Microsphere Fabrication of Polycaprolactone via Electrospray: Effect
of Different Parameters
Dandan Wang
1
, Yu Han
1
, Jie Sun
1,3
and Dejian Huang
1,2*
1
National University of Singapore Suzhou Institute, Suzhou, China
2
Department of Chemistry, National University of Singapore, Singapore
3
Department of Industrial Design, Xi'an Jiaotong-Liverpool, Suzhou, China
Keywords: microsphere, electrospray, polycaprolactone, drug delivery
Abstract: In controlled drug release systems, biodegradable and biocompatible polymer microspheres are good
candidates as drug carrier due to their large surface area. Here, we used the electrospraying technique to
fabricate polycaprolactone microspheres. By exploring the process parameters systematically, microspheres
with different morphology were produced. The increase of feed rate increased the particle size and collapse
of the particle, a feed rate of 0.2 L/min was found to produce narrow size distributed microspheres with the
average size of ~4 m. Our study shows that electrospray is a promising technique to fabricate microspheres
applied in controlled drug delivery systems.
1 INTRODUCTION
Biodegradable microspheres have been applied in
modern medical science for years. The drug delivery
at targeted site can increase local drug concentration
once the drugs are injected, which minimizes side
effects like degradation of active therapeutic
ingredient during its travel to the targeted site (Sinha
et al., 2004; Xie et al., 2007). There are several
common methods to make microspheres, like the
emulsion method, freeze-drying, precipitation and
spray drying. Among these methods, emulsion
method has achieved commercial application.
However, this method has its limitation since during
fabrication, it has tedious separation process.
Electrospray is a convenient, one step technique
that can fabricate microspheres via electric force.
Under high electrical voltage, the liquid is charged
and a Taylor cone is formed at the tip of a needle.
When the electric force overcomes the surface
tension, the liquid is dispersed into small charged
droplets and travels from nozzle to the collector.
This process involves the solidification of droplets
and evaporation of solvent from the surface of
droplets. The diameters and morphology of final
microspheres vary according to the electrospray
parameters (Kanani et al., 2011; Park et al., 2009).
The factors include solution properties like
concentration, solvent, conductivity and viscosity,
processing factors like feed rate, applied voltage,
nozzle to substrate distance and collector, ambient
conditions like humidity and temperature (Guarino
et al., 2015). Drug release rate is greatly influenced
by microsphere size and morphology, thus
controlling the electrospray parameters is important
for microsphere applications as drug carrier.
The liquid is diverse in its composition and form,
like natural polymer solution, synthetic polymer
solution, mixed solution, emulsion, and even solid
particle dispersed solution (Jafari-Nodoushan et al.,
2015;Wang et al., 2018; Ding et al., 2005; Guo et
al., 2017; Li et al., 2017). With the encapsulation of
low solubility drug celecoxib in poly(D,L-lactide-
co-glycolide) (PLGA 50:50), Bohr et al. successfully
prepared 1-4 m, nearly monodispersed
microspheres at different composition ratios of
polymer and drug (Bohr et al., 2011). Lai et. al. used
carboxymethylcellulose (CMC) to prepare
homogeneous core-shell hydrogel microspheres and
tuned the drug release sustainability by the
manipulation of processing parameters and hydrogel
composition (Lai et al., 2017). Recently Huang et al.
reported controllable preparation of porous
polycaprolactone (PCL) microspheres, via the
change of solvent composition for PCL solution
(Huang et al., 2017). In this study, we also used PCL
to fabricate microspheres since PCL is
Wang, D., Han, Y., Sun, J. and Huang, D.
Microsphere Fabrication of Polycaprolactone via Electrospray: Effect of Different Parameters.
DOI: 10.5220/0008184500050009
In The Second International Conference on Materials Chemistry and Environmental Protection (MEEP 2018), pages 5-9
ISBN: 978-989-758-360-5
Copyright
c
2019 by SCITEPRESS Science and Technology Publications, Lda. All rights reserved
5
biodegradable and biocompatible. We prepared PCL
solution with acetic acid and systemically studied
the effect of solution properties and processing
parameter. Our result lays the basis for future
microsphere studies with different materials and
shows that electrospray is a promising technique to
fabricate micro or nano particles applied in drug
delivery and controlled release system.
2 MATERIALS AND METHODS
2.1 Materials
The PCL pellets with an average molecular weight
of 80 kDa were purchased from Sigma-Aldrich
(Shanghai, China). Glacial acetic acid (99.7%) was
purchased from Aladdin Industrial Corporation
(Shanghai, China). Ethanol (99%) was purchased
from Sinopharm Chemical Reagent Co., Ltd
(Shanghai, China).
