [19, 142, 147]. In addition, 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, 17, 19, 142, 147].
So far, the PGSS process has been investigated for
various compounds such as polymers, waxes, resins, nat-
ural products, and fat derivatives [18, 19, 147]. Figure 20
displays typical SEM images of theophylline/hydrogenated
palm oil (HPO) composite particles before and after
PGSS process [155]. Recently, PGSS has been used to
CO2
Depressurization
Solution/
Suspension of
the solute
Fig. 19 Schematic representation of the PGSS process
Table 6 continued
Process Substance Particle size (nm) References
SAA BSA microspheres charged with Gentamicin sulfate (GS) 2000 [168]
SAA Lysozyme 1004000 [227]
SAA Cefadroxil Various [228]
SAA Ginkgo flavonoids 2003000 [229]
SAA Hydroxypropyl methylcellulose (HPMC) 505200 [230]
DELOS depressurization of an expanded liquid organic solution, RESSAS rapid expansion of supercritical solution into aqueous solution
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encapsulate drug particles with polymers [16, 18, 20]. In
2010, Garcia-Gonzalez et al. synthesized particulate hybrid
carriers of a glyceryl monostearate (Lumulse GMS-K), a
waxy triglyceride (Cutina HR), silanized TiO2 and dif-
ferent active agents (caffeine, glutathione, or keto-profen)with PGSS process. They studied controlled drug delivery
systems based on solid lipid particles. They obtained
4.216.1 wt% loading of the lipid particles with silanized
TiO2 and caffeine, glutathione, or ketoprofen. They also
investigated the elution profiles and concluded that
hydrophobic drugs, such as ketoprofen, were more effi-
ciently encapsulated in the lipophilic lipidic matrix than
hydrophilic drugs, such as caffeine and glutathione [156].
Some of the studies on the PGSS process since 2008 are
given in Table 6.
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, 20]. The major distinc-
tion from PGSS process is that SAA can be applied to
many solvent and solute systems instead of just organic
solvents and melt polymer systems. The process basically
relies on the solubilization of scCO2 in the liquid solution
of a solvent and a solid solute and the subsequent atom-
ization of this solution through a nozzle [10, 157, 158]. The
two atomization processes that lead to the final micro- 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. 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).
This droplet size is mainly determined by the parameters
such as viscosity, surface tension, and the amount of scCO2dissolved in the liquid solvent. Moreover, operating
parameters such as temperature and chemical characteris-
tics of the solute dictates the final material morphology
(amorphous or crystalline) [10].
In the very first study of Reverchon, nanometric and
micrometric powders of zinc acetate, aluminum sulfate,zirconyl nitrate hydrate, sodium chloride, dexamethasone,
carbamazepine, ampicillin, yttrium acetate, and tricla-
benzadol were produced. The influences of some pro-
cessing parameters such as concentration of the liquid
solution, kind of liquid solvent, and nozzle diameter on the
final particle size and distribution were investigated [157].
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. During the following years, many micro- and
nanoparticles of various materials such as griseofulvin
[160], pigment red 60 [161], cyclodextrins [162], chitosan
[163], corticosteroid [164], PMMA and PLLA [165],
levoflaxocin hydrochloride [166] were synthesized.
Recently, Wang et al. developed bovine serum albumin
(BSA) microparticles with SAA technique using water as
the solvent. They reported various particle morphologies
such as smooth hollow spherical particles, cup particles,
and corrugated particles under different process condi-
tions. The generated particles had diameters varying from
0.3 to 5 lm [167]. Another interesting study was published
in 2010 by Della Porta which additionally introduced SAA
process as a thermal coagulation technique. The authors
developed BSA micropheres charged with gentamicin
sulfate (GS) for drug delivery application. 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].
Some of the significant studies employing SAA for
nanoparticle processing that have been published since
2008 are given in Table 6.
Fig. 20 SEM images of theophylline/hydrogenated palm oil (HPO) composite particles obtained a before and b after PGSS expansion
(Reprinted from [155]) (Copyright (2011), with permission from Elsevier)
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Supercritical CO2 as an anti-solvent:
GAS/SAS/PCA/SEDS/ASES
Supercritical CO2 has also been utilized in gas anti-solvent
(GAS) process, supercritical anti-solvent (SAS) process,
precipitation with a compressed anti-solvent (PCA) system,
solution enhanced dispersion by supercritical fluids (SEDS)
system,and aerosol solvent extractionsystem (ASES). All ofthese 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, 18].
