Journal of Microencapsulation, 2012, 1–8, Early Online� 2012 Informa UK Ltd.ISSN 0265-2048 print/ISSN 1464-5246 onlineDOI: 10.3109/02652048.2012.680510

Spray drying of monodispersed microencapsulates: implications offormulation and process parameters on microstructural propertiesand controlled release functionality

Wenjie Liu1, Winston Duo Wu1, Cordelia Selomulya1 and Xiao Dong Chen1,2

1Department of Chemical Engineering, Monash University, VIC 3800, Australia and2Department of Chemical and Biochemical Engineering, College of Chemistry and ChemicalEngineering, Xiamen University, 361005 Fujian Province, P.R. China

AbstractParticulates for pharmaceutical applications require stringent control over their characteristics to realize theoptimal therapeutic performance. By generating uniform spray-dried silica particles encapsulating differentmodel drugs via a microfluidic jet spray drying technique, we demonstrated how the effects of formulationand process parameters on the investigated properties could be directly quantified without the complica-tions of wide particle distributions typical of conventional spray drying. The implemented strategiesincluded incorporating lactose to modify the internal microstructures to regulate release, and increasingdrying temperature during synthesis to modify the surface features of particles. The physicochemicalproperties of encapsulated drugs were shown to influence particle morphologies and release profiles,while the pH of initial precursors influenced the particle morphologies with slight effects on the initialrelease rates. The outcomes would be useful to indentify appropriate formulations and manufacturingparameters in designing spray-dried silica-based microencapsulates with tailor-made controlled releasefunctionalities.

Keywords: microfluidic jet spray drying, microencapsulation, controlled release, pharmaceutical particles,microstructure, design strategy

Introduction

Particulate-based dosage form is an important part of the

pharmaceutical and biotechnology industries (Vehring,

2008; Wang et al., 2009). These powders could be inhaled

as aerosols (Momeni and Mohammadi, 2009), pressed into

tablets (Corti et al., 2008), injected through a syringe needle

(Cevher et al., 2006) or delivered transdermally (El-Kamel

et al., 2007). For advanced therapeutic approaches, the par-

ticle properties are essential for the stabilization, transpor-

tation and activation of therapeutic ingredients

(Suksamran et al., 2009; Ye et al., 2010). Among the differ-

ent particle fabrication methods, spray drying offers the

advantages of rapid production and readily scalable pro-

cess (Sollohub and Cal, 2010), with almost no restriction for

the choice of excipient materials and drugs (Learoyd et al.,

2009), as long as the precursor solutions could be atomized.

For pharmaceutical applications with stringent require-

ments over the particle properties (e.g. size, morphology

and release modulation) (Tran et al., 2011), spray drying

does have some inherent limitations. Since conventional

atomizers generally generate droplets with various sizes

experiencing wide trajectories and drying profiles

(Masters, 1991), the spray-dried particles are almost

always polydisperse (often existing as aggregates) with

non-uniform shapes and morphologies (Kortesuo et al.,

2002). These issues lead to a lack of repeatability in terms

of the particles’ release behaviours, rendering it difficult to

correlate the physicochemical properties of the particles to

their functionalities, including dissolution and release

Address for correspondence: Cordelia Selomulya, Department of Chemical Engineering, Monash University, VIC 3800, Australia. Tel: þ61 3 99053436.Fax: þ61 3 99055686. E-mail: cordelia.selomulya@monash.edu

(Received 9 Nov 2011; accepted 12 Mar 2012)http://www.informahealthcare.com/mnc

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(Wang et al., 2006; Liu et al., 2011a). Hitherto, the influ-

ences of microstructural and morphological properties on

the controlled release properties for spray-dried particles

have largely been ignored, although they could be the

limiting factors in the design and quality control of phar-

maceutical products, as well as the scale up of the

manufacturing process (Sollohub and Cal, 2010).