2.2 Characterization of Solution
Viscosity
The viscosity of polymer solution was determined
using Brookfield DV2T viscometer, equipped with
LV spindle set. Briefly, 40 mL polymer solution was
prepared and LV-63 spindle was placed into the
solution until reaching the guradleg level. To
measure the viscosity ), the experiments were
performed at room temperature 25 C, the rotation
speed of the spindle was set to 200 rpm and through
torque calculation of a built-in calibrated spring,
viscosity could be read directly from the viscometer.
2.3 Fabrication of Microspheres by
Electrospray
The polymer solution was prepared by dissolving
white PCL pellets (e.g. 1 g for 10 wt.%) in 10mL
acetic acid and treated by ultra-sonication, shake the
mixture time by time until the formation of a
homogeneous colorless solution. The freshly
prepared solution was transferred to a 10 mL syringe
with a 26G stainless steel needle, which is the nozzle
for electrospray. A syringe pump (NE-4000, New
Era Pump System Inc., USA) was used to control the
feed rate (FR) of the solution and drive the liquid to
the nozzle. High electrostatic field is applied
between the substrate and the nozzle, making the
liquid in the nozzle charged and a Taylor cone is
formed under the interaction of electric force,
gravity and surface tension. An ejection of spray
formed when the electric force exceeds the surface
tension.
2.4 Characterization of Microsphere
Morphology
Surface morphology of the microspheres was
observed by scanning electron microscope (SEM,
JSM-6510, JEOL, Japan). Samples were coated with
platinum at 20 mA for 30 s before observation.
Microsphere diameter was analyzed with Image J
software.
3 RESULTS AND DISCUSSION
3.1 Solution Properties Effect
PCL is soluble in many organic solvents and there
have been reports using dichloromethane
(DCM)(Samsudin et al., 2017), chloroform (CFM),
N,N-dimethylformamide (DMF) (Huang et al.,
2017), etc. as the electrospray solvents. We chose
acetic acid (AA) as the main solvent and ethanol
(EtOH) as the auxiliary solvent for environmental
considerations. When the concentration of PCL
solution used was the same (10 wt%), microspheres
covered with fine fibres were observed in Figure 1a
using AA as solvent, while only microspheres were
observed in Figure 1b using mixed solvents.
Figure 1: SEM images a) of 10 wt% PCL in AA, b) of
10wt% PCL in AA : EtOH = 8 : 2, temperature 21 C,
humidity 50%. Red arrow was eye guide for tiny fibres.
When the polymer solution has sufficient
entanglement among chains, electrospin will happen
(Gupta et al., 2005). A critical chain overlap
concentration (c*) was proposed which was the
crossover of concentration from semidilute
unentanglement to semidilute entanglement regime.
At the same PCL concentration, by the change of
solvent composition, the morphology changed from
microspheres with fiber (Figure 1a) to microspheres
only (Figure 1b). We measured the viscosity of the
two PCL solutions and η was nearly the same as
MEEP 2018 - The Second International Conference on Materials Chemistry and Environmental Protection
6
shown in Table 1. Non-solvent assisted electrospray
can produce more regular microspheres (Gao et al.,
2014), and as a non-solvent for PCL, the addition of
ethanol had the advantage to facilitated the
formation of microspheres.
From Table 1, we can find that though the nozzle
to substrate distance increased, the feed rate
decreased, the voltage applied for the mixed solvent
system decreased significantly. On the one hand, the
surface tension for acetic acid and ethanol are 31.9
dyne/cm and 22.0 dyne/cm respectively(Bae et al.,
2017). With the decrease of surface tension for the
mixed solvent system, the required electrostatic
force to start the spray is decreased. On the other
hand, the dielectric constant for acetic acid and
ethanol are 6.2 and 24.5 respectively at 25 C(Dean,
2010), higher dielectric constant for the mixed
solvent system also attributed to the decrease in the
requisite voltage. Therefore, the addition of non-
solvent ethanol for PCL solution improved the
electrospray performance greatly.
Table 1: Comparison of electrospray parameters for the
two solutions.
Parameters
AA
AA : EtOH = 8 : 2
PCL concentration
(wt%)
10
10
Voltage (kV)
20
12
Distance (cm)
20
24
Feed rate (L/min)
0.5
0.2
Viscosity (cP)
264.6
261.0
3.2 Processing Parameters Effect
3.2.1 Jetting Mode
Taylor cone forms when the electric force equals
surface tension of the liquid. There is a critical
applied voltage for the starting of electrospray, and
when the feed rate of the polymer solution increases,
the surface tension changed and the critical voltage
alter accordingly. As Figure 2 showed, the applied
voltage increased as feed rate increased.
Figure 2: Critical voltage as a function of feed rate and
spray mode classification according to the jetting: dripping
region below the wine line, single jet region between wine
and blue line, and multi-jet region above the blue line. The
polymer concentration was 10wt% in mixed solvent AA :
EtOH = 8 : 2, nozzle to substrate distance 20 cm,
temperature 21C, humidity 50%.
