Journal of Supercritical Fluids 20 (2001) 179– 219

www.elsevier.com/locate/supflu

Review

Particle design using supercritical fluids: Literature and

patent survey
Jennifer Jung, Michel Perrut *
SEPAREX-LAVIPHARM 5, rue Jacques Monod 54250, Champigneulles, France

Received 21 November 1999; received in revised form 10 October 2000; accepted 28 December 2000

Abstract

As particle design is presently a major development of supercritical fluids applications, mainly in the pharmaceuti-
cal, nutraceutical, cosmetic and specialty chemistry industries, number of publications are issued and numerous
patents filed every year. This document presents a survey (that cannot pretend to be exhaustive!) of published
knowledge classified according to the different concepts currently used to manufacture particles, microspheres or
microcapsules, liposomes or other dispersed materials (like microfibers):
RESS: This acronym refers to ‘Rapid Expansion of Supercritical Solutions’; this process consists in solvating the
product in the fluid and rapidly depressurizing this solution through an adequate nozzle, causing an extremely rapid
nucleation of the product into a highly dispersed material. Known for long, this process is attractive due to the
absence of organic solvent use; unfortunately, its application is restricted to products that present a reasonable
solubility in supercritical carbon dioxide (low polarity compounds).
GAS or SAS: These acronyms refer to ‘Gas (or Supercritical fluid) Anti-Solvent’, one specific implementation being
SEDS (‘Solution Enhanced Dispersion by Supercritical Fluids’); this general concept consists in decreasing the solvent
power of a polar liquid solvent in which the substrate is dissolved, by saturating it with carbon dioxide in supercritical
conditions, causing the substrate precipitation or recrystallization. According to the solid morphology that is wished,
various ways of implementation are available:
GAS or SAS recrystallization: This process is mostly used for recrystallization of solid dissolved in a solvent with
the aim of obtaining either small size particles or large crystals, depending on the growth rate controlled by the
anti-solvent pressure variation rate;
ASES: This name is rather used when micro- or nano-particles are expected; the process consists in pulverizing a
solution of the substrate(s) in an organic solvent into a vessel swept by a supercritical fluid;
SEDS: A specific implementation of ASES consists in co-pulverizing the substrate(s) solution and a stream of
supercritical carbon dioxide through appropriate nozzles.
PGSS: This acronym refers to ‘Particles from Gas-Saturated Solutions (or Suspensions)’: This process consists in

* Corresponding author. Tel.: + 33-383-312424; fax: + 33-383-312483.

E-mail address: mperrut@lavipharm.com (M. Perrut).

0896-8446/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 8 9 6 - 8 4 4 6 ( 0 1 ) 0 0 0 6 4 - X
180 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219

dissolving a supercritical fluid into a liquid substrate, or a solution of the substrate(s) in a solvent, or a suspension
of the substrate(s) in a solvent followed by a rapid depressurization of this mixture through a nozzle causing the
formation of solid particles or liquid droplets according to the system.
The use of supercritical fluids as chemical reaction media for material synthesis. Two processes are described:
thermal decomposition in supercritical fluids and hydrothermal synthesis.
We will successively detail the literature and patents for these four main process concepts, and related applications
that have been claimed. Moreover, as we believe it is important to take into account the user’s point-of-view, we will
also present this survey in classifying the documents according three product objectives: particles (micro- or nano-)
of a single component, microspheres and microcapsules of mixtures of active and carrier (or excipient) components,
and particle coating. © 2001 Elsevier Science B.V. All rights reserved.

Keywords: Particle design; supercritical fluids; literature and patent

Fig. 1. RESS equipment concept.

1. Part 1: Rapid expansion of supercritical
solutions (RESS)
1.1. Concept
As presented on Fig. 1, the Rapid Expansion of
Supercritical Solutions consists in saturating a
supercritical fluid with the substrate(s), then de-
pressurizing this solution through a heated nozzle
into a low pressure chamber in order to cause an
extremely rapid nucleation of the substrate(s) in
form of very small particles — or fibers, or films
when the jet is directed against a surface — that
are collected from the gaseous stream.
The pure carbon dioxide is pumped to the
desired pressure and preheated to extraction tem-
perature through a heat exchanger. The supercrit-
ical fluid is then percolated through the extraction
unit packed with one or more substrate(s), mixed
in the same autoclave or set in different auto-
claves in series. In the precipitation unit, the
supercritical solution is expanded through a noz-
zle that must be reheated to avoid plugging by
substrate(s) precipitation.
The morphology of the resulting solid material
both depends on the material structure (crystalline
or amorphous, composite or pure, …) and of the
RESS parameters (temperature, pressure drop,
distance of impact of the jet against the surface,
dimensions of the atomization vessel, nozzle ge-
ometry, ….) [6–9,11,24,25,29,31,36,40,46,56,61].
It is to be noticed that the initial investigations
consisted in ‘pure’ substrates atomization in order
to obtain very fine particles (typically of 0.5–20
mm diameter) with narrow diameter distribution,
meanwhile the most recent publications are re-
lated to mixture processing in order to obtain
microcapsules or microspheres of an active ingre-
dient inside a carrier.
 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219
This concept can be implemented in relatively
simple equipment although particle collection
from the gaseous stream is not easy. But the
applications are limited as most attractive sub-
strates are not soluble enough into the supercriti-
cal fluid to lead to profitable processes: a
co-solvent may be used to improve this solubility,
but it shall be eliminated from the resulting pow-
der, what is not simple and cheap. Nevertheless,
we think that RESS should always be considered
at first, as it is much less costly to use than
SAS/SEDS, … when it works!
1.2. History
There is no doubt that the basic concept of
RESS was first described by the pioneers Hannay
and Hogarth [1], … 120 years ago: ‘When the
solid is precipitated by suddenly reducing pres-
sure, it is crystalline, and may be brought down as
a ‘snow’ in the gas, or on the glass as a ‘frost’, …’!
As stated by Krukonis in 1981 [3], ‘Maybe we can
use this phenomenon as a way of tailoring the size
and size distribution of difficult-to-comminute or-
ganic materials’.
However, this concept was really understood
and developed after the pioneering works of
Krukonis [4] and especially the Battelle Institute
research team [6-9,11] that described and modeled
the flow pattern and nucleation process.
1.3. Patents
In fact, very few patents has been filed on
RESS apparatus or applications:
“ Smith of Battelle Institute [6,11] patented in 1983
processes and apparatus for depositing a film of
solid material on a surface, or forming a fine
powder of solid material, according to the RESS
concept. This was the result of a very detailed
research work on pulverization of supercritical
fluids or mixtures [7] published later. This patent
details several types of nozzles. Two systems are
cited as examples: polystyrene in pen-
tane:cyclohexanol (98:2) mixture, and silica in
water.
“ A German patent [2] filed in 1979 might also be
considered as a RESS application: Best et al.
181
claimed production of very fine crystals of sev-
eral carotenoids using several fluids and co-sol-
vents; however, the expansion of the
supercritical solutions is not operated exactly as
in RESS, but after dispersion of these solutions
into an aqueous colloidal matrix that is further
depressurized to atmospheric pressure.
“ In 1991, Leibovitz of Hewlett-Packard [18]
patented a process using supercritical carbon
dioxide for producing highly accurate and ho-
mogeneous powder mixture used in high quality
ceramic superconductors formation.
“ In 1990, Sievers [16] developed a method, called
supercritical fluid transport chemical deposition
(SFT-CD), for deposition of films from
lipophilic precursors, which are dissolved in a
supercritical fluid. The solution is caused to
rapidly expand through a restrictor forming a
vapor or dense aerosol, which is directed onto
a heated surface where thermally induced sur-
face reactions take place. A variety of metal and
metal oxide thin films, including Pd, Cu, Al, Cr,
In, Ag, YBa2Cu3O7 − x, have been deposited by
this method using various supercritical solvents,
such as, diethylether, pentane, acetone, N2O and
CO2 [17,21].
“ In two other patents [28,32] filed first in 1992,
Sievers described a new method using supercrit-
ical fluids for delivery of pharmaceutical agents
directly to the lung. The physiology active solute
is dissolved into a suitable supercritical fluid,
aerosolized by rapid expansion of the resulting
supercritical solution through a nozzle and di-
rectly administered to a subject via inhalation.
Production of particles of diameter lower than
6.5 mm is claimed using this supercritical fluid
drug delivery (SFDD) technique. Claim 1 of the
European patent [28] is broader than the US
Patent claims [32] and does not refer to drug
delivery, but rather only the preparation of a
medicament by RESS for aerosol delivery.
“ In 1996, Mishima [35] claimed the formation of
polymeric microcapsules by a process called
rapid expansion from supercritical solution with
a non solvent (n-RESS). A polymer dissolved in
the supercritical fluid containing a co-solvent is
sprayed at atmospheric pressure. The co-solvent
has to be chosen in order to increase the polymer
182 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219
solubility into the supercritical fluid but must be
a non solvent of the polymer at atmospheric
pressure to avoid particles agglomeration. Mi-
crocapsules formation is claimed by making a
suspension of active principle in the supercritical
solution of polymer. In further publications
[41,58], Mishima described the encapsulation of
3-hydroxyflavone with Eudragit E-100 or
Polyethylene glycol 6000, using the process de-
scribed in this patent.
“ Combes et al. [38] patented in 1997 a process for
preparing toner additive sub-micronic wax par-
ticles by expanding a heated supercritical solu-
tion of wax. Polypropylene and polyethylene
particles formation is described using different
supercritical solvents: ethane, propane, butane,
pentane, isobutane, carbon dioxide and
chlorodifluoromethane.
“ In the pharmaceutical field, Godinas et al. [45]
used the RESS process for preparing suspen-
sions of sub-micron particles of water-insoluble
drugs. The water-insoluble drug is dissolved in
a compressed gas solvent with a surface modifier
and the resulting solution is expanded into an
aqueous solution containing a second surface
modifier. This process leads to stabilized
aqueous suspensions of water-insoluble drugs
with a particle size of 50– 2000 nm and a narrow
size distribution. Formation of a fine suspension
of fenofibrate with a mean particle size of 200
nm, by expanding a solution containing fenofi-
brate, Lipoid-80 and Tween-80 in water, is
claimed. An other example describes the expan-
sion of a carbon dioxide solution of cyclosporine
and Tween-80 into an aqueous dispersion of egg
phospholipid and mannitol that leads to a
translucent aqueous suspension of about 23 nm
particle size.
“ In 1998, A. Bausch et al. [44] claimed a technique
where a biologically active compound is dis-
solved under elevated pressure in a compressed
gas, liquid or supercritical fluid containing a
surface modifier or in compressed dimethylether
optionally containing a surface modifier. In a
special embodiment, the resulting solution is
then rapidly expanded thereby precipitating the
dissolved compound. The formation of two
active principle powders is described. Tetrahy-
drolipstatin particles formation with an average
particle size of 1.5 mm is claimed by dissolving
the active principle and a surface modifier (Brij,
96) in supercritical CO2 and expanding the
solution in water. Particles of a second active
principle, Saquinavir, is also described: a super-
critical dimethylether solution of the active and
a surfactant (aerosol OT or Brij, 96) is expanded
in water and leads to particles of diameter 1–3
mm, depending on the conditions.
1.4. Publications
As shown on the following Table 1, many
publications are related to atomization of pharma-
ceutical products, either to obtain very fine parti-
cles, or microcapsules of an active into a
carrier/excipient.
Moreover, micronic particles are typically ob-
tained with the RESS process, but some examples
report nanometric particles formation using appro-
priate nozzles (benzoic acid [39] or cholesterol [49]).
It is to be noticed that only few examples were
published on application of RESS to microspheres
generation. For example, Debenedetti [22] suc-
ceeded in encapsulating an anticholesterol drug
into PLA, or more recently, Mishima [41, 58]
reported the formation of microspheres of flavones
embedded in an excipient.
1.5. Future de6elopment
RESS is a very attractive process as it is simple
and relatively easy to implement at least at small
scale when a single nozzle can be used; however,
extrapolation to a significant production size re-
quires either a multi-nozzle system or use of a
porous sintered disk through which pulverization
occurs, in both the cases, particle size distribution
is not easy to control, and may be much wider than
in the case of a single nozzle. Moreover, particle
harvesting is complex, as it is in any process leading
to very small particles.
But, the most important limitation of RESS
development lies in the too low solubility of com-
pounds in supercritical fluids, what precludes pro-
duction at acceptable costs, as, in most cases, use
of a co-solvent to increase solubility in the fluid is
not feasible.

