1 nanoparticles production by supercritical antisolvent precipitation una interpretacion general
TRANSCRIPT
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J. of Supercritical Fluids 43 (2007) 126138
Nanoparticles production by supercritical antisolventprecipitation: A general interpretation
Ernesto Reverchon , Iolanda De Marco, Enza Torino
Universita degli Studi di Salerno, Dipartimento di Ingegneria Chimica e Alimentare, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy
Received 19 December 2006; received in revised form 11 April 2007; accepted 30 April 2007
Abstract
Supercritical antisolvent micronization (SAS) has been used to obtain microparticles of several kind of materials, but the production of nanopar-
ticles have been observed and studied in some cases only. This work is focused on the systematic production of nanoparticles using SAS. Weperformed experiments on several compounds and different solvents at selected operating conditions, obtaining nanoparticles with mean diameters
ranging between 45 and 150 nm, thus demonstrating that nanoparticles production is a general characteristic of this process. Moreover, we found
a correlation between nanoparticles mean diameter and the reduced concentration of the starting liquid solution that can allow the prediction of
the mean diameter obtainable at fixed process conditions. Nanoparticles with mean diameters as small as 45 nm have been obtained, operating
at 150 bar, 40 C and xCO2 = 0.97; but, even smaller nanoparticles can be obtained operating at higher pressures. The mechanism that produces
nanoparticles in supercritical antisolvent precipitation has also been discussed.
2007 Elsevier B.V. All rights reserved.
Keywords: Nanoparticles; Supercritical antisolvent precipitation; Drugs; Catalysts precursors; Colouring matters; Polymers
1. Introduction
Some supercritical fluidsbased processeshave beenproposed
in the literature to produce micro and/or nanosized materials;
they all try to take advantage of the specific characteristics of flu-
ids at supercritical conditions, like the adjustable solvent power
and the gas-like diffusivity [19]. Among them, Supercritical
AntiSolvent (SAS) process is well known and has been used to
micronizeor to attempt themicronization of severalkind of com-
pounds [1,2]. SAS is also known with other acronyms: Aerosol
Solvent Extraction System (ASES), Solution Enhanced Disper-
sion by Supercritical fluids (SEDS), Supercritical AntiSolvent
with Enhanced Mass transfer (SAS-EM). The main difference
among these processes is in theinjection device: in thecase of the
SAS and ASES processes, the liquid solution is sprayed in the
precipitation chamber through a thin wall nozzle, in the case of
the SEDS process, the nozzle is coaxial; whereas, the SAS-EM
process utilizes a deflecting surface that vibrates at ultrasonic
frequencies to enhance the atomization of the solution.
Corresponding author. Fax: +39 089 964057.
E-mail address: [email protected](E. Reverchon).
The scientific literature shows that SAS treated materials
can range from nanoparticles to microparticles to large emptyparticles (balloons) [15]. The products can be amorphous or
semi-crystalline; but, crystalline particulates have also been
reported [1,2]. Most of the SAS produced powders range in the
micron-size region that has been the target of several studies:
many industrial applications require these particle dimensions
to obtainthe best process performance.For example, small parti-
cles in the 15m range with a narrow particle size distribution
are needed for applicationsin pulmonary delivery andcontrolled
release systems [10,11].
The production of nanoparticles is even more ambitious than
producing microparticles of controlled dimensions. Even the
definition of nanoparticles is debated; depending on the specific
field of interest of the various authors, more or less restric-
tive definitions have been proposed. Recently, Reverchon and
Adami [6], reviewing nanotechnological applications of super-
critical fluids, discussed the various nanoparticles definitions
and selected 200 nm as the maximum dimension for the defini-
tion of nanoparticles.
At nanodimensions, it is possible to produce explosives with
a higher potential; i.e., approaching the ideal detonation; colour-
ing matter with brighter colours; toners with a higher resolution;
polymers and biopolymers with improved functional and struc-
0896-8446/$ see front matter 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.supflu.2007.04.013
mailto:[email protected]://localhost/var/www/apps/conversion/tmp/scratch_2/dx.doi.org/10.1016/j.supflu.2007.04.013http://localhost/var/www/apps/conversion/tmp/scratch_2/dx.doi.org/10.1016/j.supflu.2007.04.013mailto:[email protected] -
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E. Reverchon et al. / J. of Supercritical Fluids 43 (2007) 126138 127
tural properties; drugs with enhanced pharmaceutical activity or
that use different delivery routes and/or overcome human body
internal barriers. Metals, metal oxides and ceramic compounds
at nanodimensions can exhibit unusual strength and/or can be
used as fillers in nanostructured materials [6].
