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ISSN: 0265-2048 (print), 1464-5246 (electronic)
J Microencapsul, 2014; 31(1): 1622
! 2014 Informa UK Ltd. DOI: 10.3109/02652048.2013.799242

ORIGINAL ARTICLE

Polymer encapsulation of amoxicillin microparticles by SAS process

A. Montes, E. Baldauf, M. D. Gordillo, C. M. Pereyra and E. J. Martnez de la Ossa

Abstract

Keywords

Encapsulation of amoxicillin (AMC) with ethyl cellulose (EC) by a supercritical antisolvent

process (SAS) was investigated. AMC microparticles obtained previously by an SAS process
were used as host particles and EC, a biodegradable polymer used for the controlled release of
drugs, was chosen as the coating material. In this work, a suspension of AMC microparticles in a
solution of ethyl cellulose in dichloromethane (DCM) was sprayed through a nozzle into
supercritical CO2. Scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS)
and HPLC analyses were carried out. The effects of AMC:EC ratio, the initial polymer
concentration of the solution, temperature and pressure on the encapsulation process were
investigated. Although all the experiments led to powder precipitation, the AMC encapsulation
was achieved in only half of the cases, particularly when the lower drug:polymer ratios were
assayed. In general, it was observed that the percentages of AMC present in the precipitates
were higher on increasing the AMC:EC ratio. In these cases composites rather than encapsulates
were obtained. The in vitro release profiles of the resulting materials were evaluated in order to
ascertain whether composites can be used as encapsulated systems for drug delivery systems.

Coating, ethyl cellulose, microparticles,

supercritical antisolvent

Introduction
Microparticle encapsulation has been a field of interest for some
considerable time. The multiple applications of encapsulated
materials in the pharmaceutical, electronic, food, cosmetic, textile
and biomedical industries make this kind of process very
attractive. In particular, in the pharmaceutical field, micro- and
nano-encapsulates provide the benefits of protection from rapid
degradation, increased capability to pass materials through
physiological membranes and allow targeting of the organ, cell
or tissue where the drug must act. Furthermore, this approach can
mask the taste and/or odor of a material and enable control of
active substance delivery of pharmaceutical compounds (MiKyeong et al., 2010).
Conventional techniques for the encapsulation of microparticles are usually associated with adverse environmental impact due
to the large amounts of organic solvents, surfactants and other
additives used, leading to volatile organic compound emissions
and other waste streams (Wang et al., 2005; Esmaeili et al., 2012).
In addition, the combination of high temperatures and chemicals
required in the majority of these processes can lead to degradation
of the encapsulates.
An alternative to the conventional encapsulation process is the
application of supercritical fluids, an approach that has previously
proven to be successful. In particular, a large number of studies
concerning the encapsulation of microparticles with polymers
using the supercritical antisolvent process (SAS) have been

Address for correspondence: A. Montes, Department of Chemical

Engineering and Food Technology, Faculty of Sciences, University of
Cadiz, International Excellence Agrifood Campus (CeiA3), 11510 Puerto
Real (Cadiz), Spain. Tel: +34-956-016-458. Fax: +34-956-016-411.
E-mail: antonio.montes@uca.es

History
Received 13 November 2012
Revised 13 February 2013
Accepted 28 March 2013
Published online 23 May 2013