The microfluidic jet spray drying technique developed

in our laboratory at Monash University can produce highly

monodispersed (non-aggregating) microparticles with

excellent uniformity, and is able to handle a variety of

multi-components precursors (Amelia et al., 2011;

Fu et al., 2011; Wu et al., 2011a). In the past, we have uti-

lized the technique to investigate the release behaviour of

polymeric particles prepared with different solvents

(Liu et al., 2011a), the effects of different dopants on

silica-based microencapsulates (Wu et al., 2011c) and the

formation of core-shell polymer/silica particles (Liu et al.,

2011b). Previously, the control over the functionalities of

particles was mainly realized from the choice of the initial

excipients materials. Currently, we set to investigate the

impacts of the manufacturing process, including drying

temperatures and pH of the precursors on the release

behaviour of the particles.

We employed the same technology here to tailor the

properties of drug-loaded microencapsulates by adjusting

the manufacturing parameters for particle formation.

Silica, as a common carrier matrix with easily tunable prop-

erties and good biocompatibility, was used as the excipient,

while lactose was also used in some of the particles to

modify their properties. Two different model drugs (rhoda-

mine B (RhB) and chromotrope 2R (ChR)) were used to

study the effects of the interactions between drug mole-

cules and the carrier matrix on the release behaviour.

Both have been used for encapsulation in various matrices

(e.g. silica, polymer and organic/inorganic hybrid) in their

stable forms to study controlled release properties (Fujii

et al., 1990; Anderson et al., 2001; Xu et al., 2008). The

outcomes should enable the development of a guideline

to fabricate silica-based pharmaceutical particles and

other spray-dried functional particles, by providing infor-

mation on the likely impacts of the precursors’ composi-

tions and drying conditions on the particle properties, thus

reducing the requirement for trial and error experiments in

conventional spray drying.

Materials and methods

Materials

Tetraethoxysilane (TEOS, �99.0% (GC), molecular

weight¼ 208.33 g/mol), lactose (alpha-D-lactose monohy-

drate), RhB, ChR and phosphate-buffered saline (PBS,

pH 7.4) consisting of 0.138 M NaCl, 0.0027 M KCl, 0.01 M

Na2HPO4�2H2O and 0.00176 M KH2PO4, were purchased

from Sigma–Aldrich (NSW, Australia). Hydrochloric acid

and sodium hydroxide were from Ajax Finechem (NSW,

Australia) and Merck (VIC, Australia), respectively.

Deionized water (Milli-Q) was used for all precursor

preparation.

Precursor preparation

The compositions of precursors for spray drying are listed

in Table 1. In a typical procedure, 22.29 mL TEOS (equals to

6.0 g silica dioxide) was added to 20 mL of 0.1N HCl solu-

tion with continuous stirring at room temperature. The

acidic hydrolysis was performed for 30 min to obtain a

homogeneous transparent sol. The sol was diluted with

deionized water to certain volumes for specific concentra-

tions of silica (e.g. the certain volume of 200 mL was used

for a 3.0% silica sol). Then 200 mL of the diluted silica sols

was taken and the pH value was adjusted to pH 2 or 5 using

HCl or NaOH. Calculated amounts of lactose and either

RhB or ChR as the model drug were added into the sil-

ica sols according to the desired ratio. The amount of

model drug was kept constant at a drug-to-matrix ratio

of 1/20 (w/w), giving a maximum theoretical drug loading

of 4.76 wt% within the final spray-dried microencapsulates.

The theoretical drug loading was calculated according to

the following equation:

Theoretical drug loading ð%Þ

¼Weight of drug � 100

Weight of drug þWeight of matrix

Table 1. Compositions of the precursors for spray drying.