Table 1
Compounds atomized with the RESS processa
Substrates
Polymers and biopolymers
Krytoxdiamide of
hexamethylene (KRYTOX)
Polycaprolactone
Poly(carbosilane)
Poly(2-ethylhexyl acrylate)
Poly(heptadecafluorodecyl-
acrylate)
Poly-l-lactic acid (l-PLA)
Poly(methylmethacrylate)
Poly(phenyl sulfone)
Polypropylene
Polystyrene
Poly(vinyl chloride), KI
Inorganic and organic materials
AgI
Ag triflate
Al(hfa)3
Anthracene
Benzoic acid
J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219 183
Supercritical Results and observations References
fluid
CO2 Droplet size: from 0.6 to 4.5 mm with an Chernyak, 2000 [54]
average size of 2.8 mm
Chlorodifluoro- Powder or fibers depending on the conditions Lele, 1992 [24]
methane
Pentane B0.1-mm-diameter particles or 1-mm-diameter Matson, 1987 [7,8]
fibers of 80–160 mm length
CO2 Formation of a stable aqueous latex with Shim, 2000 [59]
particles of diameter: 2–5 mm
CO2 Particle size: 0.1–5 mm Blasig, 2000 [52]
CO2 Spherical and ‘cornflakes’ particles with a Tom, 1991 [19]
length of 4–10 mm
CO2+1 wt.% Variety of morphology: microparticles of 10–25 Tom, 1991 [19]
acetone mm (T =15–37°C), dendrites of up to 100 mm
(50°C)
Propane 0.5–1.0 mm-diameter particles or 1-mm diameter Matson, 1987 [7,8]
fibers of 100–1000 mm length
Chlorodifluoro- Powder or fibers depending on the conditions Lele, 1992 [24]
methane
Propane Agglomerated spheres (each sphere of 0.5 mm Matson, 1987 [7,8]
diameter)
CO2 Small fibers of diameter 1–5 mm Krukonis, 1984 [4]
Pentane 0.5–1.0 mm-diameter spheres or 1 mm-diameter Matson, 1987 [8]
fibers of 100–1000 mm length
Pentane Petersen, 1987 [9]
Pentane Petersen, 1987 [9]
Pentane 20-mm diameter spheres or 1-mm diameter Matson, 1987 [8]
fibers of 100–1000 mm length
Pentane+2% Particle size: 0.3 mm with extremely narrow Smith, 1983 [6]
cyclohexanol size distribution
Ethanol 7 mm diameter spheres Matson, 1987 [7]
Acetone Formation of a silver film after reaction at Hansen, 1992 [21]
600°C
Diethyl ether Formation of a silver film after reaction at Hansen, 1992 [21]
600°C
Pentane Formation of an aluminium film after reaction Hansen, 1992 [21]
at 680°C
N2O Formation of a Al2O3 film after reaction at Hansen, 1992 [21]
100°C
CO2 Change in morphology from 20-mm hexagonal Nagahama, 1997 [42]
particles to 45-mm dendritic particles with an
increase in the dilution
CO2 Tablets of size: 5–20 mm Subra, 1998 [48]
CO2 Particle size with a capillary nozzle: 2–8 mm Domingo, 1997 [39]
With a sintered nozzle: 0.2–0.3 mm
CO2 Spherical particles with diameter: 20–40 mm Peiriço, 1998 [47]
CO2 Particle size: 0.5–1.1 mm Türk, 1999 [50]
Trifluoro- Particle size: 0.4–1.4 mm Türk, 1999 [50]
methane
184 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219

Table 1 (Continued)

Substrates Supercritical fluid Results and observations References

Benzoic Acid CO2 Particle size: 2–7 mm Kröber, 2000 [57]

Caffeine+anthracene CO2 Tablet-like core with sprouting needles Subra, 1998 [48]
Cr(acac)3 Acetone Formation of a chromium film after reaction Hansen, 1992 [21]
at 800°C
Cr(hfa)3 N2O Formation of a Cr2O3 film after reaction at Hansen, 1992 [21]
100°C
Cu(oleate)2 Pentane Formation of a copper film after reaction at Hansen, 1992 [21]
740°C
Cu(thd)2 N2O Formation of a copper film after reaction at Hansen, 1992 [21]
700°C
N2O Formation of a CuO film after reaction at Hansen, 1992 [21]
100°C
GeO2 Water 5 mm agglomerates or 0.5–0.3 mm-diameter Matson, 1987 [7]
spheres depending on preexpansion
temperature
In(acac)3 CO2 Formation of an indium film after reaction at Hansen, 1992 [21]
600°C
Naphtalene CO2 45°C/220 bar [ particle size: 30–135 mm Mohamed, 1989 [13,14]
55°C/350 bar [ Particle size: 4–38 mm Particle Matson, 1987 [7]
size: 0.5–3 mm
Ni(thd)2 Pentane Formation of a nickel film after reaction at Hansen, 1992 [21]
600°C
Oil Blue N (organic dye) CO2 Particle size: 0.3–1 mm Sievers, 1993 [28]
PbS Ammonia A supercritical ammonia/Pb(NO3)2 solution is Sun, 2000 [60]
expanded in a solution of NaS in ethanol to
produce PbS nanoparticles with an average
particle size of 4 nm
Pd(tod)2 Pentane Formation of a palladium film after reaction at Hansen, 1992 [21]
600°C Hybertson, 1991 [17]
Phenanthrene CO2 Particle size: 5 mm Shaub, 1991 [20]
CO2 Particle size: 10–25 mm Nagahama, 1997 [42]
CO2 Particle size 1–5 mm Domingo, 1997 [39]
Phenanthrene+Anthracene CO2 Particle composed of homogeneous crystals Nagahama, 1997 [42]
SiO2 Water Product morphology: \1.0-mm thick film and Matson, 1987 [7]
0.1–0.5 mm diameter spheres
Si(OC2H5)4 N2O Formation of a SiO2 film after reaction at Hansen, 1992 [21]
100°C
SiO2, KI Water 20-mm agglomerates Matson, 1987 [7]
Y(thd)3 N2O Formation of an yttrium film after reaction at Hansen, 1992 [21]
687°C
Y(thd)3+Cu(thd)2 Pentane Formation of a (Yba2Cu3O7−x ) film after Hansen, 1992 [21]
reaction at 800°C
+ Ba5(thd)9(H2O)3OH
ZrO(NO3)2 Ethanol Particle size: 0.1 mm Matson, 1987 [7]
Zr(tfa)4 Diethyl ether Formation of a zyrconium film after reaction Hansen, 1992 [21]
at 600°C
Pharmaceutical compounds
Aspirin CO2 Capillary nozzle: 2–5 mm Domingo, 1997 [39]
Caffeine CO2 Needles of size: 3–5 mm Subra, 1998 [48]
Cholesterol CO2 Particle size: 0.3–0.5 mm Kröber, 1999/2000 [49,57]
Particle size: 2–3 mm Sievers, 1993 [28]
Dipalmitoylphosphatidyl- CO2+EtOH Sievers, 1993 [28]
Choline (DPPC)
b-estradiol CO2 Particle size: less than 1 mm Krukonis, 1984 [4]
 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219 185

Table 1 (Continued)

Substrates Supercritical fluidResults and observations References

Flavone and CO2+ethanol Polymeric microspheres with flavone cores Mishima, 1997 [41]
3-Hydroxyflavone+PEG Particle size: 10 mm
Griseofulvin CHF3 Reverchon, 1995 [33]
Hydrogenated palm oil CO2 Peiriço, 1998 [47]
3-Hydroxyflavone+Eudragit CO2+Ethanol The 3-hydroxyflavone is coated thoroughly by Mishima, 2000 [58]
E-100 the polymer
Ibuprofen CO2 Capillary nozzle: less than 2 mm Charoenchaitrakool
1999-2000, [51,53]
Lazaroid compound U-74389F CO2+EtOH Sievers, 1993 [28]
Lecithin CO2 Particle size: 1 mm Krukonis, 1984 [4]
Lidocaine CO2 Particle size around 100 nm with spherical shape Frank, 2000 [55]
Mevinolin CO2 Particle size: 0.1–1 mm Mohammed, 1989 [14]
CO2+5 wt.% Particle size: 10–50 mm Larson, 1986 [5]
MeOH
Nifedipin CO2 Particle size: 1–3 mm Stahl, 1988 [12]
PLA+lovastatin CO2 Microspheres containing needles of lovastatin Debenedetti, 1993 [22]
PLA+naproxen CO2 Kim, 1996 [34]
PLA+pyrene CO2 Debenedetti, 1994 [30]
Progesterone CO2 Particle size: 2–5 mm Coffey, 1988 [10]
Salicylic acid CO2 Varying conditions, a wide range of particles Reverchon, 1993 [26,27]
were obtained: particles with diameters from 1
to 5 mm and length from 1 to 170 mm
CO2 Capillary nozzle: 2–5 mm Sintered nozzle: 1–2 Domingo, 1997 [39]
mm
Stigmasterol CO2 Whisker-like crystals Ohgaki, 1990 [15]
Testosterone CO2 Particle size: 2–5 mm Coffey, 1988 [10]
Theophyllin CO2 Needles of length 4–12 mm and diameter: 0.9 mm Subra, 1996 [37]
a-tocopherol CO2 Particle size: 1–2 mm Hybertson,1993 [23]
Sievers, 1993 [28,32]
Tropic acid ester CO2 Particle size: 5–50 mm Peiriço, 1998 [47]

a
Abbreviations used. thd, bis(2,2,6,6-tetramethyl-3,5-heptanedionato); acac, tris(2,4-pentandionato); hfa, tris (1,1,1,5,5,5-hex-
afluoro-2,4-pentanedionato); tfa: tetrakis(1,1,1-trifluoro-2,4-heptanedionato); tod, bis(2,2,7-trimethyl-3,5-octanedionato).

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[52] A. Blasig, C.W. Norfolk, M. Weber, M.C. Thies, Process-
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[53] M. Charoenchaitrakool, F. Dehghani, N.R. Foster, Mi-
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[54] Y. Chernyak, R.K. Franklin, J.R. Edwards, R.D. Gould,
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[55] S.G. Frank, C. Ye, Small particle formation and dissolu-
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[57] H. Kröber, U. Teipel, H. Krause, The Formation of Small
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2. Part 2: Supercritical anti-solvent and related
processes (GAS/SAS/ASES/SEDS)
2.1. Concept
In this process, the supercritical fluid is used as
an anti-solvent that causes precipitation of the
substrate(s) dissolved initially in a liquid solvent.
The solute is recrystallized from solution in one
of the three ways.
“ In the first method, a batch of solution is
expanded several-fold by mixing with a dense
gas in a vessel (Fig. 2). Due to the dissolution
of the compressed gas, the expanded solvent
has a lower solvent strength than the pure
solvent. The mixture becomes supersaturated
and solute precipitates in microparticles. This
process has been called gas anti-solvent (GAS)
or supercritical anti-solvent 1 (SAS) recrystal-
1
Note: It is to be noticed that the term ‘supercritical’ may
be improper in regard with its exact meaning according to
thermodynamic definition; it would be more accurate to use ‘a
fluid at supercritical pressure’, or ‘at a pressure over its critical
pressure’.
188 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219
lization. As shown on Fig. 2, the precipitator is
partially filled with the solution of active sub-
stance. CO2 is then pumped up to desired
pressure and introduced in the vessel, prefer-
ably from the bottom to achieve a better mix-
ing of the solvent and anti-solvent. After a
holding time, the expanded solution is drained
under isobaric conditions to wash and clean
the precipitated particles.
“ The second method involves spraying the solu-
tion through an atomization nozzle as fine
droplets into compressed carbon dioxide (Fig.
3). The dissolution of the supercritical fluid
into the liquid droplets is accompanied by a
large volume expansion and, consequently, a
reduction in the liquid solvent power, causing a
sharp rise in the supersaturation within the
liquid mixture, and the consequent formation
of small and uniform particles.The supercritical
fluid is pumped to the top of the high pressure
vessel by a high pressure pump. Once the sys-
tem reaches steady state (temperature and pres-
sure), the active substance solution is
introduced into the high pressure vessel
through a nozzle. To produce small liquid
droplets in the nozzle, the liquid solution is
pumped at a pressure higher (typically  20
Fig. 2. GAS/SAS equipment concept.
bar) than the vessel operating pressure. Parti-
cles are collected on a filter at the bottom of
the vessel. The fluid mixture (supercritical fluid
plus solvent) exits the vessel and flows to a
depressurization tank where the conditions
(temperature and pressure) allow gas-liquid
separation. After collection of a sufficient
amount of particles, liquid solution pumping is
stopped and pure supercritical fluid continues
to flow through the vessel to remove residual
solvent from the particles. This spray process
has been called aerosol solvent extraction sys-
tem (ASES) process.
“ The third method, known as solution enhanced
dispersion by supercritical fluids (SEDS) was
developed by the Bradford University [18] in
order to achieve smaller droplet size and in-
tense mixing of supercritical fluid and solution
for increased transfer rates. Indeed the super-
critical fluid is used both for its chemical prop-
erties and as ‘spray enhancer’ by mechanical
effect: a nozzle with two coaxial passages al-
lows to introduce the supercritical fluid and a
solution of active substance(s) into the particle
formation vessel where pressure and tempera-
ture are controlled (Fig. 4). The high velocity
of the supercritical fluid allows to break up the
J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219 189

Fig. 3. ASES equipment concept.

Fig. 4. SEDS equipment concept.