reported (Tu et al., 2002; Liu et al., 2005; Kalogiannis et al.,

2006; Kalani et al., 2011; Zu et al., 2011).
The SAS technique is applicable for encapsulation due to the
low solubility of pharmaceutical compounds in supercritical
fluids once they are dissolved in the organic phase. Thus,
supercritical fluids dissolve the organic solvents and cause the
precipitation of the pharmaceutical compound in question.
Ethyl cellulose (EC), a polymer widely used for the controlled
release of pharmaceuticals, is the selected carrier for AMC
encapsulation because it fulfills all the requirements of the
pharmaceutical field, including biocompatibility, non-toxicity
and suitable resistance to preserve the properties and the activity
of the active substance. AMC was used as a model antibiotic
because it is one of the most widely prescribed drugs of its type.
Kalogiannis studied the encapsulation of AMC with poly(L-lactic
acid) (PLLA) using SEDS (solution enhanced dispersion by
supercritical fluid) process: At 200 bar and 323.15 K the loading
percentages and efficiencies were higher, but with AMC outside
surface (Kalogiannis et al., 2006). In previous studies, coprecipitation of amoxicillin with EC was carried out (Montes et al., 2011)
and the resulting composites were produced by the simultaneous
precipitation of the drug and the polymer, leading to a dispersion of
particles of the drug into a matrix of polymer. In this case the drug
was not into the core and the polymer was not the coating material
since there is no core-shell morphology. Spherical microparticles
were obtained in most of the composites except when the SAS
experiment was carried out at the highest temperature, in which
case agglomerates of particles formed by irregular blocks were
observed. Other authors have carried successfully out several
composite precipitations using the SAS process (Elvassore et al.,
2001; Moneghini et al., 2001; Kang et al., 2008).
In the work described here, it was aimed to obtain encapsulates
in which the coating material was precipitated as a shell over a

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Department of Chemical Engineering and Food Technology, University of Cadiz, Puerto Real (Cadiz), Spain

DOI: 10.3109/02652048.2013.799242

Polymer encapsulation of amoxicillin

17

core material particle (Cocero et al., 2009). In this case the AMC
particles would be surrounded by an ethyl cellulose layer. For this
purpose, spherical AMC microparticles were used that had been
successfully precipitated from N-methylpyrrolidone (NMP) by an
SAS process (Montes et al., 2010). These microparticles were
suspended in a polymer solution and then sprayed into the
chamber by a peristaltic pump, in contrast to the coprecipitation
process where a solution of both solutes is sprayed into the vessel.

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Materials and methods

Amoxicillin (AMC) (purity 97%), ethyl cellulose (EC) (48
49.5% ethoxy content) and dichloromethane (DCM) (purity
99.5%) were purchased from Sigma-Aldrich Chemical (Spain).
CO2 with a minimum purity of 99.8% was supplied by Linde
(Spain). SEM pictures of the amoxicillin and ethyl cellulose are
shown in Figures 1 and 2, respectively. Amoxicillin and ethyl
cellulose microparticles precipitated previously by an SAS
process are shown in Figure 3. The amoxicillin microparticles
shown in Figure 3 were used to prepare the suspensions assayed.
The experiments were carried out in pilot plant developed by
Thar Technologies (model SAS 200). A schematic diagram of this
equipment is shown in Figure 4. This plant was explained in detail
in a previous work (Tenorio et al., 2007). The SAS 200 system
comprises the following main components: two high-pressure
pumps, one for the CO2 (P1) and the other for the solution (P2),
which incorporate a low-dead-volume head and check valves to
provide efficient pumping of CO2 and a range of solvents; a
stainless steel precipitator vessel (V1) of 2 L volume, consisting of
two parts, the main body and the frit, all surrounded by an electrical
heating jacket (V1-HJ1); an automated high precision backpressure regulator (ABPR1), attached to a motor controller with
a position indicator; and a jacketed (CS1-HJ1) stainless steel
cyclone separator (CS1) with 0.5 L volume, to separate the solvent
and CO2 once the pressure is released by the manual back-pressure
regulator (MBPR1). The following auxiliary elements were also
necessary: a low pressure heat exchanger (HE1), cooling lines, and
a cooling bath (CWB1) to keep the CO2 inlet pump cold and to chill
the pump heads; an electrical high-pressure heat exchanger (HE2)
to preheat rapidly the CO2 in the precipitator vessel to the required
temperature; thermocouples placed inside (V1-TS2) and outside
(V1-TS1) the precipitator vessel, inside the cyclone separator
(CS1-TS1), and on the electric high pressure heat exchanger to
obtain continuous temperature measurements; and a FlexCOR
coriolis mass flowmeter (FM1) to measure the CO2 mass flow rate
and other parameters such as total mass, density, temperature,
volumetric flow rate and total volume.
In order to study the ability of EC to encapsulate AMC, several
suspensions of AMC microparticles in a solution of EC in DCM
were used. All the operating conditions are summarized in Table 1.
Pressure, temperature, drug:polymer ratio and polymer concentration effects have been evaluated. These AMC microparticle
suspensions (20 to 200 mg of AMC) in a 20 mL DCMEC solution
were sprayed through a nozzle using a P305 peristaltic pump (as
opposed to the SAS200 sample pump) to avoid blocking. The
supercritical CO2 acts as an antisolvent for the DCM. A rapid mutual
diffusion between the supercritical CO2 and the organic solvent
causes supersaturation of the polymer solution, leading to nucleation
and precipitation of the polymer to encapsulate the AMC particles.
In the precipitation carried out on a suspension of particles, the
particles behave as nuclei for the precipitation of the polymer and a
polymer matrix of encapsulated particles is produced by agglomeration (Wang et al., 2004; Cocero et al., 2009).
In this work, DCM was selected as the organic solvent to
precipitate EC using the SAS technique because it was previously
shown that the precipitated particles are not agglomerated