Run

number

Silica

(% w/v)

Lactose

(% w/v)

Model

drug (w/w)

Precursor

pH

Inlet

temperature (�C)

Particle

size (mm)

Encapsulation

efficiency (%)

1 3.0 0.0 1/20 RhB 2 146 55.30� 1.94 98.14� 3.86

2 2.5 0.5 1/20 RhB 2 146 50.78� 4.97 98.01� 2.79

3 1.5 1.5 1/20 RhB 2 146 56.71� 2.91 95.11� 3.41

4 0.5 2.5 1/20 RhB 2 146 55.29� 3.57 99.08� 4.31

5 5.0 5.0 1/20 RhB 2 146 82.26� 6.71 94.05� 1.02

6 5.0 5.0 1/20 RhB 2 200 81.57� 5.80 95.24� 1.56

7 5.0 5.0 1/20 RhB 2 235 83.01� 2.15 94.24� 2.59

8 1.5 1.5 1/20 ChR 2 146 55.24� 2.31 97.56� 2.37

9 1.5 1.5 1/20 RhB 5 146 58.29� 4.07 96.70� 3.51

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Particle fabrication

The preparation of monodisperse microencapsulates was

done by a microfluidic jet spray drying technique as

described by a previous study (Wu et al., 2011a). Briefly,

the precursor solutions were fed into a standard steel res-

ervoir and dehumidified instrument air was used to force

the liquid in the reservoir to jet through the nozzle (orifice

diameter: 75 mm). The liquid jet was broken into droplets

by disturbance from vibrating piezoceramics. The droplet

formation mode was monitored by a digital SLR camera

(Nikon, D90) with a speed-light (Nikon SB-400) and

a micro-lens (AF Micro-Nikkor 60 mm f/2.8D). The liquid

flow rate and applied disturbance frequency were

adjusted to achieve best monodisperse droplet formation

(Wu et al., 2011b). The frequency of disturbance from

vibrating piezoceramics was kept at 12 000 Hz and the

liquid flow rate was tuned to be in the range of

1.70� 0.50 mL/min for all precursors. These monodisperse

droplets obtained were well dispersed and dried at specific

inlet temperatures.

Particle characterization

Images of microencapsulates were recorded by light

microscopy (Motic B1-223A, UK). Particle size and

size distribution were analysed using the software package

Motic Images Plus 2.0 ML and ImageJ. At least 500 parti-

cles were measured and analysed for each sample. The

morphology and microstructure of microencapsulates

before and after the release test were characterized

by field-emission scanning electron microscopy

(FESEM, JEOL 7001F, Japan). Elemental distribution

maps on particle cross-section were conducted by the

energy-dispersive X-ray analysis (equipped on the

FESEM, JEOL 7001F).

In vitro drug release test

In a typical experiment, microencapsulates (25 mg) were

weighted into a 100 mL conical flask, and 50 mL of PBS

release medium (pH 7.4) was transferred into the flask.

The flask was kept in a shaking incubator at 37�C with

constant agitation (100 rpm). At certain time intervals,

1 mL of the release medium was withdrawn from the

flask and replaced with the same amount of fresh release

medium. Collected samples were transferred into 1.7 mL

microtubes, centrifuged for 5 min at 10 000 rpm (Heal

Force, Neofuge 23R) and subjected to assay immediately.

The content of model drug in the sample was determined

by a microplate reader (SpectraMax M2e, Molecular

Devices) at the wavelength of maximum absorbance

(555 and 510 nm for RhB (Ignace, 1983) and ChR

(Han et al., 2011), respectively). Both experiments and

measurements of absorbance were done in triplicate.

Drug encapsulation efficiency

The total amount of model drug encapsulated into micro-

encapsulates was determined by dissolving an accurately

weighed amount of microencapsulates in 10 mL of 5%

NaOH solution. After the dissolution of particles, the solu-

tions were centrifuged for 5 min at 10 000 rpm and the

amount of model drug in supernatant was determined by

the microplate reader under the maximum absorbance.

The encapsulation efficiency of model drug was calculated

by dividing the amount of model drug encapsulated by the

theoretical amount of model drug (calculated from the

amount of model drug added during the manufacturing

process). Both experiments and measurements of absor-

bance were done in triplicate.

Results and discussion

The average particle size and drug encapsulation efficiency

of the final spray-dried particles are summarized in Table 1.