190 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219
solution into very small droplets. Moreover,
the conditions are set up so that the supercriti-
cal fluid can extract the solvent from the solu-
tion at the solution at the same time as it meets
and disperses the solution. Similarly, a variant
was recently disclosed by University of Kansas
[31], where the nozzle design leads to sonic
waves development leading to very tiny parti-
cles around 1 mm.These three processes, that
can lead to micro-/nano-particles, are adequate
for processing solids which are difficult to dis-
solve into supercritical fluids (RESS is impossi-
ble), or are sensitive to high shear stress such as
peptides or proteins [12,20,45,51]. Moreover,
addition of a carrier (often a polymer) to the
active solution can lead to the formation of
active substance-loaded micro-/nano-spheres.
2.2. History
The origin of the GAS process is the statement
that the absorption of a gas in a liquid occurs
with an expansion of the liquid. In particular,
when a solution is expanded sufficiently by a gas,
the liquid phase is no longer a good solvent for
the solute and nucleation occurs. As far as 1954,
in its pioneering work on binary and ternary
systems involving liquid carbon dioxide, Francis
[1] clearly stated the GAS concept: ‘CO2 exerts a
demixing or precipitating effect’ and ‘the precipi-
tation action (of CO2) is recognized in at least
seven patents’. McHugh et al. [2,3] used a gaseous
anti-solvent to reduce the lower critical solution
temperature of polymer solutions to concentrate
polymers. Then, Gallagher et al. [6] demonstrated
that the rate of addition of a gas anti-solvent may
be programmed to control crystal morphology,
size, and size distribution over a wide range. They
applied this property to recrystallize difficult-to-
handle explosives. It seems that powder genera-
tion through dispersion of a liquid solution into a
supercritical fluid firstly appeared in a patent ap-
plication of Schmitt [5] filed in 1988.
2.3. Patents
“ Krukonis et al. [7] patented a method for recrys-
tallizing solid materials using a new technique:
the GAS process. Supercritical fluids had al-
ready been investigated for nucleation process
(RESS), but the solid to be recrystallized had to
be soluble in the supercritical fluid. In the GAS
process, the supercritical fluid is used as an
anti-solvent for processing solids that are insol-
uble in supercritical fluids. The process exploits
the ability of gases or supercritical fluids to
dissolve in organic liquids and to lower the
solvent power of the liquid for the solid in
solution, thus causing the solid to precipitate.
The near critical or supercritical fluid is intro-
duced in a vessel containing an organic solvent
in which the solid to be crystallized is dissolved,
causing intimate mixing of the fluid and the
liquid and resulting in liquid expansion and
particles precipitation. This patent was the re-
sult of a detailed work about recrystallization of
an extremely sensitive explosive (RDX).In a
second patent [9], filed in 1992, the GAS process
is used for the crystallization and the separation
of two explosives; RDX and HMX.
“ In 1988, Schmitt [5] patented a variant of the
GAS process, the solid to be finely divided is
dissolved in the liquid carrier and then injected
to a volume of anti-solvent sufficient to precip-
itate the solid. In this process, the injection of
the solution in the anti-solvent leads to a high
anti-solvent/liquid solution ratio compared with
the GAS process. As a result, contacting, mix-
ing and diffusion occur on a fast time scale and
the solid precipitates out of the mixture as small
particles. If contacting was operated at a slower
rate (such as in GAS process where anti-solvent
is slowly added to the solution), then larger
sized particles of precipitated solid would form.
This patent described the basis of the ASES, but
no specific system for liquid injection is claimed.
Triamcinolone particles of diameter 5–10 mm
from THF solution were processed.
“ In 1987, Fischer and Muller [4] patented a
process in which a solution containing an active
substance and a carrier is contacted with a
supercritical fluid, leading to particles forma-
tion consisting of microspheres of carrier in
which are imbedded the active substance. The
patent discloses a number of ways in which the
fluids can be contacted with one another and
 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219
describes the formation of particles during or
after the contact step.
“ Later, Debenedetti et al. [8] patented a process
for the formation of protein particles, based on
the ASES process. A protein solution is in-
jected at the top of a crystallizer through a
laser-drilled platinum disc to produce a fine
spray. Catalase and insulin particles were ob-
tained with 1–5 mm size.
“ The Bradford University [18] patented the pro-
duction of very fine particles using the SEDS
technique previously described. Formation of
very fine particles of salmeterol xinafoate,
cobaltous nitrate and nickel chloride hexahy-
drate with controlled shape is claimed. But
they noticed that preparation of particles of
sugars or proteins is problematic. Lactose, for
example, has very low solubility in conven-
tional organic solvents. But it dissolves readily
in water, which is not soluble in supercritical
fluid. The same problem arises with proteins.
Although solutions of such proteins in organic
solvents can be prepared, it is generally unde-
sirable to do so because of the risk of the
protein unfolding and denaturing. Therefore,
the Bradford university patented another pro-
cess [21] which allows to maintain these
molecules in a favorable environment until
rapid processing with modified supercritical
carbon dioxide.
“ The process is quite similar to the previous
one. As shown on Fig. 5, it is based on the
co-introduction, through a nozzle with three
Fig. 5. Three coaxial-passages nozzle.
191
coaxial passages into a particle formation ves-
sel, of:
A solution or suspension of active substance
in solvent 1.
A solvent 2, miscible with solvent 1 and
soluble in the supercritical fluid.
A supercritical fluid.
“ The dispersion of the active substance solution
(in solvent 1) and solvent 2, and the extraction
of these two solvents occur simultaneously. At
the point where the active substance solution
and solvent 2 are introduced, hydrogen-bond-
ing and/or similar interactions are formed be-
tween both solvents. The two solvents are then
extracted together by the supercritical fluid.
“ This process differs from the tee method of
Sievers et al., described in Part 3, because the
outlet of the Bradford nozzle is still pressurized
and enters a chamber with the supercritical
fluid, while the Sievers nozzle is decompressed
rapidly to atmospheric pressure and uses no
organic solvents.
“ This process was used to prepare particles of
sugars (lactose, maltose, threhalose, sucrose)
with aqueous solution of sugar/(ethanol or
methanol)/supercritical CO2 systems and parti-
cles of proteins with aqueous solution of
protein/ethanol/supercritical CO2 system [21].
Moreover, Sloan et al. [46] used this process
with two model proteins, lysozyme and trypsin.
SEDS-processing of both model proteins re-
sulted in reduced particle size with improved
size distribution. Lysozyme was processed
without loss of enzymatic activity (95%) where
as 40% of the trypsin activity was recovered
after similar processing.
“ A more recent process patented by Bradford
Particle Design [52] allows particle formation
of lipophilic substances and low polarity mate-
rials with a special anti-solvent process. In
conventional GAS/SAS methods, the supercrit-
ical fluid expands an organic solution of the
active, decreasing its solvent power and causing
the active precipitation. In this new process,
the supercritical fluid expands another super-
critical solvent, pure or modified with a co-sol-
vent, in which the active principle is dissolved,
producing fine particles of the active. This pro-
192 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219
cess cannot be considered as RESS because
particle formation is not due to a pressure
reduction but to the second supercritical fluid
action. Ibuprofen particles were obtained with
this process by mixing supercritical nitrogen
with a supercritical solution of ibuprofen in
carbon dioxide.The micronization of other
lipophilic substances (salicylic acid, ketoprofen,
salmeterol xinafoate and nicotinic acid) is also
described.
“ More recently, Subramaniam et al. [31,47,65]
patented a process and apparatus for particle
precipitation and coating using near-critical
and supercritical anti-solvents. The contact
step between a solution or suspension of a
solute and the supercritical fluid anti-solvent is
made so as to generate high frequency sonic
waves, which will break the solution into ex-
tremely small droplets. Special nozzles are used
to create high frequency sonic waves: an ener-
gizing gas stream is injected through a passage-
way perpendicular to the dispersion of the
liquid by the supercritical solvent. This energiz-
ing gas stream generates high frequency waves
that break up the fluid dispersion and generates
extremely small droplets leading to the final
particles. The energizing gas can be the same as
the anti-solvent or can be selected from a
group consisting of air, oxygen, nitrogen, he-
lium, carbon dioxide, propane, butane, isobu-
tane, trifluoromethane, nitrous oxide, sulfur
hexafluoride and mixtures thereof. Formation
of very small particles on the order of 0.1– 10
mm is claimed. The invention also includes
supercritical coating techniques that we will
examine later in this paper. Recrystallization of
four substances (hydrocortisone, poly(D,L-lac-
tide-glycolide), ibuprofen and camptothecin) is
described.
“ Pallado et al. [23] described a process for
preparing nanospheres composed of a biocom-
patible polysaccharidic polymer by precipita-
tion in a anti-solvent. These spheres are used as
vehicling agents or carriers in the preparation
of pharmaceutical compositions. The biocom-
patible polysaccharide polymer is dissolved in
an appropriate solvent and contacted with a
flow of supercritical fluid that expands the
solution causing particles precipitation. Loaded
microspheres can be produced by adding the
active principle to the polymer solution. Mi-
croparticles of acyl esters of hyaluronic acids
(HYAFF-11, HYAFF-11-p75, HYAFF-7), a
crosslinked polysaccharide of hyaluronic acid
(ACP), an ester of alginic acid, an ester of
pectinic acid, were prepared. The formation of
loaded microspheres is also described: calci-
totin/HYAFF particles, Granulocyte
Macrophage Colony Stimulating Factor (GM-
CSF)/HYAFF particles, Insulin/HYAFF
particles.
“ Anderson et al. [33] patented the formation of
small and sterile particles of prednisolone ace-
tate using the ASES process.
“ In 1998, Manning [39] patented a process for
particle production using the ASES process. A
true solution of a pharmaceutical substance is
prepared in an organic solvent in which the
substance is not normally soluble, by forming a
hydrophobic ion-pair complex involving the
substance and an amphiphilic material. This
solution is then sprayed into a compressed
supercritical fluid. To obtain micro-encapsu-
lated products, a biodegradable polymer may
be added to the solution. Pulverization of in-
sulin-SDS complex is described in this patent.
“ In 1998, Bausch et al. [34] described a process
for the manufacture of a pulverous preparation
of a (sub)micron-sized biologically active com-
pound. The compound is first dissolved under
elevated pressure in a compressed gas, liquid or
supercritical fluid containing surface modifier
or in compressed dimethylether optionally con-
taining a surface modifier. In a special embodi-
ment, the resulting solution is sprayed into an
antisolvant phase optionally containing a sur-
face modifier. According to claim 11, the anti-
solvent phase can be water or compressed
carbon dioxide.
2.4. Publications
As shown on Table 2, numerous publications
show that the SAS/GAS process (and its variants)
has been used to recrystallize many different
products (explosives, polymers, pharmaceuticals,
Table 2
Compounds atomized with the GAS/SAS/ASES/SEDS processesa

Substrates (solvent) Supercritical Process Results and observations References

fluid

Explosi6es
Cyclotrimethylenetri-nitramine (RDX) CO2 GAS Production of void-free particles Particle Gallagher, 1992 [9,10]
(acetone or cyclohexanone) sizes depending on the conditions: from
200 to 1 mm
b-HMX (acetone) CO2 GAS Particle size: 2–5 mm Cai, 1997 [24]

J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219

b-HMX (acetone) CO2 GAS Particle size: 65 mm Förter-Barth, 1999 [56]
b-HMX (g-butyrolactone) CO2 GAS Particle size: 90 mm Förter-Barth, 1999 [56]
Nitroguanidine (NMP or DMF) CO2 GAS Particle size: a few microns Different Gallagher, 1989 [6]
shapes were obtained during the tests
NTO (DMF or DMSO or methanol) CO2 GAS Variety of shapes (sphere, cube, Lim, 1998 [38]
spherical agglomerate) of sizes 0.5–20
mm depending upon the conditions
Polymers and biopolymers
ALAFF (ester of alginic acid) (DMSO) CO2 GAS Particle size: 0.8 mm Pallado, 1996 [23]
Dextran (DMSO) CO2 ASES Particle size: 0.1–0.2 mm Reverchon, 1999 [54]
Ester of pectinic acid (DMSO) CO2 GAS Particle size: 0.7 mm Pallado, 1996 [23]
HPMA (poly(hydroxypropyl CO2 ASES Spherical microparticles of diameter Reverchon, 1999 [61]
methacrylamide)) (DMSO) 0.1–0.2 mm
HYAFF 7 (ethyl ester of hyaluronic CO2 GAS Particle size: 1 mm Pallado, 1996 [23]
acid) (DMSO)
HYAFF 11 (hyaluronic acid ethyl ester) CO2 ASES Particle size: 0.3–10 mm Benedetti, 1993 [11] Reverchon, 1999
(DMSO) [54]
GAS Particle size: 0.6 mm Pallado, 1996 [23]
HYAFF 11 p75 (DMSO) CO2 GAS Particle size: 0.8 mm Pallado, 1996 [23]
Inulin (DMSO) CO2 ASES Spherical particles with a maximum Reverchon, 1999 [54,61]
diameter of 5 mm
PLA (acetone) CO2 ASES Brittle solid similar to the starting Chou, 1997 [25]
material
PLA (methylene chloride) CO2 Particle size: 1–10 mm Particle size: 1–2 Bleich, 1993 [13] Reverchon, 1999 [61]
mm
DL-PLA (n.a.) CO2+N2 SEDS Particle size: 10 mm Ghaderi, 1999 [68]
DL-PLG (n.a.) CO2+N2 SEDS Particle size: 10 mm Ghaderi, 1999 [68]
PLGA (acetone) CO2 GAS Particle size: 50 nm Dillow, 1997 [26]
Polyacrylonitrile (DMF) CO2 ASES Formation of microfibrilles Johnston, 1994 [19]
Polycaprolactone (n.a.) CO2+N2 SEDS Particle size: 25–85 mm Ghaderi, 1999 [68]
Poly(methacrylated sebacic anhydride) CO2 ASES A high powered ultraviolet source Owens, 1999 [67]
(methylene chloride) allows photopolymerisation. Particle
size: 1–5 mm

193
 194
Table 2 (Continued)

Substrates (solvent) Supercritical Process Results and observations References

fluid

Polystyrene (toluene) CO2 ASES Particle size: 0.1–20 mm Dixon, 1993 [14]
Polystyrene (toluene) CO2 SEDS Particle size: 0.5 mm Hanna, 1998 [36]
Inorganic and organic materials: coloring matters, catalysts, superconductors…
Ammonium Chloride (DMSO) CO2 GAS Particle size: 1–5 mm Yeo, 2000 [84]
Barium Chloride (DMSO) CO2 GAS Particle size: 7–9 mm with cubic shape or Yeo, 2000 [84]
needle-like crystals depending on the

J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219

conditions
Bronze Red (ethanol) CO2 ASES Spheres of diameter between 1 and 10 mm Hong, 2000 [76]
depending on experimental conditions
Bronze Red (acetone) CO2 ASES Spheres or needles of diameter between 3 Hong, 2000 [76]
and 15 mm depending on the conditions
Buckminster-fullerene (toluene) CO2 ASES Particle size: 100–300 nm Chattopadhyay, 2000 [71]
Cobaltous nitrate (acetone) CO2 SEDS Free-flowing pink powder Hanna, 1994 [18]
Epoxy powder (acetone or methyl ethyl CO2 ASES Without surfactant: agglomerates with Heater, 1998 [37]
ketone) pluronic R-17: separated particles with
uniform spherical morphology
Hydroquinone (acetone) CO2 GAS and ASES GAS: agglomerates of size 500 mm ASES: Wubbolts, 1997 [32]
needle and prismatic shaped particles of
size 50–100 mm
Nickel Chloride hexahydrate (absolute CO2 SEDS Very fine free-flowing powder Hanna, 1994 [18]
ethanol)
Phenanthrene (toluene) CO2 GAS Particle size: 160–540 mm Berends, 1994 [16]
Red Lake C pigment Pigment Yellow 1 CO2 GAS Particle size: down to 0.6 mm Gao, 1997 [27]
Pigment Blue 15 (acetone)
Samarium acetate (DMSO) CO2 ASES Particle size: 0.1–0.3 mm Reverchon, 1997 [29,44]
Samarium acetate (water+methanol) CO2 SEDS Particle size: 0.2 mm Hanna, 1998 [36]
Silver nitrate (methanol) CO2 SEDS Particle size: 0.3 mm Hanna, 1998 [36]
Superconductor precursors CO2 ASES Reverchon, 1998 [42]
Yttrium acetate (DMSO) CO2 ASES Ballons formed by submicronic elements Reverchon, 1997 [29,43] Muhrer, 2000
[78]
Zinc acetate (DMSO) CO2 ASES Particle size: 0.08–0.13 mm Reverchon, 1997 [30,63]
Pharmaceutical compounds
Acetaminophen (ethanol) CO2 SEDS Particle size: 6–8 mm Gilbert, 2000 [75]
Albumin (water) CO2+Ethanol SEDS Particle size: 50–500 nm Bustami, 2000 [70]
7-aminocephalo-sporanic acid (acetone and CO2 GAS n.a. Liang, 2000 [77]
water)
Amoxicillin (NMP) CO2 ASES Particle size: 0.2–0.8 mm Reverchon, 1999 [57,64]
Antibody Fab fragment (water) CO2+ethanol SEDS Activity of processed antibody: 45% Sloan, 1999 [58]
Antibody Fv fragment (water) CO2+ethanol SEDS Activity of processed antibody: 3% Sloan, 1999 [58]
Ascorbic acid (ethanol) CO2 ASES Particle size: 1–10 mm Weber, 1999 [55]
Table 2 (Continued)