Thermolabile compounds are even more difficult to be pro-
cessed at nanodimensions; but, they can be obtained at mild
temperatures (3550 C) using SAS [15]. However, nanoparti-
cles haveonly been occasionallyfacedby theauthors that studied
this process. Reverchon et al. [1218] obtained nanometricparti-
cles of different compounds. For example, yttrium, gadolinium,
europium, samarium and neodymium acetates, that are precur-
sors of high temperature superconductors, were micronized and
the mean diameters of the obtained nanoparticles was of about
100 nm [1214]. Nanoparticles of zinc acetate, a catalyst precur-
sor, were also produced by SAS. Particles down to 30 nm, with a
mean diameter of 50 nm,were obtained at thebest operatingcon-
ditions [15]. Some pigments were also produced using dimethyl
sulfoxide (DMSO) and N-methyl 2-pyrrolidone (NMP) as the
liquid solvents: Disperse Red 60 nanoparticles, for example, atthe best operating conditions, reached a mean diameter of 50 nm
[16]. Wu et al. [19] micronized pigment Red 177 by precipita-
tion from DMSO and analyzed the influence of several process
parameters on particle size. Spherical nanoparticles down to
46 nm mean diameter were obtained, operating at 120 bar and
50 C. Tetracycline, an antibiotic, is an example of pharmaceuti-
cal compounds processed at nanodimensions; the mean particle
size was about 150 nm [17]. Chattopadhyay and Gupta [20]
SAS precipitated Fullerene (C60) nanoparticles from a toluene
solution. The experiments were performed operating in a SAS
batch mode and fullerene particles as small as 2963 nm were
obtained.Chattopadhyayet al. [21,22] used the SAS-EM processto produce Griseofulvin (antifungal, antibiotic) particles as low
as 130 nm and Lysozyme (enzyme) particles of about 190 nm.
Nanometric Lysozyme particles with a minimum mean diameter
of 180 nm were also produced, at the best operating conditions,
by Muhrer and Mazzotti [23], using GAS process. Snavely et al.
[24] produced Insulin (antidiabetic) nanoparticles by SAS with
the aid of an ultrasonic nozzle. They obtained a powder consist-
ing of physical aggregates of 50 nm spheres forming sponge-like
and cob-web-like structures that could be deagglomerated in
smaller units. Nanoparticles of some polymers and biopolymers
were also obtained: in the case of dextran, the particles showed
a mean diameter ranging between 125 and 150 nm [18]. Subra
and Jestin [25] obtained dextran particles with a mean diameterof 70 nm. Jarmer et al. [26] successfully produced nanoparticles
of polylactic acid (PLLA) with a semi-continuous antisolvent
process, injecting the solvent in a jet-swirl nozzle, designed to
enhance the mixing within a swirl chamber. Chang et al. [27]
consistently produced nanoparticles of metallocene catalyzed
cyclic olefincopolymer (mCOC), investigatingthe effect of SAS
process parameters on morphology and size of precipitated par-
ticles. These authors concluded that, when SAS was operated in
the supercritical region, nanoparticles of mCOC were produced.
From this analysis, we can conclude that, despite the indus-
trial interest, only a relatively small number of SAS works have
beenfocused on the productionof nanoparticles.Moreover, indi-
cations about the SAS process conditions required to obtain
nanoparticles and about the mechanisms that produce powders
with these characteristics are generally missing or connected
to the single experimentation presented and to the processed
material.
To contribute at a better knowledge of SAS applicability to
nanosizedmaterials, thescope of this work is to demonstrate that
the capability of producing nanoparticles is a general feature of
the SAS process and that it is possible to describe conditions of
theSAS parameters at which nanoparticles of controlled size and
distributions can be obtained. Literature data together with an
extensive SAS experimentation have been performed to assess
the possibility of obtaining general validity rules for nanoparti-
cles production. The mechanism that can produce nanoparticles
during SAS has also been investigated.
2. Materials, apparatus and methods
2.1. Materials
Yttrium, zinc, europium, gadolinium, samarium and neodim-
ium acetates, rifampicin, astemizole, nitrotriazole and polyvinyl
alcohol (PVA) were supplied by SigmaAldrich (Italy) and
have purities of 99.9%; cellulose acetate was kindly supplied
by British & American Tobacco (USA); Amoxicillin, Dextran-
40, Hyaluronic benzyl ester (HYAFF 11) and ampicillin were
bought by ICN Biochemicals (USA) and have purities higher
than 98%; N-(2-hydroxypropyl)methacrylamide (HPMA) was
produced at the University of Paris XIII [18]; Disperse Red 60,
Solvent Yellow 56 and Solvent Blue 35 (purities 99.9%) were
supplied by Sun Chemicals (USA); Inulin was kindly supplied
by Orafti (Belgium).Dimethyl sulfoxide (DMSO, purity 99.5%), Acetone (Ac,
purity 99.8%), N-methyl 2-pyrrolidone (NMP, purity 99.5%),
methyl alcohol (MeOH, purity 99.5%), ethyl acetate (EtAc,
purity 99.5%) and dichloromethane (DCM, purity 99.5%) were
supplied by SigmaAldrich (Italy). CO2 (purity 99%) was pur-
chased from SON (Italy).
The solubilities of the materials in the solvents used were
measured at room temperature and are reported in the third
column ofTable 1 . All materials were used as received.