The encapsulation efficiency in microencapsulates was

nearly 100% of the initial drug added in the precursors in

all cases. This is desirable when dealing with valuable

ingredients in pharmaceutical and bio-related applica-

tions, as it reduces the amount of compounds that could

be lost due to poor encapsulation or from washing or sep-

aration steps. The high encapsulation efficiency was due to

the effective drying process, where each droplet was con-

verted into individual particle with virtually no waste. The

encapsulation efficiency was significantly higher than those

attainable by wet chemistry-based methods, where the

encapsulation efficiency was 550% in many cases

(Acharya et al., 2010a; Ito et al., 2011).

Effects of silica/lactose ratio on release rate

The release profiles of RhB from the spray-dried microen-

capsulates with different silica/lactose ratios are shown in

Figure 1. Pure silica microencapsulates (Run 1) showed a

very slow release rate with a cumulative release of around

10% after 48 h. Incorporation of lactose significantly

enhanced the release rate, even at the lowest concentra-

tion. Around 70% of drug was released within 48 h for

microencapsulates with 0.5% lactose (Run 2), while 80%

was released in the same period with increasing amount

of lactose added. Incorporation of lactose increased the

release rate due to its high hydrophilicity and water solu-

bility (Wu et al., 2011c). Based on our previous study,

lactose has been shown to be an effective ingredient to

boost the drug release rate (Wu et al., 2011c). By studying

the impacts systematically here, we could elucidate the

cause of the phenomenon of accelerated release from

adding lactose to the carrier matrix. Scanning electron

microscope (SEM) images of microencapsulates composed

of pure silica (Run 1) and different silica/lactose ratios

(Runs 2–4) are shown in Figure 2. All particles showed

relatively similar size and morphology with nearly spherical

Spray drying of monodispersed microencapsulates 3

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shape and relatively wrinkled surface, such that the differ-

ence in the release behaviour observed here could be

attributed solely to the addition of lactose to the matrix at

different ratios. An example of elemental distribution for

particles produced in Run 3 confirmed the relatively homo-

geneous distribution of silica and lactose (shown as

‘‘carbon’’) across the entire particle (Figure 3). As a soluble

filler, dissolution of lactose upon contact with a release

medium would provide more channels for drug diffusion,

inducing more drug molecules to be released at a given

time interval (Sinha et al., 2011). Different extents of parti-

cle degradation after the release test could be clearly

observed from the SEM pictures in Figure 4, consistent

with the observed release behaviour. In the absence of lac-

tose, only a small number of sub-micron pores were

observed after the release test, possibly due to silica erosion

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20

40

60

80

100

Cum

. Rel

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(%

)

Time (h)

3.0% Silica/ 0.0% Lactose 2.5% Silica/ 0.5% Lactose 1.5% Silica/ 1.5% Lactose 0.5% Silica/ 2.5% Lactose

Figure 1. Release profiles of microencapsulates with different silica/lactose ratios.

Figure 4. SEM images of microencapsulates after the release test:

(A: Run 1; B: Run 2; C Run 3; particles of Run 4 were not shown because

the particles were completely disintegrated).

Figure 2. SEM images of uniform spray-dried microencapsulates from:

Run 1 (3.0% silica/0.0% lactose); Run 2 (2.5% silica/0.5% lactose); Run 3

(1.5% silica/1.5% lactose); and Run 4 (0.5% silica/2.5% lactose) (inset scale

bar: 10 mm).

Figure 3. Elemental distribution maps of the cross-section of microen-

capsulates from Run 3 (1.5% silica/1.5% lactose).

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(A2 in Figure 4). However upon addition of lactose in the

matrix, relatively loose texture and large cracks were found

on the surface of the particles after release, possibly due to

the dissolution of lactose that also enhanced buffer pene-

tration into the particles (B2 and C2 in Figure 4). Hence,

lactose could be a useful regulator in tuning the speed of

drug liberated from microencapsulates.

Effects of drying temperature

Drying temperature is an important parameter in spray

drying, influencing both the products properties and the

production costs. Generally, a low drying temperature is

preferred during the production of pharmaceutical parti-

cles to conserve the properties of the active ingredients.