Substrates (solvent) Supercritical Process Results and observations References

fluid

b-carotene (ethyl acetate) CO2 GAS Particle size: platelet morphology of 2–10 Cocero, 2000 [72]
mm size
Catalase (ethanol-water 90:10) CO2 ASES Particle size: 1 mm Debenedetti, 1992 [8]
Substrates (solvent) Supercritical Process Results and observations References
fluid
Chloramphenicol (ethanol) CO2 ASES Particle size: 1–10 mm Weber, 1999 [55]
Cu2(indomethacin)4 (DMF)2 (DMF) CO2 GAS Slow expansion: rhombic crystals of 50 Warwick, 2000 [83]

J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219

mm size Fast expansion: crystals of 20 mm
size
p-HBA (methanol) CO2 GAS ASES GAS: Particle size: 1–2 mm ASES: 0.1–1.0 Thiering, 1998 [49]
mm
Hydrocortisone acetate (DMF) CO2 ASES Particle size: 5 mm Schmitt, 1995 [22]
Insulin (ethanol-water 90:10) CO2 ASES Particle size: 1 mm Debenedetti, 1992 [8]
Insulin (water) CO2+Ethanol SEDS Particle size: 50–500 nm Bustami, 2000 [70]
Insulin (DMSO or DMF) CO2 ASES Particle size [15]: B4 mm Particle size Yeo, 1993 [15] Thiering, 2000 [80, 1,82]
[80,81,82]: 1.4–1.8 mm
Insulin (Methanol) CO2 GAS Particle size: 0.2–0.7 mm Thiering, 2000 [80,81,82]
Insulin (Ethyl acetate) CO2 GAS Particle size: 0.3–0.7 mm Thiering, 2000 [80,81,82]
Insulin (Ethanol) CO2 GAS Particle size: 0.05–0.3 mm Thiering, 2000 [80,81,82]
Insulin (water) NH3 GAS Particle size: 0.2–0.3 mm Thiering, 2000 [80,81,82]
b-lactamase (water) CO2+ethanol SEDS Hanna, 1994 [18]
Lactose (water) CO2 and SEDS Particle morphology depends on the Hanna, 1995 [21] Palakodaty, 1998 [40]
methanol nozzle Particle size: 3.0–10.5 mm
Lecithin (ethanol or hexane) CO2 ASES Weber, 1999 [59]
Lobenzarit disodium (water) CO2+Ethanol ASES Particle size: 0.2–0.6 mm D. Amaro-Gonzalez, 2000 [69]
Lysozyme (water) CO2+ethanol SEDS Particle size [46]: 0.78 mm Activity of Sloan, 1998 [46] Bustami, 2000 [70]
processed enzyme: 95% Particle size [70]: Gilbert, 2000 [75]
500 nm Particle size [75]: 0.5–5 mm
Lysozyme (DMSO) CO2 GAS Particle size: 0.05–0.2 mm Thiering, 2000 [80,81,82]
Lysozyme (DMSO) CO2+DMF GAS Particle size: 0.1 mm Thiering, 2000 [80,81,82]
(30% vol.)
Lysozyme (DMSO) CO2+Ethanol GAS Particle size: 0.02–0.04 mm Thiering, 2000 [80,81,82]
(30% vol.)
Lysozyme (DMSO) CO2+acetic acid GAS Particle size: 0.05 width×0.25 length Thiering, 2000 [80,81,82]
(8% vol.)
Lysozyme (Ethanol) CO2+water GAS Particle size: 0.05–0.07 Thiering, 2000 [80,81,82]
Lysozyme (Methanol) CO2 GAS Particle size: 0.01–0.05 mm Thiering, 2000 [80,81,82]
Lysozyme (Water) NH3 GAS Particle size: 0.05–0.2 mm Thiering, 2000 [80,81,82]
Maltose (water) CO2+absolute SEDS Result: free-flowing white powder Hanna, 1995 [21]
ethanol

195
Mefenamic acid (methanol or ethanol or CO2 ASES Particle size: 10–50 mm Bustami, 1999 [66]
acetone)
 196
Table 2 (Continued)

Substrates (solvent) Supercritical Process Results and observations References

fluid

Methylprednisolone (tetrahydrofuran) CO2 or ethane ASES Particle size: 5 mm Schmitt, 1995 [22] Muhrer, 2000 [78]
Myoglobin (DMSO) CO2 GAS Particle size: 0.03–0.4 mm Thiering, 2000 [80,81,82]
Myoglobin (Methanol) CO2 GAS Particle size: 0.05–0.3 mm Thiering, 2000 [80,81,82]
Naproxen (acetone) CO2 ASES Needles-like crystals with diameter 1 mm Chou, 1997 [25]
and length 1 mm
Nicotinic acid (absolute ethanol) CO2 SEDS Particle size: 0.4–0.75 mm Hanna, 1998 [36]
Paracetamol (ethanol) CO2 ASES Particle size: 1–10 mm Weber, 1999 [55]

J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219

Phospholipids (chloroform or ethanol) CO2 ASES Spherical particles of size: 1–40 mm Magnan, 1999 [53,60]
Plasmid DNA pSVb with no protectant CO2+ethanol SEDS Activity of processed plasmids: 10% Sloan, 1999 [58]
(water)
Plasmid DNA pSVb with protectant CO2+ethanol SEDS Activity of processed plasmids: 75% Sloan, 1999 [58]
(water)
Prednisolone acetate (acetone) CO2 ASES Particle size: 1 mm Anderson, 1998 [33]
RhDNase (water) CO2+ethanol SEDS Particle size: 50–500 nm Bustami, 2000 [70]
Salbutamol(methanol+acetone) CO2 SEDS Particle size: 0.5 mm Hanna, 1998 [36]
Salmeterol xinafoate (methanol or acetone) CO2 ASES Particle size: 1–10 mm Hanna, 1994 [18] Hanna, 1998 [35]
Salmeterol xinafoate (acetone or methanol) CO2 SEDS With acetone: platelet particles with Hanna, 1998 [36]
methanol: needles-like particles
Sodium cromoglicate (methanol) CO2 ASES Particle size: 0.1–20 mm Jaarmo, 1997 [28]
Sucrose (water) CO2+absolute SEDS Result: free-flowing white powder Hanna, 1995 [21]
ethanol
Tetracycline (NMP) CO2 ASES Particle size: 0.6–0.8 mm Reverchon, 1999 [57,64], 2000 [79]
Trehalose (water) CO2+absolute SEDS Result: free-flowing white powder Hanna, 1995 [21]
ethanol
Trypsin (HCl 1mM) CO2+ethanol SEDS Particles size: 1.53 mm Activity of Sloan, 1998 [46]
processed enzyme: 36%
Urea (ethanol) CO2 ASES Particle size: 1–10 mm Weber, 1999 [55]
Microcomposites
Calcitonin+HYAFF (DMSO) CO2 GAS Particle size: 0.5–1 mm Pallado, 1996 [23]
Chimotrypsin-AOT+PLA (methylene CO2 ASES Particle size: 1–2 mm Elvassore, 2000 [73]
chloride)
Chloramphenicol and urea (ethanol) CO2 GAS Weber, 1998 [50]
Copper-, Barium- and Yttrium acetate CO2 ASES Composite particles of 50–150 nm with a Weber, 1999 [55]
(ethanol) unique homogeneous distribution of each
of the elements
GMCSF+HYAFF (DMSO) CO2 GAS Particle size: 0.5–1 mm Pallado, 1996 [23]
p-HBA (methanol)+PLGA (acetone) CO2 SEDS Crystals of p-HBA coated with a layer of Sze Tu, 1998 [48]
PLGA microspheres
p-HBA (methanol)+PLA (methylene CO2 SEDS Fibrous network of drug and polymer Sze Tu, 1998 [48]
chloride) mixture
Table 2 (Continued)

Substrates (solvent) Supercritical Process Results and observations References

fluid

J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219

Hydrocortisone + CO2+N2 SEDS Particle size: 10–60 mm Ghaderi, 1999 [68]
Poly(DL-lactide-co-glycolide):copolymer
composition 50:50 (n.a.)
Insulin+HYAFF (DMSO) CO2 GAS Particle size: 0.4 mm Pallado, 1996 [23]
Insulin-lauric acid conjugate+PLA CO2 ASES Particle size: 1–5 mm Elvassore, 2000 [73]
(methylene chloride)
Insulin+PLA (methylene CO2 ASES Particle size: 1–5 mm Elvassore, 2000 [73]
chloride+DMSO 50%)
Lysozyme+PLA (methylene CO2 ASES Particle size:1–2 mm Elvassore, 2000 [73]
chloride+DMSO 50%)
Naproxen+PLA (acetone) CO2 ASES Particle size: 5 mm Chou, 1997 [25]
Paracetamol and ascorbic acid (ethanol) CO2 GAS By variation of the composition, the Weber, 1998 [50]
product changed from needle-like
crystals (10 mm) to large tubes (length
30–100 mm, diameter 2 mm) covered
with prismatic crystals (B1 mm)
PLA+clonidine HCl (dichloromethane) CO2 ASES Hollow spheres of diameter: 100 mm Schwarz Pharma, 1987 [4]
PLA+hyoscine (butylbromide) CO2 ASES Particle size B20 mm Bleich, 1994 [17]
Salmeterol CO2 SEDS Fine white powder Hanna, 1994 [18]
xinafoate+hydroxypropyl-cellulose
(acetone)

a
Abbreviations used AOT, dioctylsulfosuccinate; DMF, N,N-dimethyl formamide; DMSO, dimethylsulfoxide; GMCSF, granulocyte macrophage colony stimulating
factor; n.a., non available; NMP, N-methyl 2-pyrrolidone; NTO, 3-nitro-1,2,4.-triazole-5-one; p-HBA, para-hydroxybenzoic acid; PLGA, poly(lactide-co-glycolide);
PLA, poly(L-lactic acid); DL-PLG, Poly(DL-lactide-co-glycolide):copolymer composition 50:50.