2.2. Apparatus
The SAS laboratory apparatus we used consists of an HPLCpump equipped with a pulse dampener (Gilson, mod. 805) used
to deliver the liquid solution, and a diaphragm high-pressure
pump (Milton Roy, mod. Milroyal B) used to deliver supercriti-
cal CO2. A cylindrical vessel with an internal volume of 500 cm3
is used as the precipitation chamber. The liquid mixture is deliv-
ered to the precipitator, for most experiments, through a thin
wall 800m length and 200m diameter stainless steel nozzle;
but, also a 80m nozzle has been used [28]. A second col-
lection chamber located downstream the precipitator is used to
recover the liquid solvent. Further information have been given
elsewhere [12] and a schematic representation of the appara-
tus has been reported in Fig. 1. Typical liquid solution flow rates
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128 E. Reverchon et al. / J. of Supercritical Fluids 43 (2007) 126138
Table 1
Mean diameters of the particles obtained by SAS at 150 bar, 40 C, xCO2 0.97
Solute Solvent Solubility (mg/mL) C(mg/mL) C/C0 d(nm) Mode (nm) S.D. (nm)
Yttrium Acetate (YAc) [12,14] DMSO 303
5 0.016 50 44 20
10 0.033 70 67 20
13.5 0.044 82 73 21
36 0.118 120 110 30
Europium Acetate (EuAc) [13] DMSO 59810 0.016 60 70 54
100 0.16 150 200 25
Gadolinium Acetate (GdAc) [13] DMSO 318
5 0.015 55 53 13
10 0.031 65 81 15
13 0.047 75 70 18
20 0.062 90 108 60
32 0.100 125 109 59
48 0.150 150 200 82
Samarium Acetate (SmAc) [12] DMSO 213
2 0.009 47 50 25
8 0.023 80 120 50
11 0.051 90 104 70
17.5 0.082 110 95 37
22 0.103 120 105 43
26 0.154 130 140 25
Neodimium Acetate (NdAc) [12] DMSO 202 5 0.024 67 65 11
Zinc Acetate (ZnAc) [15]DMSO (1) 530
5 0.0094 45 30 25
10 0.018 60 51 24
15 0.028 75 60 30
50 0.094 110 100 30
75 0.14 150 155 33
NMP (2) 478 10 0.016 55 55 20
Cellulose Acetate (Cell Ac) Ac 93 10 0.107 125 160 65
Nitrotriazole (NTO) DMSO 450 20 0.044 65 65 11
Rifampicin (Rifa) [30]
DMSO (1) 1223 0.024 70 70 83
10 0.081 115 105 90
MeOH (2) 273 10 0.044 60 55 30
EtAc (3) 120 5 0.041 70 60 33
DCM (4) 60 5 0.083 100 120 50
Amoxicillin (Amoxi) [17,31,35] NMP 195 20 0.102 118 150 72
Astemizole (Aste) DMSO 1105 0.045 95 80 45
10 0.090 115 105 48
Ampicillin (Ampi) [17] DMSO 480 15 0.031 45 100 60
Inulin (Inul) [18] DMSO 335 25 0.075 100 140 47
Dextran 40 (Dext 40) [18] DMSO 147
2.5 0.017 50 110 60
5 0.034 65 55 42
10 0.068 95 80 37
15 0.102 125 140 23
HYAFF 11 DMSO 247 10 0.04 95 85 53
PVA DMSO 236 10 0.042 60 75 30HPMA [18] DMSO 250 10 0.04 85 80 37
Disperse Red 60 (DR60) [16]
DMSO (1) 180
5 0.027 58 47 26
10 0.055 88 80 29
15 0.083 102 90 53
NMP (2) 150
5 0.033 93 85 53
10 0.066 105 60 30
15 0.1 112 97 57
Ac (3) 100 10 0.1 100 104 70
Solvent yellow 56 (SY56)NMP (1) 345 20 0.057 70 60 17
Ac (2) 207 20 0.096 115 99 38
Solvent Blue 35 (SB35)NMP (1) 90 5 0.055 70 75 21
Ac (2) 90 5 0.055 70 60 27
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E. Reverchon et al. / J. of Supercritical Fluids 43 (2007) 126138 129
Table 1 (continued)
Solute Solvent Solubility (mg/mL) C(mg/mL) C/C0 d(nm) Mode (nm) S.D. (nm)
mCOCa [27]
Toluene (1) 435b
2.175 0.005 41.1 41.1 4.8
4.35 0.01 46.2 46.2 7.6
8.7 0.02 47.9 47.9 9.4
17.4 0.04 62.8 62.8 8.9
o-Xylene (2) 574b 5.74 0.01 50.3
m-Xylene (3) 574b 5.74 0.01 52.8 p-Xylene (4) 574b 5.74 0.01 53.5
THF (5) 440b 4.40 0.01 42.5
a For this data, the xCO2 is equal to 0.94.b Private communication.
rangedbetween 0.5 and2.0 mL/min andSC-CO2 flow rates were
correspondingly adapted to produce a XCO2 0.97. In each
experiment, liquid solvent was injected first, to obtain steady
state fluid phase concentration conditions in the precipitator;
then, the solution was delivered in quantities ranging from 50 to
about 300 mL, depending on the scope of the experiments and
on the quantity of powder that we want to collect.