Figure 1. SEM image of unprocessed ethyl cellulose.

Figure 2. SEM image of unprocessed amoxicillin.

(Duarte et al., 2006). The low solubility of ethyl cellulose in

carbon dioxide and their relatively high solubility in DCM
provided suitable conditions to employ the SAS process for
controlled particle formation. As a consequence, the encapsulation process was carried out by suspending AMC microparticles
in polymer solutions with different AMC:polymer ratios, i.e. 1:1,
1:2, 1:5 and 1:10. The conditions for AMC encapsulation are
summarized in Table 1. Different initial concentrations of the
polymer solution (5, 10 and 15 mg/mL) were considered in order
to establish the relationship between the particle sizes of
encapsulates and the initial concentration of the solution.
Pressures in the range 80150 bar and temperatures in the range
3565  C were investigated. The liquid flow rate (QL) was
2 mL/min in order to ensure that the solution was atomized and a
small nozzle diameter (n) of 100 mm was used to guarantee the
turbulence and higher supersaturations at the border of the jet in
order to obtain small particles (Tenorio et al., 2009).
Encapsulate powder precipitated on the wall was observed
using a QUANTA 200 scanning electron microscope (SEM). The
samples had previously been placed on carbon tape and then
covered with a coating of gold using a sputter coater. The applied
current was 15 mA and the coating time was 150 s.


mass of AMC
100
LP
mass of AMC mass of EC precipitated
LP
LE
LP0

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Figure 3. SEM image of microparticles

precipitated by SAS process of (a) amoxicillin obtained at 55  C (T), 180 bar (P), 66 g/
min (QCO2), 5 mL/min (QL), 180 min (tw),
100 mm (n) and (b) ethyl cellulose at 35  C
(T), 80 bar (P), 11 g/min (QCO2), 2 mL/min
(QL), 90 min (tw) and 100 mm (n).

Figure 4. Schematic diagram of the pilot plant.

Table 1. Encapsulation experiments with SAS process.

Run
1
2
3
4
5
6
7
8
9
10

AMC:EC
ratio (wt/wt)

Ethylcellulose
concentration
(mg/mL)

Pressure
(bar)

Temperature
( C)

XPS*
(%Nitrogen)

Loading
percentages
(%)

Loading
efficiency (%)

Encapsulation
success

1:1
1:2
1:5
1:10
1:2
1:2
1:10
1:10
1:10
1:10

10
10
10
10
5
15
10
10
10
10

80
80
80
80
80
80
110
150
150
150

35
35
35
35
35
35
35
35
50
65

3.67  0.18
1.06  0.22
0.00  0.00
0.00  0.00
1.96  0.12
0.86  0.08
0.00  0.00
0.00  0.00
0.00  0.00
0.00  0.00

39.32
13.98
8.47
3.72
13.28
14.02
4.25
3.39
3.41
3.25

78.00
41.94
48.19
44.44
39.39
42.42
47.22
37.66
37.88
36.11

Note: *XPS X-ray photoelectron spectroscopy.