197
198 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219
coloring materials, …) in order to make fine
powders or microspheres of an active embedded
into a carrier (see details on microspheres below).
It is to be noticed that Reverchon [41,62] and
Foster et al. [74] published reviews about super-
critical anti-solvent precipitation applications.
2.5. Future de6elopment
There is no doubt that anti-solvent processes
have a bright future, especially for drug delivery
systems, as they permit to monitor the properties
and composition of the particles with a great
flexibility and for almost any kind of compounds!
Nevertheless, scale-up is presently foreseen only
for high-value specialty materials (pharmaceuti-
cals, cosmetics, superconductors…) with produc-
tions ranging from a few kilograms to a few
hundreds kilograms per day.
Regarding intellectual property, this complex
situation may lead to some limitations of process
applications until it will be cleared so as to ensure
that no patent infringement is to be feared by
potential users.
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Lecithin from Egg Yolk-Extracts by Gas Anti-solvent
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[60] C. Magnan, E. Badens, N. Commenges, G. Charbit, Soy
Lecithin Micronization by Precipitation with a Com-
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[62] E. Reverchon, Review: Supercritical Anti-solvent Precipi-
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[63] E. Reverchon, G. Della Porta, D. Sannino, P. Ciambelli,
Supercritical Anti-solvent Precipitation of Nanoparticles
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[64] E. Reverchon, G. Della Porta, Production of antibiotic
micro- and nano-particles by supercritical anti-solvent
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[65] B. Subramaniam, S. Saim, R.A. Rajewski, V. Stella, US
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[66] R. Bustami, H.K. Chan, F. Dehghani, N.R. Foster,
Recrystallisation and Micronisation of Mefenamic Acid
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[67] J. Owens, K. Anseth, C. Lengsfeld, T. Randolph, Photo-
polymerization of polymer microparticles using com-
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[68] R. Ghaderi, P. Artursson, J. Carlfors, Preparation of
Biodegradable Microparticles using Modified Solution-
Enhanced Dispersion by Supercritical Fluids (SEDS) and
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[69] D. Amaro-Gonzalez, G. Mabe, M. Zabaloy, E.A. Brig-
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aqueous solutions. Journal of Supercritical Fluids, 17,
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[70] R.T. Bustami, H.K. Chan, F. Dehghani, N.R. Foster
Generation of Protein Micro-Particles Using High Pres-
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International Symposium on Supercritical Fluids, 8 – 12
April, Atlanta (USA), 2000.
[71] P. Chattopadhyay, R.B. Gupta, Supercritical CO2 Based
Production of Fullerene Nanoparticles. Proceedings of
the 5th International Symposium on Supercritical Fluids,
8 – 12 April, Atlanta (USA), 2000.
[72] M.J. Cocero, S. Ferrero, S. Vicente, GAS Crystallization
of b-Carotene From Ethyl Acetate Solutions Using CO2
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posium on Supercritical Fluids, 8 – 12 April, Atlanta
(USA), 2000.
[73] N. Elvassore, A. Bertucco, P. Caliceti, Production of
Protein-Polymer Micro-Capsules by Supercritical Anti-
Solvent Techniques. Proceedings of the 5th International
Symposium on Supercritical Fluids, 8 – 12 April, Atlanta
(USA), 2000.
[74] N.R. Foster, K.Bezanehtak, M. Charoenchaitrakool, G.
Combes, F. Dehghani, L. Sze Tu, R. Thiering, B. War-
wick, R. Bustami, H.K. Chan, Processing Pharmaceuti-
cals Using Dense Gas Technology. Proceedings of the 5th
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International Symposium on Supercritical Fluids, 8 –12
April, Atlanta (USA), 2000.
[75] D.J. Gilbert, S. Palakodaty, R. Sloan, P. York, Particle
Engineering for Pharmaceutical Applications — A Pro-
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[76] L. Hong, S.R. Bitemo, Y. Gao, W.K. Yuan, Precipitation
of Microparticulate Organic Pigment Powders by Super-
critical Antisolvent (SAS) Process. Proceedings of the 5th
International Symposium on Supercritical Fluids, 8 –12
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[77] M.T. Liang, J.Y. Wu, R.C. Liang, Precipitation of 7-ACA
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national Symposium on Supercritical Fluids, 8 –12 April,
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[78] G. Muhrer, W. Dörfler, M. Mazzotti, Gas Antisolvent
Recrystallization Of Specialty Chemicals: Effect Of Pro-
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[79] E. Reverchon, G. Della Porta, M.G. Falivene, Process
Parameters and morphology in amoxicillin micro and
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[80] R. Thiering, F. Dehghani, N.R. Foster, Micronization of
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[81] R.Thiering, F. Dehghani, A. Dillow, N.R. Foster, The
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[82] R.Thiering, F. Dehghani, A. Dillow, N.R. Foster, Solvent
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[83] B. Warwick, F. Dehghani, N.R. Foster, Synthesis, Purifi-
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Fig. 6. PGSS equipment concept.
201
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[84] S.D. Yeo, J.H. Choi, T.J. Lee, Crystal formation of BaCl2
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3. Part 3: Particles from gas-saturated
solutions/suspensions (PGSS)
3.1. Concept
As the solubilities of compressed gases in liq-
uids and solids like polymers are usually high, and
much higher than the solubilities of such liquids
and solids in the compressed gas phase, the pro-
cess consists in solubilizing supercritical carbon
dioxide in melted or liquid-suspended sub-
stance(s), leading to a so-called gas-saturated so-
lution/suspension that is further expanded
through a nozzle with formation of solid particles,
or droplets (Fig. 6).
Typically, this process allows to form particles
from a great variety of substances that need not
to be soluble in supercritical carbon dioxide, espe-
cially with some polymers that absorb a large
concentration (10–40 wt.%!) of CO2 that either
swells the polymer or melts it at a temperature
much below ( 10–50°C) its melting/glass transi-
tion temperature [3,4,45]. This process can also be
used with suspensions of active substrate(s) in a
polymer or other carrier substance leading to
composite microspheres.
202 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219
3.2. History
In 1979, Best et al. [1] described a procedure for
preparing very finely divided carotenoids using
supercritical gases. Crystalline substrates were dis-
solved in a mixture of supercritical gas and en-
trainer. The solution was then dispersed in a
colloidal matrix before being decompressed result-
ing in active precipitation into the matrix. It
seems to us that the mixture carotenoids, super-
critical gas and entrainer leads to a gas-saturated
solution that is further expanded. It is clear that
this process cannot be considered as PGSS as the
solution is not decompressed through a nozzle but
the patent can be considered as anterior art of this
process.
But the basis of the PGSS technique was de-
scribed later by Graser [2] who patented a process
to prepare pigments by crystallizing finely milled
crude organic pigments. Recrystallisation is car-
ried out in a solvent at high temperatures and
under atmospheric or higher pressure. In particu-
lar cases, solvents are under supercritical pres-
sures. Moreover, to isolate the formed pigments,
the authors described different processes like dis-
tillation or ‘forcing the conditioning mixture
through a valve by means of an inert gases’ that
would ‘isolate the pigment by a type of spray
drying’.
3.3. Patents
In fact, many patents were filed for processes
that can be considered to use the PGSS concept:
“ Many patents describe the use of supercritical
carbon dioxide as a viscosity reducing material
in spray applications of different products
(paint, adhesives, plastic additives, …). In
those patents, the solid material is suspended in
a liquid carrier and mixed with a supercritical
solvent. The mixture is then sprayed onto a
substrate to form a coating. The most ad-
vanced applications are related to paint appli-
cation (UNICARB® process
[5,6,7,9,10,11,14,17,20,21,28,37] from Union
Carbide, or a similar process from Nordson
[8,13,18]), and dry paint production with a very
large production unit developed by Ferro
[23,27,32]. Powder coating production was also
patented by Morton [35,38], Nippon Paint [19]
and Otefal Spa. [24]. The process developed by
Union Carbide and Nordson involves the use
of supercritical carbon dioxide both as an at-
omization vector and as a solvent. Smooth and
high-quality coatings without defects or bub-
bles are attained with this technology. More-
over, a drastic reduction of volatile organic
compounds (VOC’s) release is claimed from 30
to 70%. In 1991, Kishimoto [12] developed a
process in order to obtain a quick-drying and
pollution-free adhesive without using a large
quantity of dispersion medium. The adhesive is
prepared by compression, under high pressures,
of an adhesive prepolymer and carbon dioxide
and sprayed onto a surface.
“ In the VAMP™ process [27,32] developed by
Ferro, supercritical fluid is used as a processing
aid for powder coating formulation and atom-
ization. The supercritical fluid, mixed with the
powder coating raw materials (resins, harden-
ers, fillers and additives), swells the resins and
the polymers resulting in better additives dis-
persion. Several distinct advantages leading to
improved product quality have been demon-
strated: low temperature and low shear forces,
low molecular weight products, superior gloss
control, better hiding, excellent color control.
“ In 1995, Weidner et al. [26] patented a process
for preparing particles and powders using what
they called the PGSS technique. A supercritical
fluid is dissolved into a melted substance or a
suspension of a substance in order to make a
gas-saturated solution. This mixture is then
expanded through a nozzle and solid particles
are formed due to the sharp temperature de-
crease caused by fluid expansion.
“ Also in 1995, Sievers et al. [25] patented a new
CO2-assisted aerosolization process, related to
PGSS, that permits the use of any compound
that is water-soluble. The active substance is
dissolved into an aqueous solution, which is
mixed under pressure with supercritical CO2,
forming an emulsion. The supercritical emul-
sion flows through a restrictor and is rapidly
decompressed to form an aerosol. Because CO2
is one of the most soluble gases in water (1.6
 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219 203

mole% at 63°C and 100 bar), its use enhances
the expansion process.Several variants of this
technique have been described. A schematic
representation of the continuous CO2-assisted
nebulization process is presented on Fig. 7. The
supercritical CO2 and the active substance solu-
tion are mixed in a low-dead-volume (B1 ml)
mixing tee. The mixture is then depressurized
through a restrictor to form an aerosol (Fig.
8).To obtain dry particles, the aerosol droplets
are directed into a high temperature furnace
where they are desolvated [39,42]. Particle size
can be controlled by varying the concentration
of the precursor solution, and other aerosoliza-
tion parameters (temperature, pressure, flow
rates and restrictor diameter).In fact, it is not
clear that fluid dissolution does happen during
the extremely short contact time in this tee,

Fig. 7. Schematic representation of the continuous nebulization process.

Fig. 8. The ‘mixing tee’.

204 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219
Fig. 9. Particles formation with static nebulization process
[25].
Fig. 10. Portable device using static nebulization process [25].
although the equipment used by Sievers [25]
may lead to phase mixing not only in the
capillary after the tee but also inside the liquid
solution tubing due to liquid pump strokes.
Obviously, dispersion results from a mechani-
cal effect caused by high velocity expansion of
the two-phase mixture, but, according to Siev-
ers [43], CO2 solubility is so high in aqueous
media that even within this short contact time,
some dissolution happens and improves disper-
sion; according to this author, it is proven by
two observations: Aqueous droplets become
acidic due to CO2 dissolution and dispersion is
not at all as efficient when CO2 is substituted
by nitrogen or air at similar pressure. Never-
theless, there is no doubt that saturation is far
from reached and this process cannot be explic-
itly considered as a PGSS application. Con-
seguently it is difficult to understand how this
system differs from conventional aerosol tech-
nology, known from many decades.Moreover,
it is to be noticed that this clever-because so
simple and inexpensive!- method to obtain par-
ticles of water-soluble products may lead to
problems when applied on large scale due to
the sharp temperature decrease caused by car-
bon dioxide depressurization (possible ice for-
mation), although this problem is far less
critical than for the RESS process as the heat
to dry the droplets is provided by an inert gas
(generally nitrogen) after the aerosol is formed
and moved away from the nozzle into the
atomization vessel [25,39,41,42]. Indeed, the tee
and the restrictor are usually heated to 50–
100°C to avoid restrictor obstruction due to
the Joule-Thomson effect [25,42].A static
method according to the PGSS concept is also
described in the same patent [25]: The super-
critical fluid is introduced under pressure in a
vessel containing the solution. The mixture is
then decompressed through the restrictor (Fig.
9). Moreover Sievers et al. describes a portable
device composed of a canister equipped with a
septum, containing an immiscible mixture of a
supercritical fluid and a solution (suspension)
of a substance, and a threaded cap equipped
with a puncturing pin and a restrictor (Fig. 10).
In operation, the cap is screwed down onto the
canister until the puncturing pin ruptures the
septum, releasing the mixture. The rapid pres-
sure release causes the formation of an aerosol
comprising fine particles (B 6.5 mm). More-
over, the development of pocket-type of drug
 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219 205

delivery system according to this concept is far
from easy due to consumer acceptance and
protection (risk of canister explosion).
“ Karasawa [30] patented in 1997 a method of
pulverizing solid particles using supercritical
fluids. The solid particles are suspended in a
fluid in a supercritical state. The suspension is
expanded through a jet to form particles. It is
claimed that a major advantage of this method
is to avoid agglomeration of the processed
particles.
3.4. Publications
The PGSS process can be applied in various
fields ranging from inorganic powders to pharma-
ceutical compounds as shown in Table 3.

Table 3
Compounds atomized with the PGSS processa

Substrates Supercritical fluid Results and observations References

Inorganic and organic materials

Adhesives CO2 n.a. Cole, 1989 [6]
Benzoic acid CO2 Aerosolization of an aqueous solution Sievers, 1999 [39]
Glucose CO2 Aerosolization of an aqueous solution Sievers, 1999 [39]
Glycerides CO2 Particle size: 20–50 mm Novak, 1993 [15]
Metal oxides CO2 Aerosolization, dehydration and pyrolysis of a metal acetate or nitrate Sievers, 1999 [39]
aqueous solution
Phosphors CO2 Aerosolization, dehydration and pyrolysis of an aqueous solution Xu, 1998 [40]
(Y2O3:Eu) Xu, 1997 [34]
Plastic additives CO2 n.a. Prince, 1993 [16]
Polyethyleneglyc CO2 Particle size: 150–400 mm Weidner, 1996
ol [29]
Powder coating CO2 n.a. Mandel, 1997
[31]
Powder coating CO2 Particle size: 1–30 mm Weidner, 1999
[44]
Powder lacquer CO2 n.a. Kieser, 1998 [36]
Spinels CO2 Aerosolization, dehydration and pyrolysis of an aqueous solution Xu, 1998 [40]
(Co3−x Mx O4,
M=Fe, Cr)
Pharmaceuticals
Albuterol CO2 Aerosolization of an aqueous solution Particle size: 0.69 mm Sievers, 1998,
sulfate 2000 [39,46]
Alkaline CO2 Aerosolization of an aqueous solution Sievers, 1999 [41]
phosphatase
Cromolyn CO2 Aerosolization of an aqueous solution Particle size: 1 mm Sievers, 1998,
sodium 2000 [39,46]
DL-alanine CO2 Aerosolization of an aqueous solution Particle size: 0.3–0.5 mm Sievers, 1995 [25]
Glucose oxidase CO2 Aerosolization of an aqueous solution Sievers, 1999 [41]
Glutathione CO2 Aerosolization of an aqueous solution Sievers, 1999 [41]
Horseradish CO2 Aerosolization of an aqueous solution Sievers, 1999 [41]
peroxidase
Na2Fe(DTPA) CO2 Aerosolization of an aqueous solution Sievers, 1995 [25]
Nifedipine CO2 Particle size: 15.4 mm Weidner, 1994
[22]
RhDNase CO2 Aerosolization of an aqueous solution Particle size: B3 mm Sievers, 1999 [41]
Tobramycin CO2 Aerosolization of an aqueous solution Particle size: 1–2 mm Sievers, 1998 [39]