The view cell SAS apparatus is similar to the previously
described one and differs only for the precipitator, that con-
sists of a stainless steel cylindrical vessel (375 cm3 i.v.) with
two quartz windows put along two longitudinal sections (NWA,
Germany). It is possible to visually observe the formation of
different phases and the macroscopic evolution of the precipita-
tion process from the liquid jet break-up to the precipitation of
particles [29,30].
The pilot plant used in this study is a closed-loop plant con-
sisting mainly of a CO2 storage vessel, a precipitator, a liquid
separator, two pumps, a heat exchanger, and a condenser. The
water-jacketed precipitator has an internal volume of 5.2 dm3
and a L/D ratio of 9.4. The liquid solution and SC-CO2 are fed
to the chamber through a tube-in-tube injection system (inter-
nal tube d= 3 mm; annulus d= 8.5 mm). The generation of small
liquid droplets is ensured by the presence of a 500-m nozzle
fitted on the tip of the internal tube [31]. A more detailed descrip-
tion of the pilot plant can be found in previous works [14,31]; a
photograph of the plant is reported in Fig. 2.
2.3. Methods
Samples of the precipitated powder, collected in different
points of the precipitation chamber, were observed using a Scan-
ning Electron Microscope (SEM) (Assing, mod. LEO 420).
SEM samples were covered with 250 A of gold using a sput-
ter coater (Agar, mod. 108A). Particle size (PS) and particle size
distributions (PSDs) were measured usingan imageanalysisper-
formed using Sigma Scan Pro software (Jandel Scientific), an
image processing program that counts, measures and analyzes
digital images; from about 700to 1000 particleswere considered
Fig. 1. Schematic representation of SAS apparatus: S1, CO2 supply; S2, liquid supply; B, refrigerating bath; P1P2, pumps; D, pressure dampener; CS, precipitation
vessel; M, manometer; TC, thermocouple; VM, micrometering valve; SL, liquid separator; BP, back-pressure valve; A, calibrated rotameter; CR, wet test meter.
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130 E. Reverchon et al. / J. of Supercritical Fluids 43 (2007) 126138
Fig. 2. SAS pilot plant located at the University of Salerno.
in each PSD calculation. The number of particles was chosen
in agreement with the criteria used in the image analyses of
powders: 5001500 measured particles represent a good com-
promise between the time spent for the analysis and the accuracy
of results [32].
X-ray diffraction pattern (XRD) analyses were performed
using a Rigaku mod. RINT RAPID XRD apparatus to ascertain
if changes occurred in the crystal habit of the materials as a
consequence of the SAS process.
A SAS experiment begins by delivering supercritical CO2 tothe precipitation chamber until the desired pressure is reached.
Antisolvent steady flow is established; then, pure solvent is sent
through the nozzle to the chamber with the aim of obtaining
steady state composition conditions during the solute precipita-
tion. At this point, the flow of the liquid solvent is stopped and
the liquid solution is delivered through the nozzle. The experi-
ment ends when thedelivery of theliquidsolutionto thechamber
is interrupted. However, supercritical CO2 continues to flow to
wash the chamber for the residual content of liquid solubilized
in the supercritical antisolvent. If the final purge with pure CO2is not performed, the solvent condenses during the depressur-
ization and can solubilize or modify the powder. More details
have been given elsewhere [12].
3. Results and discussion
3.1. Conditions for successful SAS micronization
The prerequisites for successful SAS process are the com-
plete miscibility between the liquid solvent and the antisolvent
and the insolubility of the solute in the antisolvent (or, rather,
in the solution solventantisolvent formed in the precipitator).
Considering the binary system solventantisolvent, this condi-
tion is obtained at pressures larger than the mixture critical point
(MCP); it represents, in a pressure-composition plane at a fixed
temperature, the pressure at which only a single supercritical
phase can exist. However, it should be also considered that the
presence of a solute can modify the binary system vaporliquid
equilibria (VLEs), as a rule, moving the MCP of the ternary sys-
tem towards higher pressures than for the corresponding binary
one [16,29,33]. If the ternary system shows poorer solubility
when compared with the binary systems antisolvent + solvent
and antisolvent + solute, it is called non-cosolvency(antisolvent)
system [33]. The VLEs of a binary system and their hypothe-sized modifications due to the addition of a third component are
reported in Fig. 3.
Fig. 3. A possible qualitative modification of the VLEs of a binary (solid line)
system, when a third component (Z) is added (dotted line) at a given concentra-
tion.
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Fig. 4. Experimental data for the binary system DMSOCO2 andfor theternary
system CefonicidDMSOCO2 in a pressure vs. CO2 molar fraction diagram.
VLEs modifications can be enhanced as the concentration
of the solute increases. Therefore, in the selection of the SAS
operating conditions, it could be not possible to consider that
the MCP of the ternary system is coincident to the one of the
binary system, except from the cases in which the concentration
of the liquid solution is very low. For example, in the case of the
system CefonicidDMSOCO2, we observed experimentally,
with a view cell, that VLEs of the system at low concentra-
tions are substantially the same of the binary one; whereas, at
higher concentrations, the VLEs change (see Fig. 4) [34]. In
SAS experiments performed using windowed precipitator, we
observed that the ternary system could be at subcritical condi-tions even when the corresponding liquidCO2 binary system is
supercritical.