However, the practical drying temperature should also be

at the level where complete drying of the initial atomized

droplets could be achieved to obtain a reasonable produc-

tion yield in a short period. Here, we investigated the effects

of three inlet temperatures (146�C in Run 5, 200�C in Run 6

and 235�C in Run 7) on a specific formulation (5% silica/5%

lactose with RhB) to understand the influence of different

drying temperatures on particle properties. The tempera-

ture range was chosen to reflect the conditions that parti-

cles may experience in a typical spray drier for aqueous

solutions (He et al., 1999). The drying temperature

showed a noticeable impact on the morphology of the par-

ticles (Figure 5). High drying temperature resulted in

spherical microencapsulates with smooth surface, while a

low drying temperature led to nearly spherical particles

with rough surface. Particles dried in between these tem-

peratures showed the transition states in both shape and

surface features.

This change in particle morphology was caused by dif-

ferent drying rates (Tonon et al., 2008). Higher drying tem-

perature results in faster drying/solvent evaporation rate,

and leads to a quick formation of a smooth and hard crust

with little time to deform and form wrinkles, whereas a

slower drying rate could enhance the surface roughness

with more time to form the shell (Maa et al., 1997;

Mezhericher et al., 2010). Figure 6 showed the release pro-

files with a slightly slower release rate for the smooth par-

ticles formed at higher drying temperature. Since the

particles were relatively of the same size, the wrinkled sur-

face for lower temperature spray-dried particles could

increase the contact area with the buffer and promote a

faster release rate (Lamprecht et al., 2003).

Effects of drug type

Different model drugs (RhB/ChR with detailed physico-

chemical properties as presented in Table 2) were added

to precursors with the same compositions. The two model

drugs have very similar molecular weights and are both

highly water-soluble. The major difference is that after ion-

ization, RhB is positively charged while ChR is negatively

charged. Figures 7 and 8 displayed the SEM photos and

release profiles of microencapsulates spray-dried with

RhB (Run 3) and ChR (Run 8). The particles containing

ChR formulation had a relatively faster initial release rate

than those containing RhB.

The drug release from the matrix should be dependent

on several factors: concentration gradient of the drug,

surface area and diffusion coefficient (Acharya et al.,

2010b). Since the molecular weights of the drugs and the

drug loadings were similar with the same matrix formula-

tion, we could assume that the concentration gradient of

each drug was comparable. In addition, the minor differ-

ence in surface roughness (Figure 7) and the similar parti-

cle size implied equivalent surface areas of the particles.

Hence the difference on the initial release kinetics was

primarily caused by the diffusion coefficients due to

drug–matrix interactions. For silica-based matrix materials,

the release barriers consist of tetrahedral latticed siloxane

units with the silanol functional groups on the surface

(Wu et al., 2004). The protonation or deprotonation of

the silanol groups is dependent on the solution pH, with

the negative charges on the silica surface remaining low

Figure 5. SEM images of microencapsulates spray-dried at different inlet drying temperatures: (A) Run 5 (146�C); (B) Run 6 (200�C); and (C) Run 7 (235�C).

0 10 20 30 40 50

0

20

40

60

80

100

Cum

. Rel

ease

(%

)

Time (h)

0 1 2 3 4 50

20

40

60

80

Run 5_146oC Run 6_200oC Run 7_235oC

Figure 6. Release profiles of microencapsulates spray-dried in Runs 5–7

(under different inlet temperatures).

Spray drying of monodispersed microencapsulates 5

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until the solution pH reaches 6, and then increasing sharply

between pH 6 and 11 (Atkin et al., 2003). Since the release

test was performed at pH 7.4, there should be relatively

strong electrostatic repulsions between ChR and the silica

matrix especially at the initial stage (Burke and Barrett,

2004), with the rate decelerating at the later stage when

there was less drug available for release (thus reducing

drug gradient for diffusion).