a
n.a non available.
206 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219
Moreover, it is possible to form microspheres
when a suspension of the active substance into a
carrier is saturated by supercritical carbon dioxide
prior to atomization, as claimed by Shine and
Gelb [33] in a recent patent of a process called
polymer liquefaction using supercritical sol6ation
(PLUSS). The main interest of this process is that
it is not necessary that the carrier/polymer and the
active substance are soluble in the supercritical
fluid, what opens wide fields of applications. The
mixture of the core material and the encapsulating
polymer is supplied with a supercritical fluid capa-
ble of swelling the polymer under a temperature
and a pressure sufficient to maintain the fluid in a
supercritical state. The pressure is then rapidly
released what results in solidification of the poly-
mer around the core material to form
microcapsules.
3.5. Future de6elopment
Particle design using the PGSS concept is al-
ready widely used at large scale, at the difference
with other process concepts presently under devel-
opment yet. The simplicity of this concept, lead-
ing to low processing costs, and the very wide
range of products that can be treated (liquid
droplets or solid particles from solid material or
liquid solutions or suspensions) open wide av-
enues for development of PGSS applications, not
only for high-value materials but also perhaps for
commodities, in spite of limitations related to the
difficulty to monitor particle size.
Recently, many patents were successively
granted. Most are related to paint application
(pulverization of suspensions to make coatings)
and powder coating manufacture (combination of
chemical reaction and pulverization of a suspen-
sion); more surprisingly, the basic PGSS process
patent filed in 1995 [26] for formation of solid
particles from polymer or solid substances has
been successfully granted in Europe and recently
in the US. Moreover, a patent for aerosol drug
delivery [25] was also granted, describing several
different processes and apparatus: The ‘tee’ pro-
cess and equipment although it is not clear that
pulverization is not caused only by the mechanical
effect of gas expansion well known for long, and
a portable device for static nebulization using
RESS or PGSS concepts.
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and T.C. Williamson (Eds.), Oxford University Press,
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[41] R.E. Sievers, U. Karst, P.D. Milewski, S.P. Sellers, B.A.
Miles, J.D. Schaefer, C.R. Stoldt, C.Y. Xu, Formation of
Aqueous Small Droplet Aerosols Assisted by Supercriti-
cal Carbon Dioxide. Aerosol Science and Technology, 30,
1999, 3 – 15
[42] R.E. Sievers, S.P. Sellers, K.D. Kusek, G.S. Clark, B.J.
Korte, CO2-Activated Nebulization and ‘Bubble’ Spray
Drying to Form Fine (1 –5 mm) Particles of Proteins and
small Molecules for Inhalation Drug Therapy. Confer-
ence on Drug Delivery, Breckenbridge, July, 1999.
207
[43] R.E. Sievers, Private conversation, October, 1999.
[44] E. Weidner, M. Petermann, K. Blatter, H.U. Simmrock,
Manufacture of Powder Coatings by Spraying of Gas
Saturated Melts. Proceedings of the 6th Meeting on Su-
percritical Fluids, Chemistry and Materials; M. Poliakoff,
M.W. George, S.M. Howdle (Eds.), ISBN 2-905-267-30-5,
10 – 13 April, Nottingham, 1999.
[45] E. Gulari, C.W. Manke, Rheological Properties of Ther-
moplastics Modified with Supercritical Gases. Proceed-
ings of the 5th International Symposium on Supercritical
Fluids, April 8 – 12, Atlanta (USA), 2000.
[46] R.E. Sievers, P.D. Milewski, S.P. Sellers, B.A. Miles, B.J.
Korte, K.D. Kusek, G.S. Clark, B. Mioskowski, J.A.
Villa, Supercritical and Near-critical Carbon Dioxide As-
sisted Low Temperature Bubble Drying. Proceedings of
the 5th International Symposium on Supercritical Fluids,
April 8 – 12, Atlanta (USA), 2000.
4. Part 4: Reactions in supercritical media leading
to particle formation
Over the past decade, supercritical fluids have
received considerable attention as solvent for the
synthesis of a number of ceramics and closely
related oxide materials. These new applications
have been developed in order to improve the
characteristics of the obtained powders, such as
chemical homogeneity or structural properties.
Contrarily to the previously described processes
(RESS, SAS, PGSS) where only physical transfor-
mation occurs, the supercritical fluid is here used
for chemical transformation of the materials, as
described for the two different processes presented
here below.
4.1. Thermal decomposition with a supercritical
sol6ent
Precursors are thermally decomposed in a su-
percritical media; at the end of the reaction, su-
percritical solvent is depressurized and the
solvent, turned to gas phase, separates from the
particles which remain in a highly divided state.
The advantage of processing in a supercritical
media is that high nucleation rate and low crystal-
growth rate can be achieved, leading to ultra fine
particles formation. Moreover, the high density of
the supercritical fluid avoids aggregation prob-
lems encountered in liquid-solid separation steps
of conventional wet chemistry processes [8-10].
208 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219

Table 4
Compounds obtained by thermal decomposition on supercritical media

Substrates (precursor) Supercritical fluid Results and observations References

Ceria and Yttria co-doped Methanol Yin, 1997 [23]

Zirconia/Alumina
composites
Chromium oxide powder
(Cr(III)acetylacetonate or
Cr(III)acetate hydroxide)
Cu
(Cu(hexafluoroacetyl-acetona
te)2)
Fe3O4 (Fe(acetylacetonate)3)
Ga2O3 (Ga(acetylacetonate)3)
MgAl2O4 (Mg(Al(O-secBu)4)
MgO (Magnesium chelate or
acetate)
Oxide silica compound
(Tetraethoxysilane)
TiO2 (Ti(O-iC3H7)4)
TiO2 (Ti(O-iC3H7)4)
TiO2 (Ti(O-iC3H7)4)
TiO2 (Ti(O-iC3H7)4)
Zirconia powder (zirconium
butoxide)
Methanol Synthesis of nanometric Znaidi, 1998 [24]
powders with various surface
areas depending on conditions
CO2+ethanol Average particle size: 1 mm Pessey, 1999 [27]
CO2+ethanol Particle size: 1 mm Pessey, 1999 [27]
Ammoniac Particle size: 0.5 mm Pessey, 1999 [27]
Ethanol Spherical particles of diameter: Barj, 1992 [8] Chhor, 1992
0.5-2 mm [9]
CO2+ethanol Particle size: 0.5–2 mm Chhor, 1995 [15] Znaidi,
1996 [20]
CO2+water Different structures: fibers, Papet, 1998 [25]
spherical powders
Ethanol Spherical particles of diameter: Barj, 1992 [8] Chhor, 1992
0.5–2 mm [9]
CO2+isopropanol Pommier, 1994 [13]
Gourinchas, 1996 [18]
CO2+water Spherical particles of diameter: Papet, 1998 [25] Papet, 1999
0.1-1 mm [26]
CO2+aqueous solution of Spherical particles of diameter: Tadros, 1996 [19]
surfactant (Zonyl FSJ) 0.1-2 mm
CO2+water Papet, 1998 [25]

When the thermal stability of the precursor
does not allow dissolution in the supercritical
fluid, a variant process can be used: a sol-gel
reaction is conducted at high pressure and high
temperature, followed by supercritical drying.
Fine powders (diameter: 50 nm) can be obtained
using this process [12].
4.2. Patents
“ Yamanis [5] (Allied-Signal Inc.) patented a
continuous process for production of
fine particulate ceramics, in 1989. Con-
tinuous production of a fine ceramic powder
by drying at supercritical conditions is de-
scribed.
“ More recently, Sarrade et al. [22] (CEA-Com-
missariat à l’Energie Atomique) patented a
process where the organic precursors are con-
tacted with supercritical CO2 (31–100°C, 300–
500 bar) to form metallic and silicon oxides. A
simple decompression of the reaction mixture
allows separation and recovery of the final
products. Manufacture of particles of various
oxides (titanium, aluminum, magnesium, thal-
lium, silicon, barium, beryllium, and zirco-
nium) is claimed.
4.3. Publications
As shown in Table 4, numerous publications
are related to thermal decomposition.
4.4. Synthesis using supercritical fluid as a
reactant
In this process, supercritical fluid is used as a
solvent and a reactant. The processes described in
 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219 209

Table 5
Compounds synthesized using a supercritical reactant

Substrates (precursor) Supercritical fluid Results and observations References

AlOOH (Al(NO3)3) Water Particle size: 100-600 nm Hexagonal, rhombic or Adschiri, 1992, 1994
needle shape [6,7,11]
CeO2 (Ce(NO3)4) Water Octahedral particles of size: 300 nm Adschiri, 1994 [11] Hakuta,
1997 [21]
Co3O4 (Co(NO3)2) Water Octahedral particles of size: 50 nm Adshiri, 1992, 1994 [6,7,11]
Cr2O3 Water Yoshimura, 1980 [2]
Hirano, 1976 [1]
Cu3N Ammoniac Pessey, 1999 [27]
Fe2O3 (Fe(NO3)3, Water Spherical particles of size: 50 nm Adshiri, 1992, 1994 [6,7,11]
FeCl2 or Fe2(SO4)3)
Fe3O4 Water Spherical particles of size: 50 nm Adshiri, 1992, 1994 [6,7,11]
(Fe(NH4)2
H(C6H5O7)2)
GaN Ammoniac Doradzijnski, 1995 [16]
HfO2 Water Particle size: 20–30 nm Toraya, 1982 [3,4]
LaCrO3 Water Yoshimura, 1980 [2]
Hirano, 1976 [1]
NiO (Ni(NO3)2) Water Rod-like particles of size: 100 nm Adshiri, 1994 [11]
TiO2 (TiSO4 or TiCl4) Water Prismatic particles of size: 20 nm Adshiri, 1992, 1994 [6,7,11]
ZrO2 (ZrOCl2) Water Spherical particles of size: 10 nm Adshiri, 1992, 1994 [6,7,11]

patents and publications generally use supercriti-
cal water; however, supercritical ammoniac is also
reported.
Hydrothermal synthesis has been used for mi-
croparticles or large crystals elaboration:
For large crystals formation, the material is first
dissolved in sub- or supercritical water. Because
of thermal convection, the material moves to
colder regions where a seed allows crystal growth.
This operation can last up to several months for
large crystals (10 cm) formation. Using this pro-
cess, inorganic monocrystals (oxides, sulfides …)
can be prepared at lower temperature than
conventional.
For oxide powders formation, low-cost precur-
sors (oxides, hydroxides or salts...) are first dis-
solved in water, sometimes with ore-forming
agents (halides or alkali hydroxides); and the solu-
tion is introduced into a reactor operated at su-
percritical conditions.
This method has a potential to adjust the direc-
tion of crystal growth, morphology, particle size
and size distribution, because of the controllabil-
ity of thermodynamics and transport properties
by pressure and temperature. In addition, high
reaction rate leads to ultra fine powder formation.
Moreover, this technique avoids crushing and cal-
cination steps used in conventional processes. But
filtration, washing and drying are still necessary,
and corrosion problems associated with supercrit-
ical water have to be considered.
4.5. Patents
“ In 1995, Nissan Chemical Industries [14]
patented a process for fine particles of barium
ferrite formation by heat-treating an aqueous
solution comprising an iron compound, a bar-
ium compound and an alkaline substance. De-
composition of the precursors leads to fine
barium ferrite particles. A more general patent
was filed in 1996 [17] concerning fine metal
oxide particles production using the same
process.
“ Recently, Yamasaki [28] patented a method
and an apparatus for continuous hydrothermal
synthesis. A heated material slurry is mixed
with a sub- or supercritical aqueous liquid and
pulverized, reducing the particle size of the
material slurry, before hydrothermal reaction.
210 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219
4.6. Publications
Table 5 gathers publications concerning
particles production using a supercritical reactant.
References
[1] S. Hirano, S. Somiya. Journal of the American Ceramic
Society, 59 (11 – 12), 1976, 534.
[2] M. Yoshimura, S. Somiya. Am. Ceram. Soc. Bull., 59 (2),
1980, 246.
[3] H. Toraya, M. Yoshimura, S. Somiya. Communications
of the American Ceramic Society, 65 (5), 1982, C –72.
[4] H. Toraya, M. Yoshimura, S. Somiya. Communications
of the American Ceramic Society, 65 (9), 1982, C-159-160.
[5] J. Yamanis, US Patent 4 845 056, 1989.
[6] T. Adshiri, K. Kanazawa, K. Arai. Journal of the Ameri-
can Ceramic Society, 75 (4), 1992, 1019 –1022.
[7] T. Adshiri, K. Kanazawa, K. Arai. Journal of the Ameri-
can Ceramic Society, 75 (9), 1992, 2615 –2618.
[8] M. Barj, J.F. Bocquet, K. Chhor, C. Pommier. Journal of
Materials Science, 27, 1992, 2187.
[9] K. Chhor, J.F. Bocquet, C. Pommier. Materials Chem-
istry and Physics, 32, 1992, 249.
[10] Y. Garrabos, B. Le Neindre, P. Subra, F. Cansell, C.
Pommier. Ann. Chim. Fr, 17, 1992, 55.
[11] T. Adshiri, S. Yamane, S. Onai, K. Arai, Hydrothermal
Synthesis of Metal Oxide Fine Particles in Supercritical
Water. Proceedings of the 3rd International Symposium
on Supercritical Fluids, Tome 3; G. Brunner, M. Perrut
(Eds.), ISBN 2-905-267-23-8, October 17-19, Strasbourg,
1994, 241-247.
[12] A. Lefevre, L. Znaidi, K. Chhor, J.F. Bocquet, C. Pom-
mier. Proceedings of the 3rd International Symposium on
Supercritical Fluids, Tome 3; G. Brunner, M. Perrut
(Eds.), ISBN 2-905-267-23-8, October 17-19, Strasbourg,
1994, 309.
[13] C. Pommier, K. Chhor, J.F. Bocquet. Silicates Industriels,
3 (4), 1994, 141.
[14] K. Arai, T. Ajiri, S. Yuki, I. Ota, US Patent 5 433 878,
1995.
[15] K. Chhor, J.F. Bocquet, C. Pommier. Materials Chem-
istry and Physics, 40, 1995, 63.
[16] R. Doradzijnski, J. Garczynski, L. Sierzputowski. Acta
Physica Polonica A, 88, 1995, 833 –836.
[17] K. Arai, T. Ajiri, US Patent 5 480 630, 1996.
[18] V. Gourinchas-Courtecuisse, J.F. Bocquet, K. Chhor, C.
Pommier. The Journal of Supercritical Fluids, 9, 1996,
222.
[19] M.E. Tadros, C.L.J. Adkins, E.M. Russick, M.P. Young-
man. The Journal of Supercritical Fluids, 9, 1996, 172.
[20] L. Znaidi, K. Chhor, C. Pommier. Mater. Res. Bull., 31,
1996, 1527.
[21] Y. Hakuta, H. Terayama, S. Onai, T. Adshiri, K. Arai,
Hydrothermal Syntesis of CeO2 Fine Particles in Super-
critical Water. The 4th International Symposium on Su-
percritical Fluids, May 11 – 14, Sendai, Japan, 1997,
255 – 258.
[22] S. Sarrade, L. Schrive, C. Guizard, A. Julbe, French
Patent FR9705994, 1997, Patent WO/9800963, 1998.
[23] S. Yin, Y. Fujishiro, S. Uchida, T. Sato, Characterization
of Ceria and Yttria Co-doped Zirconia/Alumina Com-
posites Crystallised in Supercritical Methanol. The 4th
International Symposium on Supercritical Fluids, May
11-14, Sendai, Japan, 1997, 275-278.
[24] L. Znaidi, C. Pommier, A New Process for Nanometric
Chromium(III) Oxide Powder Synthesis in Supercritical
Alcohol. Proceedings of the 5th Meeting on Supercritical
Fluids, Tome 2; M. Perrut, P. Subra (Eds.), ISBN 2-905-
267-28-3, March 23 – 25, Nice, 1998, 913 – 918.
[25] S. Papet, S. Sarrade, A. Julbe, M. Carles, C. Guizard, An
Innovative Method for Ceramic Oxide Synthesis from
Alkoxide Precursors in Supercritical CO2 Media. Proceed-
ings of the 5th Meeting on Supercritical Fluids, Tome 2;
M. Perrut, P. Subra (Eds.), ISBN 2-905-267-28-3, March
23 – 25, Nice, 1998, 855 – 860.
[26] S. Papet, S. Sarrade, A. Julbe, C. Guizard, Titanium
Hydroxide Synthesis in Supercritical Solvent. Proceedings
of the 6th Meeting on Supercritical Fluids, Chemistry and
Materials; M. Poliakoff, M.W. George, S.M. Howdle
(Eds.), ISBN 2-905-267-30-5, April 10 – 13, Nottingham,
1999, 17 – 22.
[27] V. Pessey, R. Garriga, B. Chevalier, J. Etourneau, F.
Weill, F. Cansell, Synthèse et Elaboration de Matériaux
en Milieux Fluides Supercritiques. In Fluides Supercri-
tiques et Matériaux, F. Cansell, M.H. Delville, P. Subra
(Eds.), ISBN 2-905-267-31-3, Juillet 4 – 9, Biarritz, 1999.
[28] N. Yamasaki, T. Mochida, A. Maeda, T. Fukuda, T.
Morimura, US Patent 5 910 298, 1999.
5. Part 5: Composite micro-spheres/capsules
5.1. Introduction
Research, development, and sales of drug-deliv-
ery systems are increasing at a rapid pace
throughout the world. This trend will intensify
along the next decade in the pharmaceutical in-
dustry as lower costs and higher efficiency will be
demanded; many efficient drugs have to be refor-
mulated to allow control of delivery location and
rate, the active substance being distributed di-
rectly to the target to enhance the treatment effi-
ciency and reduce the doses and related
side-effects; this is of particular importance for
 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219 211

long-term treatments (cancer, chronic diseases,

…), vaccination or delivery of very fragile active
drugs as microencapsulation allows to enhance
material stability. Similar objectives are also
aimed in other areas, like agrochemicals, cosmet-
ics, food ingredients, xerocopy or carbonless copy
paper.