For these reasons, it should be advisable to select pressure
relatively higher than the MCP pressure of the binary system, to
avoid the risk of working at subcritical conditions.
An initial analysis of the literature data on SAS process con-
ditions, at which it is possible to produce nanoparticles, allows to
approximately indicate following ranges: pressures between 120
and 180 bar and temperatures between 35 and 60 C [1218,27].
These operating conditions should assure that we work at super-
critical conditions at least for the binary solventantisolvent
system. Since we have several previous data on tests performed
at 150 bar, 40 C, the following experimentation has been ini-
tially performed at these process conditions; xCO2 = 0.97 has
been also selected to operate on the right of the MCP.
The new experimental results are in part obtained for com-
pounds different from those previously published; however, we
also performed some new experiments on materials that were
previously published, with the scope of producing the largest
data set possible. Indeed, in our previous works, frequently,
the major interest of the experimentation was the production of
micro- and sub-microparticles, not of nanoparticles. All data are
summarized in Table 1. In this table, the processed compounds,
the solvents used, the concentration, the mean particle size of the
powders obtained (d50), the mode and the standard deviations
of the distributions have been reported. In Table 1, also the sol-
ubilities of the selected compounds in the liquid solvent used to
perform SAS experiments are reported. This data has been sys-
tematically measured also for materials previously processed, to
obtain the same accuracy for all compounds. Indeed, in previous
works solubility data were in some cases approximated, because
they were measured to avoid the use of solutions that were too
near to the saturation value.It is possible to observe that many experiments have been
performed using DMSO as the liquid solvent; it is due to the
fact that it does not tend to produce strong interactions with
solutes. Therefore, the ternary system DMSOCO2solute fre-
quently tends to maintain VLE characteristics that are similar
to those of the corresponding binary system (DMSOCO2)
and is simpler to find the process conditions for successful
SAS.
Some examples of nanoparticles obtained operating at
150barand40 Careshownin Fig.5ah fordifferent solutes and
well illustrate the similarities observed among different solutes.
In all cases, quasi-spherical nanoparticles with a maximumdiameter smaller than 200 nm have been obtained, as shown in
Fig. 6ad, that report some PSDs calculated from SEM images,
as described in Section 2. These nanoparticles form a colloidal
system suspended in the supercritical solution and can tend to
form aggregates, as it can be expected by this kind of nanodis-
persions [36].
In some cases, however, it has not been possible to obtain
nanoparticles for selected couples soluteliquid solvent and, in
some other cases, the nanoparticles showed a further evolution
with the formation of solid bridges among groups of particles.
These latest systems have been reported in Table 2 and shown as
examples in Fig. 7a and b. They have not been further considered
in the following elaboration of the results.
Table 2
Coalesced nanoparticles obtained at 150 bar and 40 C
Solute Solvent Solubility (mg/mL) C(mg/mL) C/C0 Morphology
Prednisolone Ac 100 40 0.4 Needle-like particles
Salbutamol
[37]DMSO 15
5 0.333 Microparticles
10 0.667
Pentamidine DMSO 100 10 0.1 Agglomerated particles
Cefonicid [29,33] DMSO 150 10 0.067 Solid bridges among nanoparticles
Nalmefene EtOH 150 15 0.1 Solid bridges among nanoparticles
Polistyrene CHCl3 20 5 0.25 Solid bridges among nanoparticles
-Cyclodextrin DMSO 700 5 0.007 Solid bridges among nanoparticles
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Fig.5. Nanoparticlesobtainedat 150bar, 40 C: (a) Yttrium acetate/DMSO, 5 mg/mL; (b) Gadolinium acetate/DMSO, 100mg/mL; (c) Amoxicillin/NMP, 20 mg/mL;
(d) Rifampicin/DMSO, 10 mg/mL; (e) Astemizole/DMSO, 10 mg/mL; (f) Dextran 40/DMSO,15 mg/mL; (g) HPMA/DMSO, 10 mg/mL; (h) SolventBlue 35/Acetone,
5 mg/mL.
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Fig. 6. Particle size distributions of different materials SAS processed at 150 bar, 40C: (a) Solvent Blue 35; (b) Astemizole; (c) Rifampicin; (d) HPMA.
It is interesting to observe that nanoparticles size, fixed all
the other process parameters, largely depends on the concentra-
tion of the starting liquid solution. For concentrations larger
than those reported in Table 1, no more nanoparticles have
been obtained: sub-micro- and microparticles have instead been
obtained with a corresponding enlargement of the PSD. Sub-
micro- and microparticles also present a different morphology:
the particles are perfectly spherical (see Fig. 8a and b for exam-
ple); whereas, nanoparticles are only approximately spherical.
We also tested the possibility of producing nanoparticles bySAS at pressures and temperatures different than 150 bar, 40 C.