Amoxicillin loading in the encapsulates was determined by

high-performance liquid chromatography (HPLC). The HPLC
equipment consisted of a chromatograph (Agilent Technologies
1100 Series) with a UVvisible detector. A C18 Hypersil ODS
(5 mm particle size) column (250 mm  4.6 mm) (Supelco) was
used. The samples were dissolved with the aid of stirring and

sonication during 5 minutes in a mixture of methanol:distilled

water (90:10) to ensure complete dissolution of the drug. AMC
was eluted using a mixture of 80% phosphate buffer at pH 2, 16%
acetonitrile and 4% methanol (Kalogiannis et al., 2006) as the
mobile phase with a flow rate of 0.3 mL/min and detection at
230 nm. The amoxicillin loading percentage (LP), the theoretical

Polymer encapsulation of amoxicillin

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Figure 5. SEM images of microparticles of

amoxicillin and ethylcellulose obtained at
35  C (T), 80 bar (P), 11 g/min (QCO2),
2 mL/min (QL), 90 min (tw) and 100 mm
(n).

loading of amoxicillin in the organic solution (LP0) and loading

efficiency (LE) were calculated as follows:
Drug release profiles were obtained for the pure drug and for
the precipitated microparticles. Simulated gastric fluid (SGF)
without pepsin and simulated intestinal fluid (SIF) without trypsin
were prepared to carry out the release experiments. SGF was
made by dissolving sodium chloride (2 g L1) and hydrochloric
acid (0.2 N) and adjusting to pH 1.2  0.1, and SIF was made by
dissolving monobasic potassium phosphate (6.8 g L1) in a
solution of 0.2 N sodium hydroxide and adjusting to pH
6.8  0.1. In these experiments 40 mg of AMC were added to
20 mL of simulated fluid and the solutions were kept at 37  C with
continuous stirring at 170 r.p.m. The absorbance at 288 nm was
measured on a Shimadzu mini 1240 UV-visible spectrophotometer and this was used for quantitative analysis of AMC on the
basis of a calibration curve. Samples were collected at regular
intervals within 24 h.
X-ray photoelectron spectroscopy (Kratos Axis Ultra DLD)
was used to determine the possible location of AMC in the
precipitates, with chemical analysis of the surface of these
microspheres also carried out because SEM images are not
suitable to observe the distribution of both compounds: the AMC
could be located on the surface of the microspheres and/or within
the core. It is possible to differentiate between composites, which
are formed by dispersions of particles within the core material in a
matrix of coating material, and encapsulates, which are produced
when the coating material is precipitated as a thin shell over a
previously existing core material particle (Cocero et al., 2009).
So, XPS was used to determine the success of the encapsulation
process (Morales et al., 2007). In this procedure the powder

samples were mounted on a double-sided adhesive conducting

polymer tape and analyzed without any further treatment. The
elements that differentiate AMC from EC are sulfur (S) and
nitrogen (N), so the absence of these elements in the XPS analysis
would indicate that the drug was contained within the core of the
encapsulates. However, the detection of these elements would
indicate that AMC is present at the surface and that there is AMC
that is not encapsulated. The XPS data are collected in Table 1.

Results and discussion

The successful precipitation of amoxicillin and ethyl cellulose on
the wall of the precipitator vessel was achieved in all experiments.
SEM images of the products are shown in Figures 5 and 6. In most
cases, the formation of spherical or quasi-spherical agglomerated
microparticles was obtained. In any case, the resulting particles
were significantly smaller than the unprocessed compounds
(Figures 1 and 2) but, according to the SEM images, larger than
AMC and EC precipitated separately by an SAS process
(Figure 3). The SAS process also led to marked improvements
in the morphologies of particles. The morphology of the particles
changed from irregular blocks to spherical microparticles.
Drug polymer ratio
In the first set of experiments (runs 14) the effect of AMC:EC
ratio on size and morphology was investigated and AMC loading
percentages (LP) and efficiencies (LE) of the resulting systems
were calculated. As one would expect, the LP and LE increased
on increasing the AMC:EC ratio, with the highest LP obtained
when the drug and polymer were in the same ratio. In general, the

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A. Montes et al.