Effects of pH of precursors

It is well known that the hydrolysis process of silicon oxides

is accompanied with a condensation process (Brinker and

Scherer, 1990). The rates of the hydrolysis and condensa-

tion are dependent on the environmental pH values and

can influence the final structures of the formed silica mate-

rials (Brinker, 1988). The condensation of silica species in a

strong acid solution is at a minimum for the pH from 1.5

to 2, which is near to the isoelectirc point (IEP), and at a

maximum for pH ranging from 6 to 7 (Cihlar, 1993). Thus,

pH 2 (near IEP) and 5 were selected here to investigate the

influence of pH values while still maintaining stable solu-

tions for the microfluidic jet spray drying. Precursors with

the same compositions but different pH values were spray-

dried under the same conditions (pH 2 for Run 3 and pH 5

for Run 9). The morphology of particles was shown

to be dependent on pH values, with particles spray-dried

from precursor with pH 5 showing more deformed shapes

than those at pH 2 (the 1st column in Figure 9). The release

profiles are shown in Figure 10, illustrating similar release

behaviours, with a slightly faster initial release rate for

those spray-dried at pH 5. Comparison of the states of par-

ticles after the release test (the 2nd column in Figure 9),

demonstrated that the particles from precursors at pH 5

showed more fragmented morphology, illustrating that

pH influenced the microstructures and consequently the

Table 2. Physicochemical properties of the two model drugs.

Name RhB ChR

Chemical structure

O

COOH

NCH3

N+

CH3

CH3

ClCH3

SONa

O

OS

ONa O

O

N

N OH OH

Molecular weight 479.01 g/mol 468.37 g/mol

Water solubility Very soluble: �50 g/L Very soluble: 4100 g/L

Figure 7. SEM images of microencapsulates spray-dried with different model drugs: Run 3 (model drug: RhB) and Run 8 (model drug: ChR) (inset scale

bar: 1 mm).

0 10 20 30 40 50

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40

60

80

100

Cum

. Rel

ease

(%

)

Time (h)

0 1 2 3 4 5

0

20

40

60

80

100

Run 3_RhB Run 8_ChR

Figure 8. Release profiles of microencapsulates spray-dried from Runs

3 and 8.

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initial release rate. The effects of processing pH could be

explained by the stabilities of silica sols (Kortesuo et al.,

2002). For sols of hydrous oxides, the repulsive barrier

could be adjusted by tuning the charge-determining ions

Hþ and OH� (i.e. pH) with the colloids usually aggregating

around the IEP (Brinker and Scherer, 1990). However in the

unique case of silica (Mou and Lin, 2000), a hydration layer

around the silica species influences the surface properties,

making the interactions among the silica species only

weakly attractive and preventing the coagulation at IEP

(Horn, 1990). It has been reported that the degree of aggre-

gation of oxide species in a sol precursor could affect the

structure of the spray-dried particles (Sizgek et al., 1998),

with the densest particles actually produced by silica sols at

the IEP (Kortesuo et al., 2002).

Conclusion

Particulates with predefined specifications are crucial in

the manufacturing and development of pharmaceutical

products. By generating uniform particles, we could sys-

tematically investigate the influence of formulation and

process parameters on the production of silica-based

microencapsulates for controlled drug release. The addi-

tion of a small molecular disaccharide (lactose) signifi-

cantly altered the microstructure of the particles, and

resulted in significantly faster release kinetics. The surface

features of the particulates were affected by the drying tem-

peratures, while the physicochemical properties of the

model drugs showed moderate influence on the release

properties. The results demonstrated a degree of control-

lability over particle properties and controlled release

behaviours through formulation and manufacturing pro-

cesses and the knowledge would be useful in designing

silica-based pharmaceutical particles for specific

applications.

Acknowledgements

Wenjie Liu would like to acknowledge Monash University

and China scholarship council for providing the collabora-

tive PhD scholarship.

Declaration of interest

The authors report no conflicts of interest. The authors

alone are responsible for the content and writing of the

article.

Figure 9. SEM images of the microencapsulates spray-dried from precursors with different pH values.

0 10 20 30 40 50

0

20

40

60

80

100

Cum

. Rel

ease

(%

)

Time (h)

0 1 2 3 4 5

0

20

40

60

80

Run 3_pH=2 Run 9_pH=5

Figure 10. Release profiles of microencapsulates spray-dried from Runs

3 and 9.

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