Assembling together the new results reported in this work and
some literature data, the pressure tested range between 100 and
180 bar at temperatures from 35 to 50 C. These further results
are summarized in Table 3.
X-ray analyses were performed on the untreated and on the
SAS precipitated particles in order to check their crystalline
patterns. The X-ray traces revealed that the SAS micronized
powders were amorphous, whereas the untreated materials show
crystalline patterns.
Some experiments have also been performed using the quartz
windowed precipitator. In the experiments in which nanoparti-
cles have been produced, the jet, at the exit of the injection
device, was not visually detectable and a single gaseous phase
was present in the precipitator.
3.2. Organization of the experimental evidences
To attempt an organization of the experimental evidences,
we have to consider that nanoparticles have been obtained for
several materials (Table 1) that belong to differentgroups: super-
conductor precursors, pigments, pharmaceuticals, polymers.Also different liquid solvents have been used, though the results
obtained using DMSO are prevalent, as previously explained.
It means that nanoparticles production does not depend on the
specific material or on the liquid solvent used: it is a general
feature of the SAS process. The characteristic that connects
all the results is that the pressure to produce nanoparticles is
above the MCP of the binary system liquidCO2: as a rule,
pressures at values much higher than the supercritical condition
of the selected system are required. We can summarize these
observations stating that completely developed supercritical
conditions are required. In contrast, pressures near the MCP
can be described as at near critical conditions.
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Fig. 7. Coalescing nanoparticles obtained at 150 bar, 40C: (a) Cefonicid and
(b) Nalmefene HCl.
An increase of pressure produces smaller particles, as demon-
strated by the experiments performed at 180 bar. Temperature
dependence on nanoparticles production is not relevant; but,
seems that an increase of temperature produces an effect that
is opposite to that of an increase of pressure.
We performed the experiments using two different injection
devices: the first is a laser hole on a thin wall nozzle (differ-
ent diameters have been used), the second is a coaxial injection
device assisted by a liquid injection system (see Section 2); at
the best of our measurements, the injection device seems to have
no or negligible influence on nanoparticles size. Also Chang
et al. [27] performed experiments using two different injection
devices and found that the difference in diameter of mCOCnanoparticles was practically negligible at pressures higher than
100 bar. This observation does not mean that the characteristics
of the injector do not play a role in the SAS process; but that, at
the process conditions where nanoparticles have been observed,
this influence seems to be negligible.
The dependence on the concentration of the liquid solution
is evident: the increase of the solute concentration in the liq-
uid phase produces an increase of nanoparticles mean size (see
Table 1). We tried to report on a diagram the mean nanoparticles
diameter against the concentration of the liquid solution for three
of the tested compounds (Fig. 9). The mean diameter depends
somewhere linearly on the liquid solution concentrations, as
Fig. 8. Spherical submicro- and microparticles: (a) Samarium acetate and (b)
Cefonicid.
shown from the linear regression we added in this figure; but,each compound follows a different trend. The minimum mean
diameter is similar for the three compounds compared (Fig. 9).
It means that the dependence of particle size concentration is
Fig. 9. Mean diameter (d) vs. concentration for three different materials pro-
cessed at 150bar, 40
C.
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E. Reverchon et al. / J. of Supercritical Fluids 43 (2007) 126138 135
Table 3
Experiments performed at different pressures and temperatures
Solute Solvent Solubility (mg/mL) P (bar) T(C) C(mg/mL) C/C0 dm (nm)
Cellulose acetate Ac 93 120 40 10 0.107 85
Yttrium acetate [12,14] DMSO 303
12040
13.5 0.044
200
150 82
160 50 120
Dextran 40 [18] DMSO 147
110
40 10 0.068
180
130 120
150 95
Samarium acetate [12] DMSO 213
100
40
15 0.070200
120 180
150 17.5 0.082 110
180 15 0.070 55
30 0.140 80
Amoxicillin [31,35] NMP 195
150 35
20 0.102
147
40118
180 58
Rifampicin [30] DMSO 122
120
40
10 0.081 150
20 0.164 17040 0.328 200
70 0.574 250
1503 0.024 70
10 0.081 115
180 20 0.164 40
PVA DMSO 236150
40 10 0.04260
180 50
demonstrated, but the results should be correlated in a different
way with the concentration.
To understand if the experimental results can be organized in
a more systematic arrangement,one of thepossiblehypotheses is
that nanoparticle size could not depend on the concentration but
on the ratio between the concentration of the liquid solution (C)
and its saturation concentration (C0); i.e., the reduced concen-
tration CR = C/C0. Therefore, we organized the mean diameter
data (d) obtained at 150 bar, 40 C in a diameter (d) against CRdiagram that is reported in Fig. 10. The mean particle diameters
for all compounds tested are fairly well described by a linear
dependence against CR with a correlation factor (R) of about
0.942. These results mean that (given the operating pressure,
temperature and xCO2 ) the diameter of the nanoparticles does
not significantly depend on the solute adopted. An explanationof this result is that the precipitation process could be driven by
the relative distance from the saturation conditions and by solid
nucleation and growth. The growth process is favoured by an
increase of solute concentration, since this phenomenon super-
imposes on the nucleation process. As expected, it also produces
wider particle sizedistributionsas the concentrationincreases, as
shown in this work. Theminimum diameter of nanoparticles the-
oretically obtainable can also been obtained by extrapolation of
the results in Fig. 10. It is about 45 nm. However, it is important
to remember that this is the mean diameter of the PSD; nanopar-
ticles as small as about 10 nm have been observed at low CR
values.