In Figure 2, the wine line is the critical voltage
for electrospray. When voltage lower than the
critical voltage was applied, the liquid at the nozzle
tip accumulated and under the electric force and
gravity, quick drops formed, namely dripping
region. When voltage higher than blue line was
applied, Taylor cone disappeared due to larger
electrostatic force and multiple streams were
observed, i.e. multi-jet region. The single jet region
is narrow but important in the fabrication of
microspheres. In this region, the applied voltage was
the critical voltage or slightly higher, which
produced Taylor cone with stable single stream of
spray. When the Taylor cone was not stable, the
droplets sprayed were unstable and broke up into
primary or main large droplets and secondary or
satellite small droplets. Consistent with previous
studies(Park et al., 2009; Ioan et al., 2004; Enayati et
al., 2010), our experimental results also showed that
microspheres produced in single jet region were
more mono-dispersed, and less satellite spheres
were produced.
3.2.2 Feed Rate
Feed rate is one important parameter that affect the
diameter of the microspheres. There has been many
studies on the particle size and feed rate relationship
(Park et al., 2009; Jafari-Nodoushan et al., 2015; Xie
et al., 2007), and all were based on Ganan-Calvo et
al.'s theoretical formulation (Equation 1), where is
a constant related to permittivity, Q is the solution
feed rate, is dielectric constant in a vacuum, , ,
are the density, surface tension, conductivity of the
solution respectively (Ganan-Calvo et al., 1999).
Microsphere Fabrication of Polycaprolactone via Electrospray: Effect of Different Parameters
7
𝑑 = 𝛼(
𝑄
3
𝜀𝜌
𝜋
4
𝜎𝛾
)
1/6
(1)
Figure 3: SEM images of 10wt% PCL in AA : EtOH = 8 :
2, at feed rate a) 0.2 L/min, b) 0.4 L/min, c) 0.6
L/min, d) 0.8 L/min, distance 24 cm, temperature 20
C, humidity 50%.
Figure 4: Gaussian fitted curves of size distribution
histograms of 100 PCL particles at different feed rate.
Ganan-Calvo demonstrated that the diameter of
microspheres is proportional to the square root of the
solution feed rate, and as shown in Figure 3, the size
of microspheres increases approximately 2 times
when the feed rate increases from 0.2 L/min to 0.8
L/min, consistent with Ganan-Calvo's theory.
Figure 4 shows the Gaussian curve of PCL
microspheres for each feed rate. As the feed rate
increases, the full width at half maximum (FWHM)
become wider indicating heterogeneous size
distribution. As the feed rate increased, more
satellite microspheres were fabricated as shown in
the insert SEM images, and the standard derivation
of particle size increased greatly. Our research
shows that when feed rate was 0.2 L/min, the
microsphere diameter was 3.92 ± 0.64 m,
indicating mono-dispersed microspheres.
3.2.3 Nozzle to Substrate Distance
Nozzle to substrate distance (D) is also call working
distance, which is the distance from the tip of nozzle
to the collector. D affects the applied voltage (V): E
= V / D, where E is the electrostatic force generated.
Table 2 shows that as D decreases from 24 cm to 15
cm, lower voltage was applied, and the size change
of microsphere was negligible (within 0.1 m),
however, the standard derivation increases
indicating that heterogeneous microspheres were
fabricated. Figure 5 shows that more collapsed
microspheres were produced when D decreased.
This morphology was attributed to insufficient
solvent evaporation within the microspheres when D
decreased.
Table 2: Applied voltage and microsphere diameters for
different working distance.
Distance
(cm)
Voltage
(kV)
Diameter
(m)
24
12.5
5.04
20
11.5
4.98
15
9.5
5.01
Figure 5: SEM images of 10wt% PCL in AA : EtOH = 8 :
2, at nozzle to substrate distance a) 24 cm, b) 20 cm, c) 15
cm, feed rate 0.2 L/min, temperature 21C, humidity
50%.
4 CONCLUSIONS
Choice of solvent for microsphere fabrication is
important and the addition of non-solvent for PCL
solution facilitate microsphere formation. We
studied the processing parameters and showed the
importance of using single jet mode for electrospray.
The optimization of feed rate, applied voltage and
nozzle to substrate distance is important for the
fabrication of mono-dispersed microspheres. The
microsphere diameter around 4 m with low
standard derivation could be produced and our study
shows that electrospray is a facile and effective
method to produce monodispersed microspheres and
in the future we will fabricate drug loaded
MEEP 2018 - The Second International Conference on Materials Chemistry and Environmental Protection
8
microspheres for drug delivery and controlled
release studies.
ACKNOWLEDGEMENTS
This work was supported by Suzhou Technology
support program, China, under grant no.
SYG201617.
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