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Figure 6. SEM images of microparticles of amoxicillin and ethylcellulose obtained at polymer concentration of 10 mg/mL with 1:10
amoxicillin:ethylcellulose ratio at different operating pressure.

Figure 7. SEM images of microparticles of amoxicillin and ethylcellulose obtained at polymer concentration of 10 mg/mL with 1:10 amoxicillin:
ethylcellulose ratio at different operating temperature.

efficiency of the process was consistently around 4048%

(Table 1). However, it was observed that the success of the
encapsulation process was greater when the drug:polymer ratio
was lower (runs 3 and 4). When the ratio was higher there was
insufficient ethyl cellulose to cover completely the amoxicillin
particles. Thus, there is a balance between drug content and
success of the encapsulation process and this aspect must be taken
into account. On the other hand, a significant difference in
particle size and morphology of the resulting systems was not
found according to the SEM images, as can be seen in Figure 5.
Polymer concentration
Experiments were carried out with different initial EC concentrations in the solution pumped into the vessel (runs 2, 5 and 6).
The EC concentration used in this work is not a critical parameter
for the success of the encapsulation, as can be seen from the
results in Table 1. However, the particle size of encapsulates was
higher when the EC initial concentration was higher, as shown in
Figure 5.
The relationship between the initial concentration of the
solution and particle size has two possible influences. On one
hand, a higher concentration allows higher supersaturation to be
achieved, thus leading to a smaller particle size. On the other
hand, an increase in the condensation rate at higher concentrations
increases the particle size. The operating conditions used in this
work led to the second effect prevailing; so, the higher the initial
concentration of the solution, the higher the condensation rate and
therefore the larger the particle size produced (Martin and Cocero,
2004). This same trend for the initial concentration effect has been
observed in previous studies (Montes et al., 2010, 2012).
Pressure and temperature effects
Pressure and temperature assayed did not have an appreciable
effect on success of encapsulation. On the other hand, as can be

seen in Figure 6, the particle size of systems obtained decreased

slightly as the pressure increased, as can be observed in the SEM
images. This result can be explained by considering that an
increase in pressure at constant temperature enhances the solvent
power of supercritical CO2 towards DCM, thus the liquid solvent
molecules are more strongly captured by the CO2. In contrast, the
possibility of interaction between DCM and AMC is reduced
(Reverchon and Della Porta, 1999; Snavely et al., 2002). On the
other hand, pressure seems to be able to affect the process
efficiency being the optimum pressure 110 bar and after that the
efficiency decreases as can be seen in Table 1.
The effect of temperature on the process is illustrated by runs
810. As can be seen in Figure 7, the particle size of the
encapsulates increased as the operating temperature was
increased. CO2 and solvent mass transfer rates are expected to
be increased only slightly by small increases in temperature. The
increases in mass transfer rates, which would tend to increase
supersaturation ratios and decrease particle sizes, may be offset by
particle growth rates that increase with temperature (Randolph
et al., 1993). Increasing the temperature has no advantages on the
process efficiency as can be seen in Table 1.
Drug location
It was not possible to use the SEM images to determine whether
the AMC was within the core of the precipitates covered by EC
and therefore we were unable to gauge the success of the
encapsulation process. The AMC could be located on the surface
of the microspheres and/or within the core. In a previous study the
presence of AMC on the surface was detected when AMC and EC
were coprecipitated by an SAS process to give composites
(Montes et al., 2011). As a result, XPS was used to determine the
success of the encapsulation process through chemical analysis
of the particles on the precipitate surface as it was explained in
the previous section. The XPS data are collected in Table 1.

Polymer encapsulation of amoxicillin

DOI: 10.3109/02652048.2013.799242

21

120

Drug Fraction Release (%)

100

run 1-SIF
run 2-SIF
run 3-SIF
run 4-SIF
run 5-SIF
run 6-SIF
run 7-SIF
run 8-SIF
run 9-SIF
run 10-SIF
amoxicillin

80

60

40

0
0

4
t(h)

Figure 8. Release profile of the amoxicillin from obtained systems in Simulated Intestinal Fluid.