Fig. 10. Mean diameter (d) vs. reduced concentration (CR) for all the materials
processed at 150bar, 40 C: () YAc; () ZnAc-1; () ZnAc-2; () EuAc; ()
GdAc; ( ) SmAc;() Rifa-1; ( ) Rifa-2; () Rifa-3; ( ) Rifa-4; ()NTO;()
Dext40; () Aste; () Inul; () Hyaff; () CellAc; ( ) NdAc; ( ) PVA; ( )
Ampi; (+) HPMA; ( ) DR60-1; ( ) DR60-2; ( ) DR60-3; ( ) SY56-1; ( )
SY56-2; ( ) SB35-1; () SB35-2; ( ) Amoxi; ( ) mCOC-1; () mCOC-2;
( ) mCOC-3; ( ) mCOC-4; ( ) mCOC-5.
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136 E. Reverchon et al. / J. of Supercritical Fluids 43 (2007) 126138
Fig. 11. Mean diameter (d) vs. pressure (P) for some materials at 40 C.
Using the diagram reported in Fig. 10, it can be also possible
to find the expected diameter for a material different from those
proposed in this work; fixed the SAS conditions, it is sufficient to
know the solubility in the given liquid solvent, calculate CR and
obtain as a result the expected mean diameter of nanoparticles
produced. The diagram in Fig. 10 can be, therefore, a very useful
tool to organize the experiments to produce nanoparticles of
predetermined dimensions.
Other experimental data are available at 40 C, as previously
reported in Table 3. These data in a mean particle diameter
against CR diagram produce a fair good linear correlation. The
decrease of nanoparticles diameter with pressure increase canbe observed in Fig. 11, where the experimental data reported
have been chosen for selected CR values approximately ranging
between 0.07 and 0.08.
This analysis of particle diameter data, thus, produces a gen-
eral definition, not only of the process conditions to be used to
produce nanoparticles by SAS; but, also of the expected diam-
eter of the particles that can be produced, that depends on the
relative distance of the concentration to the saturation of the
selected material in the liquid solvent. The percentage yield of
the SAS process, when nanoparticles are produced, is frequently
very high (higher that 90%) [31], since it substantially depends
on the saturation concentration of the solute in the fluid phase
formed in the precipitator. Since solutes that are not soluble orare only sparingly soluble in SC-CO2 are selected for this pro-
cess, it is expectedthat in a supercritical solution atxsolvent = 0.03
(at which we operate), only a small increase of solute solubility
will be obtained. From the point of view of powders recovered
in the precipitator, nanoparticles are easy to be collected, since
they are released from the colloidal suspension formed in the
precipitator as a fluffy powder substantially free of electrostatic
charges. Moreover, when we performed long pilot scale exper-
iments, we observed that the quantity of powder lost on the
walls of the precipitator was substantially constant, therefore,
its relative percentage decreased with the length of the experi-
ments.
3.3. Precipitation mechanism postulation
To explain the particles formation process in the jet of the liq-
uidsolution, it is possible to propose three differentmechanisms.
In the first one, the atomization of the liquid solution through the
injector results in the formation of droplets; the fast solubiliza-
tion of the SCF in the liquid solvent produces the formation of a
solid particle that can retain the shape of the originating droplet.
This mechanism is called one dropletone particle. The Weber
number
We =u2d
,
where is the liquid density, u the flux velocity, d the nozzle
diameter andis the surface tension, is the ratio between inertial
and surface forces and may be used to evaluate the droplet size
in sprays [38]. When the surface tension reduces, the Weber
number rapidly increases.
The second mechanism is a modification of the one
dropletone particle theory. In this case, the droplets are formedas described above; but, the rapid mass transfer of solvent
and antisolvent results in high supersaturation of the solute,
that causes the formation of several nuclei within the same
droplet. The result is the growth of several particles from one
droplet.
The third possible mechanism is that the surface tension
between the liquid and the antisolvent disappears at a time scale
smaller than the jet break-up of the liquid solution; therefore,
no droplets are formed and nucleation and growth of nanopar-
ticles could be the result of gas-like mixing; i.e., gas-to-particle
precipitation.
