Microsphere Fabrication of Polycaprolactone via Electrospray: Effect

of Different Parameters

Dandan Wang

, Yu Han

, Jie Sun

1,3

and Dejian Huang

1,2*

National University of Singapore Suzhou Institute, Suzhou, China

Department of Chemistry, National University of Singapore, Singapore

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

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 (η), 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

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 : EtOH = 8 : 2

PCL concentration

(wt%)

Voltage (kV)

Distance (cm)

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 21C, 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

𝑑 = 𝛼(

𝑄

𝜀𝜌

𝜋

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)

Standard

derivation

12.5

5.04

0.54

11.5

4.98

0.67

9.5

5.01

0.96

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 21C, 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

microspheres for drug delivery and controlled

release studies.

ACKNOWLEDGEMENTS

This work was supported by Suzhou Technology

support program, China, under grant no.

SYG201617.

REFERENCES

Bae, J., Lee, J. & Hyun Kim, S. 2017. Effects of polymer

properties on jetting performance of

electrohydrodynamic printing. Journal of Applied

Polymer Science, 134, 45044.

Bohr, A., Kristensen, J., Stride, E., Dyas, M. &

Edirisinghe, M. 2011. Preparation of microspheres

containing low solubility drug compound by

electrohydrodynamic spraying. International Journal

of Pharmaceutics, 412, 59-67.

Dean, J. A. 2010. Lang's handbook of chemistry.

Advanced Manufacturing Processes, 5, 687-688.

Ding, L., Lee, T. & Wang, C. H. 2005. Fabrication of

monodispersed Taxol-loaded particles using

electrohydrodynamic atomization. J Control Release,

102, 395-413.

Ganan-Calvo, A. M. 1999. The surface charge in

electrospraying: its nature and its universal sacling

laws. Journal of Aerosol Science, 30, 863.

Gao, J., Li, W., Wong, J. S.-P., Hu, M. & Li, R. K. Y.

2014. Controllable morphology and wettability of

polymer microspheres prepared by nonsolvent assisted

electrospraying. Polymer, 55, 2913-2920.

Guarino, V., Altobelli, R., Cirillo, V., Cummaro, A. &

Ambrosio, L. 2015. Additive electrospraying: a route

to process electrospun scaffolds for controlled

molecular release. Polymers for Advanced

Technologies, 26, 1359-1369.

Guo, F., Chen, X., Wang, G., Hua, Z., Wang, X., Zhang,

Q., Zhao, X. & Xiao, P. 2017. Hollow ceramic

microspheres prepared by combining electro-spraying

with non-solvent induced phase separation method: A

promising feedstock for thermal barrier coatings.

Materials & Design, 139, 343-350.

Gupta, P., Elkins, C., Long, T. E. & Wilkes, G. L. 2005.

Electrospinning of linear homopolymers of

poly(methyl methacrylate): exploring relationships

between fiber formation, viscosity, molecular weight

and concentration in a good solvent. Polymer, 46,

4799-4810.

Huang, X., Gao, J., Li, W., Xue, H., Li, R. K. Y. & Yiu

Wingmai 2017. Preparation of poly(ε-caprolactone)

microspheres and fibers with controllable

surfacemorphology. Materials & Design, 117, 298-

304.

Ioan M., Lida P., Linda H. & Akos V. 2004. Flexing the

Electrified Meniscus: The Birth of a Jet in

Electrosprays.

Enayati, M., Ahmad, Z., Stride, E. & Edirisinghe, M.

2010. Size mapping of electric field-assisted

production of polycaprolactone particles. J R Soc

Interface, 7 Suppl 4, S393-402.

Jafari-Nodoushan, M., Barzin, J. & Mobedi, H. 2015. Size

and morphology controlling of PLGA microparticles

produced by electro hydrodynamic atomization.

Polymers for Advanced Technologies, 26, 502-513.

Kanani, G. A. & Bahrami, S. H. 2011. Effect of Changing

Solvents on Poly(-Caprolactone) Nanofibrous Webs

Morphology. Journal of Nanomaterials, 2011, 1-10.

Lai, W.F., Susha, A. S., Rogach, A. L., Wang, G., Huang,

M., Hu, W. & Wong, W.-T. 2017. Electrospray-

mediated preparation of compositionally

homogeneous core-shell hydrogel microspheres for

sustained drug release. RSC Advances, 7, 44482-

44491.

Li, S., Xiao, L., Deng, H., Shi, X. & Cao, Q. 2017.

Remote controlled drug release from multi-functional

/GO/Chitosan microspheres fabricated by an

electrospray method. Colloid Surf Biointerfaces, 151,

354-362.

Park, C. H. & Lee, J. 2009. Electrosprayed polymer

particles: Effect of the solvent properties. Journal of

Applied Polymer Science, 114, 430-437.

Samsudin, N., Hashim, Y. Z. H., Arifin, M. A., Mel, M.,

Salleh, H. M., Sopyan, I. & Hamid, M. A. 2017.

Surface modification of Polycaprolactone (PCL)

microcarrier for performance improvement of human

skin fibroblast cell culture. IOP Conference Series:

Materials Science and Engineering, 290, 12-16.

Sinha, V. R., Bansal, K., Kaushik, R., Kumria, R. &

Trehan, A. 2004. Poly-ϵ-caprolactone microspheres

and nanospheres: an overview. International Journal of

Pharmaceutics, 278, 1-23.

Wang, H., Li, W. & Li, Z. 2018. A Facile Strategy for

Preparing PCL/PEG Block Copolymer Microspheres

via Electrospraying as Coatings for Cotton Fabrics.

Macromolecular Materials and Engineering, 1800164.

Xie, J. & Wang, C.H. 2007. Encapsulation of proteins in

biodegradable polymeric microparticles using

electrospray in the Taylor cone-jet mode.

Biotechnology and Bioengineering, 97, 1278-1290.

Microsphere Fabrication of Polycaprolactone via Electrospray: Effect of Different Parameters