Journal of Microencapsulation, 2012, 1–8, Early Online ß 2012 Informa UK Ltd. ISSN 0265-2048 print/ISSN 1464-5246 online DOI: 10.3109/02652048.2012.680510 Spray drying of monodispersed microencapsulates: implications of formulation and process parameters on microstructural properties and controlled release functionality Wenjie Liu 1 , Winston Duo Wu 1 , Cordelia Selomulya 1 and Xiao Dong Chen 1,2 1 Department of Chemical Engineering, Monash University, VIC 3800, Australia and 2 Department of Chemical and Biochemical Engineering, College of Chemistry and Chemical Engineering, Xiamen University, 361005 Fujian Province, P.R. China Abstract Particulates for pharmaceutical applications require stringent control over their characteristics to realize the optimal therapeutic performance. By generating uniform spray-dried silica particles encapsulating different model drugs via a microfluidic jet spray drying technique, we demonstrated how the effects of formulation and 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 strategies included incorporating lactose to modify the internal microstructures to regulate release, and increasing drying temperature during synthesis to modify the surface features of particles. The physicochemical properties 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 initial release rates. The outcomes would be useful to indentify appropriate formulations and manufacturing parameters in designing spray-dried silica-based microencapsulates with tailor-made controlled release functionalities. 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: [email protected](Received 9 Nov 2011; accepted 12 Mar 2012) http://www.informahealthcare.com/mnc 1 Journal of Microencapsulation Downloaded from informahealthcare.com by Monash University on 07/30/12 For personal use only.
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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.
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
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(%
)
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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60
80
100
Cum
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(%
)
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
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(%
)
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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