The interface between two miscible fluids at static equilib-riumat supercritical fluidconditionsshowsno significant surface
tension. But, in the case of theliquidjet injectionin the supercrit-
ical fluid phase, a time lag exists between the liquid injection and
the time at which equilibrium is obtained. The time evolution
of the interfacial tension between a liquid and a supercritical
fluid has been discussed by Lengsfeld et al. [39]. They found
that, for the CO2 + methylene chloride system, at 85 bar and
35 C; i.e., at the complete miscibility conditions, the transient
surface tension drops rapidly from approximately 2.5 mN/m at
the exit to 0.01 mN/m at about 1 m from the nozzle tip and
the Weber number based approach is no longer applicable. They
also verified these results injecting a jet of supercritical triflu-
orometane in supercritical carbon dioxide. For this system, thesurface tension driven droplet formation mechanismis obviously
not applicable. Sarkari et al. [40] also studied the evolution of
surface tension at the exit of the jet and found a time as short
as 2 ms for its complete elimination in supercritical CO2-based
systems. The velocity of reduction of the surface tension also
depends on the distance from the operating pressure from the
MCP. Moreover, near the MCP, small changes in the process
conditions can produce large changes in the equilibrium surface
tension.
Thus, the results we obtained are in favour of the gas mix-
ing precipitation mechanism: droplets are not formed at the
exit of the injector, but the liquid solution is almost instanta-
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E. Reverchon et al. / J. of Supercritical Fluids 43 (2007) 126138 137
neously mixed in the gas phase, from which solids nucleate and
eventually grow.
This hypothesis of precipitation mechanism is thus supported
by the following experimental evidences:
The irregular spherical shape of the nanoparticles. If parti-
cles are generated from droplets, the surface tension confers
them a perfectly spherical shape and the resulting particles
obtained by droplet drying will be spherical too. The genera-
tion of the nanoparticles from a gaseous phase is compatible,
instead, with the irregular shape observed in SEMimages (see
Fig. 5ah).
As previously discussed, calculations from Lengsfeld et al.
[39] demonstrated that when SAS process is performed at
completely developed supercritical conditions, the time scale
of the surface tension disappearance in jets of miscible fluids
(solvent and antisolvent) determines the jet evolution as a gas
plume; i.e., no droplets are formed. During the experiments
performed usingthe windowed precipitator, the jet was practi-
cally not detectable when completely developed supercriticalconditions were obtained.
The dependence of nanoparticles diameter on CR also sup-
ports this mechanism of particles generation; indeed, Fig. 10
shows that particles diameter is correlated to nucleation and
growth mechanisms that are connected to the reduced con-
centration and their dimension depends on the distance from
the saturation value.
The position of the SAS operating point in the P-x diagram
is also consistent with the role played by the surface tension
in determining or not the formation of droplets. If the surface
tension of the liquid injected in the precipitator goes almost
instantaneously to zero, no droplets are formed. This pro-cess is faster, the more the process conditions are selected at
full developed supercritical conditions; i.e., as the pressure
increases. As long as the operating point goes to the vicinity
of the MCP, this process can compete with the formation of
droplets.
At near critical conditions, equilibrium surface tension can
be not zero or the time of its disappearance will be compara-
ble with jet break-up and small droplets can be produced: in
this case, the mechanism of powders formation becomes the
one dropletone particle. Therefore, the precipitation process
is also regulated by the position of the operating point with
respect to MCP.
A point that has to be clarified is how to determine the posi-
tion of the MCP. Frequently, the authors working on SAS use
as a reference the binary system solventantisolvent VLEs data;
thus, the MCP considered is the one of the binary system. How-
ever, in SAS precipitation, a ternary system is involved and
the presence of the solute can modify the VLEs of the corre-
sponding binary system. The most common effect could be the
movement of the MCP to higher pressures and an enlargement
of the two-phases region, caused by the reduction of affinity
between solvent and antisolvent due to the presence of a third
component. However, also the opposite effect could be observed
[33].
In some cases:
(a) when the solute concentration is very low;
(b) when thesolute is completely immiscible in thesupercritical
solution solvent + CO2;
the binary system data could be used as an approximation of
the real behaviour; but, in the other cases, they can suggest aposition of the MCP and SAS operating conditions, different
from that expected. As a consequence, SAS operation in the
two-phase region or at near-critical or subcritical conditions can
be performed and nanoparticles are not produced.
For example, at high values ofCR and for many of the mate-
rials proposed in Tables 1 and 2, microparticles with a perfect
spherical shape have been produced [13,14,18,2931,33,35] at
thesame SAS operating conditions, since theMCP of the ternary
mixture at higher solute concentration is continuously moving
towards higher pressures until the operating point is no more
at completely developed supercritical conditions. Sub-micro-
and microparticles generated by the one-droplet one-particle
mechanism are obtained.
For some solutes, solid bridges are formed among groups
of nanoparticles (see Table 2); we think that this phenomenon
could be due to the presence of small quantities of solvent in
the solid nanoparticles that, when these collided in the colloidal
suspension, formed a liquid bridge that upon drying produced
the solid connection among groups of them.
4. Conclusions
Nanoparticles production is a general feature of the SAS
process: the experimental results on more than 20 materials,
different liquid solvents and different apparatus confirm thispossibility.
Nanoparticles can be produced when the operating point is
at pressures far from the MCP of the ternary mixture. A gas to
solid precipitation occurs.
The results proposed can be used to predict when nanoparti-
cles are produced and which could be their expected diameters
on thebasisof their solubility in theselectedliquid solvent andof
the SAS operating conditions with respect to the ternary mixture
VLEs.
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