The anti-solvent methods benefit from the ability of CO2to dissolve in organic liquids, which causes the precipitation
of a solute initially dissolved in the organic liquid [147]. The
solute to be precipitated, which has negligible solubility in
CO2, is dissolved in an organic solvent that can also dissolve
CO2 [142]. After the contact of scCO2 with the solution, a
rapid mass transfer of CO2 into the solution occurs due to the
high diffusion rate, and as a consequence the density of
binary CO2/solvent mixture decreases, the volume expan-sion of the solution occurs and the viscosity is reduced
[13, 20]. As the solvent power of a liquid is often propor-
tional to its density, the solubility of the solute of interest in
the organic solvent is significantly decreased bringing about
the precipitation as fine particles [13, 1620].
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 precipi-
tates [13]. In addition, the addition rate of CO2 was also
shown to play a key role in final product characteristics
[13, 147]. Other factors that affect the supersaturation ratio,
nucleation and particle growth rate, particle size, size dis-
tribution, shape and morphology are temperature, pressure,
nozzle characteristics, solvent composition, chemical and
physical properties of the solute and the solvent, intermo-
lecular interaction between scCO2solvent and scCO2
solute and the binary and ternary phase behavior of the
system [147]. 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. However, Reverchon et al. revealed that when
operating at higher pressures than the critical pressure of
the mixture, the mixing between the scCO2 and the solution
is faster than the precipitation, and thus the aforementioned
parameters have negligible effect on the precipitation [13,
158]. The particle size and size distribution can also bemodulated by the mode of addition of the anti-solvent;
batch or semi-continuous [147].
The aforementioned anti-solvent processes differ in
the way the solvent and the anti-solvent are contacted
[19, 147]. In the GAS process, scCO2 is introduced into the
solution of solute to be precipitated and the organic solvent
[14, 18, 20, 142]. In the SAS technique, scCO2 and the
solution are separately and continuously fed into a pre-
cipitation chamber from the nozzles [14, 18, 20]. The
organic solution is dispersed in scCO2 in the PCA method
which is also known as the ASES method [14, 17, 18, 20,
142, 169, 170]. The SEDS process, which is similar to theSAS technique, allows for the introduction of scCO2 and
the solution through a coaxial nozzle [14, 15, 17, 18, 20,
169, 170]. The main factor distinguishing SEDS from SAS
is that scCO2 is also used as the dispersing agent as well
as anti-solvent [14, 18, 20]. Figure 21 displays these anti-
solvent processes.
There have been many studies involving anti-solvent
processes since 2008. Garay et al. investigated the behavior
of an acrylatemethacrylate copolymer (Eudragit L100
and Eudragit EPO) in scCO2 and developed microparticles
by GAS process. The copolymer microparticles were pre-
cipitated from a H2O/ethanol solution at 313 K. Figure 22
displays the SEM images of copolymer microparticles
obtained [171].
c-Indomethacin (IMC) was processed with SAS process
by varying the solvent (acetone, dichloro-methane, and
dimethylsulfoxide), concentration (0.21.5% w/v), tem-
perature (3555 C), and pressure (83117 bar). The
CO2
Vent
Expandedorganicsolution
Particleformation
GAS Process
OrganicSolution
CO2
Vent
Coaxialnozzle
Particleformation
SEDS Process
OrganicSolution
CO2
Vent
SAS/ASES/PCA Processes
Fig. 21 Schematic representation of the GAS, SEDS, and SAS/ASES/PCA processes [142]
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authors obtained pure, needle-like particles of the a-poly-morph [172]. In another study, Park et al. [173] produced
micron and submicron particles of poly-lactic acid (PLA)
by SAS-EM technique with sizes ranging from 0.4 to
1.0 lm. Figure 23 displays the SEM images of particles
obtained with these SAS and SAS-EM processes.
In 2009, Chu et al. derived fine particles of cefpodoxime
proxetil (CPD) by utilizing ASES technique. They obtained
primary particles of sizes 0.10.2 lm. By the use of ethyl
acetate and acetone as solvents to reduce the degree of
agglomeration, 0.20.6-lm-sized secondary particles were
also generated [174]. SEM images of raw and ASES pro-cessed CPD particled are given in Fig. 24.
In another study, Fe3O4-poly(L-lactide) (Fe3O4-PLLA)
magnetic microparticles were generated by SEDS process by
Chen et al. The properties such as their morphology, particle
size, magnetic mass content, surface atom distribution, and
magnetic properties were investigated. Fe3O4-PLLA micro-
pa