Synthesis of Nanostructured Materials Using ScCO2 Part I

7/28/2019 Synthesis of Nanostructured Materials Using ScCO2 Part I

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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: [email protected]

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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]

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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]

3012 J Mater Sci (2012) 47:29953025

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Table 6 continued


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


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]

3016 J Mater Sci (2012) 47:29953025

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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

Documents

Synthesis of Nanostructured Materials Using ScCO2 Part I