5.2. Definition and description of composite Fig. 11. Structure of the different microparticles.
microparticles
Production of microcapsules will be described
Microparticles have a variety of structures (Fig. in the next chapter dealing with particle coating.
11):
“ Particles with irregular geometry, composed of
5.3.1. RESS process (rapid expansion of
an active substance in form of aggregates or
supercritical solution)
molecularly dispersed solid embedded into a
This process is composed of two phases: active
matrix. They are called ‘microspheres’;
substance and carrier extraction with supercritical
“ Particles with spherical geometry, composed of
CO2 and atomization of the supercritical solution.
a core of active substance surrounded by a
This technique is of great interest as an alternative
solid polymeric or proteic shell. They are called
method to conventional size-reduction methods
‘microcapsules’.
and a novel route to solvent-free drug loaded
There is no universally accepted size classifica-
microspheres. But its use is limited because of the
tion of these particles. However, many workers
low solubility of most of the polymers and thera-
classify spheres/capsules smaller than 1 mm as
peutic drugs in supercritical fluids.
nano-spheres/capsules and those larger than 1000
Examples
mm as macro-spheres/capsules. Commercial mi-
“ Debenedetti et al. [2] obtained microparticles
cro-spheres/capsules typically have a diameter be-
by the RESS co-precipitation of a drug (lovas-
tween 3 and 800 mm and contain 10– 90 wt.%
tatin) and a biodegradable polymer (poly(D,
carrier/core. A wide range of materials has been
l-lactic acid) (DL-PLA)).The co-precipitation
embedded/encapsulated, including adhesives,
of the polymer and the drug led to a heteroge-
agrochemicals, live cells, active enzymes,
neous population of microparticles consisting
flavors, fragrances, pharmaceuticals, and inks.
of microspheres containing a single lovastatin
Most carrier/shell materials are natural or syn-
needle, larger spheres containing several
thetic organic polymers, but fats and waxes are
needles, microspheres without protruding
also used.
needles and needles without any polymer
coating.
5.3. Composite microparticles production using
“ Mishima [7,9,17] described the formation of
supercritical fluids
microspheres of flavones and a polymer (Eu-
dragit-100 or PEG 6000) by spraying at atmo-
The three processes previously described can be
spheric pressure, a suspension of flavonoids in
used to produce composite microparticles, rather
a supercritical solution of the polymer and a
microspheres than microcapsules, and liposomes.
co-solvent.
On the other hand, supercritical fluids are unique
vectors of impregnation of porous particles with
substrates as they exhibit a very high diffusivity 5.3.2. PGSS process (particles from gas-saturated
and variable solvent power that permits to carry solutions)
substrate inside pores where it is precipitated by It is possible to form microspheres when a
rapid depressurization. suspension of the active substance into a carrier is
212 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219
saturated by supercritical carbon dioxide prior to
atomization. The main interest of this process is
that it is not necessary that the carrier/polymer
and the active substance are soluble in the super-
critical fluid, what opens wide fields of
applications.
Example: Shine and Gelb [10] recently filed a
patent of a process called polymer liquefaction
using supercritical solvation (PLUSS). The carrier
is a polymer that is saturated with carbon dioxide
under supercritical conditions, causing polymer
swelling and liquefaction at a temperature much
below its glass transition or fusion temp-
erature. The active-carrier mixture is atomized
through a nozzle into a low pressure vessel, lead-
ing to microcapsules, as claimed on the example
of IBDV vaccine inside polycaprolactone (MW
4000).
5.3.3. SAS (supercritical anti-sol6ent) process
An active substance and a carrier dissolved or
suspended in an organic solvent are sprayed to-
gether or separately in an anti-solvent. The anti-
solvent expands the solvent(s) that leads to
microparticles formation.
Examples:
“ Schwarz Pharma patented a process [1] for
microspheres formation in which a solution
containing an active substance and a carrier is
contacted with a supercritical fluid. The result-
ing supercritical solution is depressurised what
leads to particles formation. The patent dis-
closes a number of ways in which the fluids can
be contacted with one another and describes
the formation of particles during or after the
contact step.
“ This technique was used to prepare PLA-mi-
crospheres loaded with 0.1% of clonidine.
“ Elvassore [16] described the formation of
protein-polymer microcapsules by supercritical
anti-solvent techniques. Homogeneous protein/
polymer mixtures were contacted with super-
critical carbon dioxide in order to produce
microspheres with diameter ranging from 1 to
5 mm and containing around 80% of protein.
Different procedures were used to have a better
protein dissolution in the polymer solution (hy-
drophobic ion pairing, protein conjugation to
acylic moieties or solubilization in solvent mix-
tures). Production of PLA microparticles con-
taining insulin, lysozyme and chimotrypsin is
claimed.
“ Chou and Tomasko [8] studied GAS crystal-
lization of a pharmaceutical (naproxen) and a
biodegradable polymer (poly-Lactic acid). The
results from GAS studies showed very small
spherical particles composed of a naproxen
core surrounded by a polymer shell.
“ Pallado [6] described formation of loaded
polysaccharidic micro-/nano-spheres using the
GAS process. Three active principles calci-
tonin, insulin and granulocyte macrophage
colony stimulating factor were embedded in
HYAFF microspheres.
“ Sze Tu et al. [11] used the ASES technique for
the coprecipitation of a model drug, parahy-
droxybenzoic acid (p-HBA) with the
biodegradable polymers, poly(lactide-co-glycol-
ide) (PLGA) and poly(l-lactic acid) (PLA) as
presented on Fig. 12. A multiple nozzle assem-
bly arranged coaxially was designed for the
co-introduction of the drug and polymer solu-
tions (Fig. 13). In this configuration, solutions
are expanded at a much faster rate than in the
conventional ASES process since minute vol-
umes of the solution continually dispersed by
the nozzle suddenly enter a region of high
anti-solvent concentration. The rapid expan-
sion causes the solid to precipitate out of solu-
tion almost instantaneously. In this case,
supercritical fluid is used only for its anti-sol-
vent properties. Coprecipitation of the p-HBA
and PLGA resulted in the formation of p-HBA
particles coated with the polymer microspheres.
The coprecipitation of p-HBA with PLA re-
sulted in the formation of a product where the
drug and polymer were incorporated together
in a fibrous network.
5.3.4. SEDS (solution enhanced dispersion by
supercritical fluids) process
As describer earlier, in this process patented by
the Bradford University [4,5], the supercritical
fluid is used both for its chemical properties and
as ‘spray enhancer’ by mechanical effect. Two
types of nozzles can be used:
 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219 213

Fig. 12. Process flowsheet by Sze Tu et al. [11].