100

80
Drug Fraction Release (%)

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20

run 1-SGF
run 2-SGF
run 3-SGF
run 4-SGF
run 5-SGF
run 6-SGF
run 7-SGF
run 8-SGF
run 9-SGF
run 10-SGF
amoxicillin

60

40

20

4
t(h)

Figure 9. Release profile of the amoxicillin from obtained systems in Simulated Gastric Fluid.

AMC was present on the particle surface in experiments with

higher AMC:EC ratios (runs 1, 2, 5 and 6). At the same time, the
LP values calculated by HPLC analyses confirmed that AMC is
present in the products from all of the experiments, as can be seen
from the results in Table 1. This finding could be due to the
presence of excess AMC microparticles with the EC unable to
cover all of the AMC in the precipitation process. As a result,
composites with AMC on the surface and encapsulates without
AMC on the surface were obtained.
Drug release
The drug release behavior was evaluated in simulated fluids
prepared in the laboratory: simulated gastric fluid (SGF), pH
1.2  0.1, and simulated intestinal fluid (SIF), pH 6.8  0.1, were
obtained as described previously in the Materials and methods
section. Samples and pure drugs were taken periodically and
measured at 288 nm in these fluids. The profiles show the

percentage of antibiotic released with time. A comparison of these

results is presented in Figures 8 and 9. It was found that all
formulations led to slower release than the pure drug.
The delayed release from the precipitated particles in
comparison to the pure drug is more marked in SIF than SGF.
In a previous study (Montes et al., 2011) a relationship was
established between the presence of N, i.e. AMC on the
precipitate surface, and the release profile. The release of the
drug from precipitates in which N was present on the surface was
faster than in cases where N was not present: i.e. AMC on the
surface is more accessible for rapid delivery. A similar trend can
be seen in this work for the SIF profile. Thus, in runs 1, 2, 5 and 6
in SIF there was AMC on the surface and in these cases there is a
burst release during the first hour, during which around 50
70% of the total drug is released.
Drug release from microcapsules should theoretically be
slower as the amount of polymer is increased due to the increase
in the path length through which the drug has to diffuse. The total

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A. Montes et al.

cumulative quantity of drug released at the end of the 12 h

dissolution test was below 100% for all dosage forms. This may in
part be due to the relatively slow erosion of the matrix under the
test conditions, with a resultant slow release of entrapped drug
from the matrices under investigation.
The influence of the operating conditions on the release
profiles was analyzed, although it is difficult to establish
relationships between drug release and the pressures and
temperatures investigated. However, in run 1 a slower release
took place and this reached only 510% of the AMC in the first
hour. It can be seen from the results for runs 58 (assayed in SIF)
that it is possible to tune the operating conditions to develop
different release behavior.

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Conclusions
Encapsulation of amoxicillin in ethyl cellulose from a suspension
of amoxicillin microparticles in a solution of ethyl cellulose in
dichloromethane was studied. The supercritical antisolvent process provides a feasible approach for the formation of encapsulates and composites of these two compounds. Encapsulates were
obtained with a lower amoxicillin:ethyl cellulose ratio and
composites with a higher ratio. It was observed that the
percentages of amoxicillin are maintained in the precipitates
with regard to the initial suspended drug and there is no
significant difference in particle size and morphology on
changing the drug:polymer ratio. However, SEM images show
that the particle size of encapsulates was higher on increasing the
initial ethyl cellulose concentration. The effects of pressure and
temperature on particle size were also evaluated. The size
decreased on increasing pressure but increased as the operating
temperature was increased. The release of drug from precipitates
in which N was present on the surface was faster than in cases
where N was absent. However, in both cases the release was
slower than the dissolution profile of the pure drug.

Declaration of interest
The authors report no declarations of interest. We gratefully acknowledge
the Spanish Ministry of Science and Technology (Project CTQ201019368) for financial support.

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