“ A nozzle with two coaxial passages allows to taneously. The methods have drawbacks such
introduce the supercritical fluid and a solution as residual toxic organic solvent and low en-
containing more than one substance to form capsulation efficiency.Frederiksen and al. [3]
micro-spheres/capsules. developed a new method for preparation of
“ A nozzle with three coaxial passages is used to liposomes suitable to encapsulate a water-solu-
introduce three different fluids to form micro- ble substance, where supercritical carbon diox-
spheres/capsules (Fig. 14): supercritical fluid-
solution of a substance 1-solution of a
substance 2.
Hanna et al. described in this patent [4] the
preparation of particles of salmeterol xinafoate
with a polymer matrix. Two separated solutions
of the active substance and the polymer (hydrox-
ypropylcellulose) in acetone were prepared and
co-introduced with supercritical CO2 in a precipi-
tator using a three-passage nozzle. Analyses confi-
rmed the inclusion of the product into the
Fig. 13. Nozzle principle [11].
polymer matrix material.
“ Liposomes: Liposomes are spherical vesicles
consisting of one to several bilayers of phos-
pholipids entirely enclosing an aqueous vol-
ume. Due to their similarity to natural
membranes, and their ability to entrap and
release many substances, liposomes are consid-
ered as useful drug carriers in intravenous ap-
plications. In most existing preparation
methods, the phospholipids are first dissolved
in a organic solvent (diethylether, chloroform,
methanol …) and after various preparation
steps, brought into contact with an aqueous Fig. 14. Schematic representation of a nozzle with three coax-
phase, whereby the liposomes are formed spon- ial process.
214 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219
Fig. 15. Process flowsheet by Frederiksen et al. [3].
ide modified with ethanol replaces the organic
solvents used in other techniques. The 1-palmi-
toyl-2-oleoyl-sn-glycero-3-phosphocholine
(POPC) and cholesterol were dissolved in su-
percritical carbon dioxide modified with etha-
nol.Rapid expansion of the supercritical
solution into an aqueous phase containing a
marker results in the formation of liposomes
encapsulating the marker (Fig. 15). Liposomes
have an average size of approximately 40– 50
nm.In 1998, Ma [12] described a method for
liposoluble medicinal liposome production. Af-
ter dissolution of a phospholipid, cholesterin
and a liposoluble drug in critical or supercriti-
cal carbon dioxide, the pressure is slowly re-
leased until the carbon dioxide density becomes
lower than that of liposoluble drug. The car-
bon dioxide is then quickly released and a
dispersing liquid is loaded into the vessel.
Through immersion and stirring, a liposome
coated with the liposoluble medicine is formed.
“ Powder impregnation: Supercritical fluid-solu-
ble substrates can be easily impregnated inside
porous media as demonstrated by many inves-
tigators using various matrixes like polymers,
wood, paper, … Domingo et al. [15] used this
process to prepare controlled drug delivery sys-
tems. In this work, zeolite, several amorphous
mesoporous inorganic matrices (silica gel, alu-
mina and florisil) and a polymeric matrix (am-
berlite) have been impregnated with various
thermally labile organic compounds (benzoic
acid, salicylic acid, aspirin, triflusal, ketopro-
fen) by diffusion from saturated supercritical
carbon dioxide solutions.It is of special interest
to combine on-line supercritical fluid extraction
and impregnation when extract is difficult to
handle, in form of a very viscous liquid or
pasty solid; this is generally the case when
natural products are processed, leading to ole-
oresins or ‘concretes’, especially for nutraceuti-
cals production that are often finally wished in
form of powder for further incorporation into
tablets. Majewski and Perrut [13] recently
patented a process that is claimed to lead to an
homogeneous distribution of substrate into the
excipient and is illustrated by kava-kava ex-
traction with on-line impregnation of the
kavalactones-rich extract into maltodextrine.
 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219
“ The Concentrated Powder Form technology:
According to Weidner [14], powdery agglomer-
ates with unusual high liquid concentrations of
up to 90 wt.% can be obtained by spraying gas
saturated solutions and admixing a solid car-
rier material with the spray. One function of
the gas, which must be at least partially soluble
in the liquid is to generate small droplets.
These droplets may infiltrate porous substrates
or may agglomerate solid, non-porous materi-
als. Infiltration and agglomeration is promoted
by the expanding gas which causes an intensive
mixing between liquid and solid substrate. The
formed powders are then separated by sedi-
mentation, centrifugal forces or filters. A basic
flow scheme of a continuously operated plant is
given in Fig. 16.The powder formation and
liquid loading was tested for several combina-
tions of liquids (extracts of celery, oregano,
laurel, pepper, ginger, nutmeg, basil, tumeric,
paprika, rosemary, lemon oil, strawberry
aroma, cheese aroma, butter fat, a-tocopherol,
whiskey and vinegar) and solid carriers (silica,
maize starch, waxy maize starch, potato starch,
cellulose, maltodextrin, powdered spices, citric
Fig. 16. Flow scheme of the CPF-process [14].
215
acid, powdered sugar, titanium dioxide, sodium
chloride, polymers and emulsifiers).
References
[1] W. Fischer, B. Müller, Patent EP 0 322 687, 17 December,
1988.
[2] P. Debenedetti, J.W. Tom, S.D. Yeo, G.B. Lim, Applica-
tion of Supercritical Fluids for the Production of Sus-
tained Delivery Devices. Journal of Controlled Release,
24, 1993, 27 – 44.
[3] L. Frederiksen, K. Anton, B.J. Barrat, P. Van Hoogevest,
H. Leuenberger. Proceedings of the 3rd International
Symposium on Supercritical Fluids, Tome 3; G. Brunner,
M. Perrut (Eds.), ISBN 2-905-267-23-8, 17 – 19 October,
Strasbourg, 1994, 235 – 240.
[4] M. Hanna, P. York, Patent WO 95/01221, 1994.
[5] M. Hanna, P. York, Patent WO 96/00610, 1995.
[6] K. Mishima, S. Yamaguchi, H. Umemoto, Patent JP
8-104830, 1996.
[7] P. Pallado, L. Benedetti, L. Callegaro, Patent WO 96/
29998, 1996.
[8] Y. Chou, D. Tomasko. The 4th International Symposium
on Supercritical Fluids, 11-14 May, Sendai, Japan, 1997,
55 – 57.
[9] K. Mishima, K. Matsuyama, H. Uchiyama, M. Ide,
Microcoating of Flavone and 3-Hydroxyflavone with
Polymer Using Supercritical Carbon Dioxide. The 4th
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International Symposium on Supercritical Fluids, 11 – 14
May, Sendai (Japan), 1997, 267 – 270.
[10] A. Shine, J. Gelb, Patent WO 98/15348, 1 October, 1997.
[11] L. Sze Tu, F. Dehghani, A.K. Dillow, N.R. Foster.
Proceedings of the 5th Meeting on Supercritical Fluids,
Tome L., M. Perrut, P. Subra (Eds.), ISBN 2-905-267-28-
3, 23 – 25 March, Nice, 1998, 263 –270.
[12] S. Ma (Dalian Medicine Inst.), Patent CN 1221607, 1998.
[13] W. Majewski, M. Perrut, Patent FR 99.12005, 27 Septem-
ber, 1999.
[14] E. Weidner, Powder Generation by high pressure Spray
Processes. GVC-Fachausschub ‘High Pressure Chemical
Engineering’, 3 – 5 March, Karlsruhe (Germany), 1999,
225-230.
[15] C. Domingo, J. Garcia-Carmona, J. Llibre, R. Rodriguez-
Clemente, Impregnation of porous supports by solute
diffusion from SC-CO2. A way of preparing controlled
drug delivery systems. Proceedings of the 6th Meeting on
Supercritical Fluids, Chemistry and Materials; M. Poli-
akoff, M.W. George, S.M. Howdle (Eds.), ISBN 2 –905-
267-30-5, 10 – 13 April, Nottingham, 1999, 101 – 107.
[16] N. Elvassore, A. Bertucco, P. Caliceti, Production of
Protein-Polymer Micro-Capsules by Supercritical Anti-
Solvent Techniques. Proceedings of the 5th International
Symposium on Supercritical Fluids, 8 –12 April, Atlanta
(USA), 2000.
[17] K. Mishima, K. Matsuyama, S. Yamauchi, H. Izumi, D.
Furudono, Novel Control of Crystallinity and Coating
Thickness of Polymeric Microcapsules of Medicine by
Cosolvency of Supercritical Solution. Proceedings of the
5th International Symposium on Supercritical Fluids, 8 –
12 April, Atlanta (USA), 2000.
6. Part 6: Particle coating
Supercritical carbon dioxide can be used to coat
particles of active substance, which have the de-
sired size, with a coating agent. Several
processes are under investigation and develop-
ment, depending on the size of the particles
(nano-particles to tablets) and nature of the coat-
ing. The precipitation methods previously de-
scribed (RESS, SAS, PGSS and thermal
degradation) can be used for particle coating;
however, RESS can only be used when the coat-
ing is soluble in the supercritical fluid. It is to be
noticed that an organic solvent is introduced
when SAS is employed and may lead to presence
of residual solvent in the tablets and VOC emis-
sion; and PGSS is not always possible, depending
on the interactions coating-fluid and fusion tem-
perature of the coating.
6.1. Tablets coating
“ Ciba-Geigy [1] patented a process for tablets
coating using supercritical fluid. In fact, the
tablets are coated by classical means, using a
solution of coating agent in an organic solvent,
and then subjected to extraction with a super-
critical fluid leading to tablets with a residual
solvent content of 0.01–0.001% by weight.
However, this method is not generally applica-
ble as the active component may be extracted
or altered during this solvent stripping.
“ Separex is presently developing a process
derived from classical coating equipment in
order to avoid organic solvent use and to re-
duce coating duration. This process, according
to a pending patent [12], is founded on the
pulverization of the coating agent(s) suspension
into a supercritical fluid.
6.2. Particles coating
The precipitation methods previously described
(RESS, SAS, PGSS and thermal decomposition)
can be used for particle coating, and most
processes are derived from the Wurster process
where coating agent is atomized onto fluidized
particles:
“ Subramaniam et al. [2] patented a special case
of ASES process for spraying the coating solu-
tion into the supercritical fluid so as to gener-
ate high frequency anti-solvent sonic waves.
According to the described implementation, the
solution of the coating agent is sprayed with a
specific system into a closed precipitation vessel
containing the anti-solvent. Simultaneously, a
turbulent fluidized flow of the core particles is
created within the precipitation vessel. Condi-
tions are maintained so that the anti-solvent
rapidly depletes the solvent and precipitates the
coating agent on the core material.
“ Kobe Steel Ltd. [3] patented a process related
to the RESS concept for microparticles forma-
tion and coating. Primary microparticles are
formed by rapid decompression of a supercriti-
cal solution of the core material. These parti-
cles are mixed with a supercritical solution of
the coating agent and depressurized to form
 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219
microcapsules. Coating with multiple layers
can be achieved using this process. Applica-
tions of this process are limited as the core
material and the coating agent have to be
soluble in a supercritical fluid.
“ Krause et al. [5,6] patented a process for the
application of a coating agent dissolved in
supercritical fluid onto fine substrate particles
(of diameter less than 100 mm) moving in a
fluidized bed. Very smooth and regular coat-
ings can be achieved with this process related
to RESS concept.
“ Sunol [4,7] used a different process for coating
polymeric thin films on particles. The method
involves a recirculation system that includes
dissolution of the polymer into the supercritical
solvent and coating the particles through a
temperature swing operation in the fluidized
bed of particles. This system has been tested
with hydroxyl-terminated polybutadiene
(HTTB) as coating polymer and particles of
salt (30– 500 mm). The film thickness was as
low as 0.2 mm.
“ The Centre de Microencapsulation d’Angers,
now called Mainelab (France) patented two
processes [8– 10]:
1. In the first method, [8,10] the coating agent
is solubilised into supercritical carbon diox-
ide. In a stirred vessel, active substance
particles are dispersed into the supercritical
solution. By changing the pressure and the
temperature, the solubility of the coating
agent in the supercritical fluid can be re-
duced so that it can precipitate on the parti-
cles. Microcapsules of active substance are
collected after depressurization. This pro-
cess allows to have a good control of the
structure (composition, thickness) of the
microcapsule without using organic sol-
vents. This process was used to encapsulate
substances such as: dyes, antibiotics, vita-
mins, proteins. Coating agents must be sol-
uble in supercritical carbon dioxide such as
waxes, glycerides, alcohols, fatty acids and
esters.
2. The second method [9] used a suspension of
active substance in a solution of a slightly
polar polymer (insoluble in liquid or super-
217
critical -carbon dioxide) in an organic sol-
vent. This suspension is contacted with
supercritical carbon dioxide so that the or-
ganic solvent is solubilized in such a man-
ner that there is coacervation of the coating
polymer onto the particles. Microcapsules
are collected after decompression.
These techniques, proven at lab-scale, are inter-
esting even if extrapolation to industrial-scale re-
mains to be demonstrated.
“ Wakayama [13] developed in 1999 a coating
process in which a supercritical solution of a
reaction precursor is brought into contact with
a substrate in the presence with a reaction
initiator. The reaction between the precursor
and the initiator leads to the formation of a
coating product onto the substrate.
“ More recently, Pessey et al. [11] (ICMCB-Insti-
tut de Chimie de la Matière Condensée de
Bordeaux) patented a process for surfaces coat-
ing including particles coating. ‘Core-shell’
structures production is claimed. The supercrit-
ical fluid is introduced in the high-pressure cell
containing the coating material and the parti-
cles. Pressure and temperature are regulated to
obtain thermal decomposition of the coating
material. The coated powder is then collected
after decompression and temperature decrease
of the system. Coating of nickel particles (di-
ameter, 5 mm) with copper is described. Coat-
ing of permanent magnet SmCo5 with copper
using the same method is further described
[14].
References
[1] L.T. Heit, J.M. Clevenger, Patent EP 0 412 053, 1991.
[2] B. Subramanian, S. Said, R.A. Rajewski, V. Stella, Patent
WO 97/31691, 1997.
[3] Kobe Steel Ltd, Patent J 05057166, 1993.
[4] A.K. Sunol, Patent US 0062332, 1997.
[5] H. Krause, M. Niehaus, U. Teipel, Patent DE 19711393,
1998.
[6] M. Niehaus, U. Teipel, H. Krause, W. Weisweiler, Coat-
ing of Particles in a Fluidized Bed using Supercritical
Carbon Dioxide. Proceedings of the 5th Meeting on
Supercritical Fluids, Tome 1; M. Perrut, P. Subra (Eds.),
International Society for the Advancement of Supercriti-
cal Fluids, 23 – 25 March, Nice, 1998, 361 – 367.
218 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219

Table 6
Generation of mono-constituent particles

Substrate is substantially soluble in Available Advantages Drawbacks

supercritical fluid process

Yes RESS Particle size monitoring Low solubility of most complex

(sub-micronic and micronic
particles)
No organic solvent use
Thermal Ultrafine particles
degradation
No organic solvent use
No Anti-solvent Particle size monitoring
(sub-micronic and micronic
particles)
PGSS Low fluid consumption
Low to medium pressure
Small volume of pressurized
equipment
molecules
High fluid consumption
Only used for metal, silicon and
metal oxides
Organic solvent use
Difficult fluid/solvent separation
and fluid recycling
Medium to large volume of
pressurized equipment
Impossible to produce
sub-micronic particles and to
monitor particles size

[7] A.K. Sunol, J. Kosky, M. Murphy, E. Hansen, J. Jones,
B. Mierau, S. Sunol, Supercritical Fluid Aided Encapsula-
tion of Particles in a Fluidized Bed Environment. Pro-
ceedings of the 5th Meeting on Supercritical Fluids, Tome
1; M. Perrut, P. Subra (Eds.), International Society for
the Advancement of Supercritical Fluids, 23 –25 March,
Nice, 1998,409 – 412.
[8] J.P. Benoit, H. Rolland, C. Thies, V. Van de Velde, Patent
EP 0 706 821, 1996, WO 96/11055, 1996.
[9] J.P. Benoit, J. Richard, C. Thies, Patent FR 2 753 639,
1996, WO 96/13136, 1998.
[10] J. Richard, C. Thies, V. Gajan, J.P. Benoit, A Novel
Solvent-Free Process to Prepare Drug Delivery Systems,
Paper for Club Hétérochimie CRIV, Paris, 14 October,
1998.
[11] V. Pessey, F. Cansell, B. Chevalier, F. Weill, J. Etourneau,
French Patent FR 9904175, 1999.
[12] Sanofi, Pending patent, 1999.
[13] H. Wakayama, Patent WO 99 10167, 1999.
[14] V. Pessey, R. Garriga, F. Weill, B. Chevalier, J.
Etourneau, F. Cansell, Core-Shell Materials Elaboration
in Supercritical Media. Proceedings of the 5th Interna-
tional Symposium on Supercritical Fluids, 8 –12 April,
Atlanta (USA), 2000.
7. Conclusion: how to choose a process of particle
design?
From this literature review, the reader may be
puzzled by the process variety and complexity,
and need some help to optimize the route to the
desired particles. Even if this may be subjected to
criticism, we would try to summarize the problem
in Table 6 for mono-constituent particles produc-
tion and Table 7 for composite particles produc-
tion, with advantages and drawbacks of each
technique.
To choose a process for particle design, the first
thing to consider is the solubility of the substrate
and, when used, of the matrix, in the supercritical
fluid. The choice between different methods will
then be made considering the desired particle size,
shape and structure, processing costs and produc-
tion scale. For particle generation, RESS applica-
tion must be considered at first, even if substrate
 J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219 219

Table 7
Formation of composite microparticles

Substrate Matrix Available process Type of Remarks

solubility solubility particles
produced

Yes Yes RESS Microspheres Particle size monitoring Very few

substrates and coatings are both
soluble in supercritical fluids
Yes No Supercritical impregnation Microspheres No change in particle geometry. Can
be operated on-line downward
extraction at large scale
No Yes Liposomes-RESS process Liposomes
RESS Fluidized-bed coating Microcapsules Very few coatings are soluble in
supercritical fluids
Polymer coacervation onto Microcapsules Impossible to apply at large scale
substrate particles
Coating using thermal Microcapsules Dedicated to metal precursors
decomposition
No No Anti-solvent processes (GAS, Microspheres Many types of nozzles available for
ASES, SEDS) or particle size and shape monitoring Use
microcapsules of organic solvent(s) Difficult organic
solvent/ fluid separation
Anti-solvent Fluidized-bed Microcapsules Difficult solvent/ fluid separation
.
coating
PGSS process Microspheres ‘Large’ particles generation Large scale
development
CPF process Microspheres Continuous process that can be
operated at large scale

(and matrix) solubility is very often too low to
lead to a profitable process. Then, anti-solvent
processes are to be considered especially for phar-
maceutical applications as they allow to control
particle size, shape and structure on a very wide
range from nano-particles to micro-particles or
spheres, even if they lead to high processing costs
and are difficult to operate at large scale, mean-
while PGSS processes should be preferred for
larger particles and lower-value material.
It also appears from this review that industrial
property is complex with many patents pending,
in spite of many anterior published works. This
may refrain many companies to use these very
promising techniques that offer new exciting
solutions.
We would not conclude this work without
stressing on the difficulties of particle harvesting
and handling downward the formation process, as
it would be of no interest to generate particles if
collection is not possible in conditions where they
are needed: in most cases as a dry powder, in few
cases in form of a suspension in a liquid in which
they are totally insoluble. This is a difficult chal-
lenge in most cases!
Acknowledgements
The authors thank Professors Gerd Brunner,
Ernesto Reverchon and Robert Sievers for fruitful
discussions about this work and the European
Union for financial support (Brite-Euram pro-
gramme BRPR-CT98-0765).