Chemical Engineering Science 64 (2009) 4115 -- 4122

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Chemical Engineering Science

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Continuous production of solid lipid nanoparticles by liquid flow-focusing and gas

displacing method in microchannels
Junxian Yun a , Songhong Zhang a,b , Shaochuan Shen a , Zhuo Chen a , Kejian Yao a, , Jizhong Chen b
a

State Key Laboratory Breeding Base of Green Chemistry Synthesis Technology, College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou
310032, China
b
Department of Chemical and Biochemical Engineering, Zhejiang University, Hangzhou 310027, China

A R T I C L E

I N F O

Article history:
Received 22 November 2008
Received in revised form 1 June 2009
Accepted 5 June 2009
Available online 21 June 2009
Keywords:
Particle formation
Nanostructure
Transport processes
Hydrodynamics
Slug flow microreactor
Solid lipid nanoparticles

A B S T R A C T

The liquid flow-focusing and gas displacing method is developed to produce solid lipid nanoparticles
(SLNs) continuously in a microchannel, which has a cross-junction for the focus of lipid and aqueous
solutions and a T-junction for the injection of gas bubbles. The liquid flow-focusing was achieved by
introducing a lipid solution with a water-miscible organic solvent and an aqueous surfactant solution
simultaneously through the two branches of the cross-junction into the main channel, while the gas displacing was accomplished by injecting an inert gas (N2 ) through the T-junction at the downstream of the
cross-junction into the main flow streams upward to form gasliquid slug flow. Solid lipid nanoparticles
were formed due to the local supersaturation of lipid induced by the diffusion of the solvent from the
lipid solution stream into the aqueous phase. The liquid suspension containing solid lipid nanoparticles
then passed freely through the microchannel without any blockage by the contribution of gas slug flow.
The flow behaviors were observed by a digital inversion microscope system and the hydrodynamics of
the liquid flow-focusing streams and the gas slug flow were investigated. Particle size distributions of the
solid lipid nanoparticles obtained under various conditions were measured by dynamic light scattering
and the particle morphology was examined by transmission electron microscopy. The influences of liquid velocity and lipid concentration under the gas displacing condition on the properties of solid lipid
nanoparticles were studied experimentally. The solid lipid nanoparticles with small size (the mean size
in the range of 120200 nm) and narrow particle size distribution (with values of polydispersity index in
the range of 0.140.19) had been produced by this method. The crucial roles of Taylor bubbles and liquid
slugs in the formation of solid lipid nanoparticles were considered and the transfer mechanism of slug
flow on the formation and passage of solid lipid nanoparticles in the microchannel were also discussed.
Compared with other production methods for SLNs (e.g., hot homogenization, warm microemulsions and
supercritical fluid technique), the proposed method in this work is simple and no overcritical operations
are needed during the preparing process. Therefore, it can be employed to prepare SLNs with small sizes
and a narrow diameter distribution.
2009 Elsevier Ltd. All rights reserved.

1. Introduction
Solid lipid nanoparticles (SLNs) are an alternative drug delivery system compared to conventional emulsions, liposomes and
polymeric nanoparticles. It has attracted the intensive interest of
researchers due to the excellent properties of controlled release,
long-term stability, good tolerability and potential applications in

pharmaceutical areas (Muller

et al., 1995, 2000; Mehnert and Ma der,
2001; Wissing et al., 2004; Gasco, 2007). Most preparation methods

Corresponding author. Tel.: +86 571 88320706; fax: +86 571 88320712.
E-mail address: yaokj@zjut.edu.cn (K. Yao).
0009-2509/$ - see front matter 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ces.2009.06.047

for SLNs such as high pressure homogenization, sonication, microemulsion, membrane contactor method and supercritical fluid

technology have many advantages (Muller

et al., 2000; Mehnert and
Ma der, 2001; Wissing et al., 2004; Charcosset et al., 2005, 2006;
Almeida and Souto, 2007; Chattopadhyay et al., 2007), but suffer
some overcritical operation conditions. Preparation of SLNs with
small diameter and narrow size distribution under the conditions
without overcritical operations like high speed, toxicological solvents
and high temperature or pressure, is a challenging work. Micro-sized
reactor or microchannels have been applied successfully to prepare
micro-sized liquid drops, lipid microspheres, nano-sized metal particles and nano-scale phospholipids (Sugiura et al., 2000; Schubert

and Muller-Goymann,
2003; Takagi et al., 2004; Wagner et al., 2004;
Jahn et al., 2004; van der Graaf et al., 2005; Salazar-Alvarez et al.,

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J. Yun et al. / Chemical Engineering Science 64 (2009) 4115 -- 4122

2006; Vladisavljevic et al., 2008; Kockmann et al., 2008; Ying et al.,

2008). The particle formation by the liquid flow-focusing method
(LFM) using microchannels has also been suggested as an effective
approach for preparation of SLNs with narrow size distribution. We
have prepared SLNs with the mean size diameters of 100300 nm
and relatively narrow size distributions in a co-flowing micro-tube
system and a microchannel system with a cross-junction (Zhang
et al., 2008a,b). However, due to the SLNs contained in the liquid
the blockage or deposit of particles within the microchannel occurs,
which could result in the break down and failure of particle preparation sometimes, especially in the continuous production process.
In this work, we will propose an improved method, i.e., the liquid
flow-focusing and gas displacing method (LFGDM), for the continuous production of SLNs in microchannels. The method is achieved by
employing a microchannel system with a cross-junction for the formation of stable liquid flow-focusing streams of lipid solution and
aqueous phase and a T-shaped branch channel for the accomplishment of gas displacing to prevent the deposit and blockage of SLNs
and ensure the continuous process. The principle of LFGDM will be
introduced and the effects of liquid velocities, lipid concentration
as well as gas displacing conditions on the properties of SLNs will
be investigated experimentally. The related mechanisms will also be
discussed.
2. Principles of LFGDM
In general, microchannels possess several advantages like efficient mass transfer, stable flow field and uniform concentration distribution. As demonstrated by Jahn et al. (2004) and Zhang et al.
(2008b), stable fluid streams can be obtained in microchannels by
hydrodynamic focusing of liquids through a cross-shaped junction.
Based on the rationale of hydrodynamic focusing, SLNs with small
sizes and narrow size distribution can be produced by LFM (Zhang et
al., 2008b). In fact, the formation of SLNs by LFM in microchannels is
a complex process combining the flow focusing of liquid phases, the
mass transfer of solvent and the flow of suspension containing nanosized particles. The focused flow patters can be adjusted by varying
the liquid flow velocities and thus the formation of SLNs with different properties of morphology and size. However, blockage of particles within the microchannels could break down the continuous
production of SLNs.
Actually, the deposit or fouling of solids within channels like
hollow fiber membranes, can be released by gas sparging using
gasliquid slug flow (Cabassud et al., 2001; Cui et al., 2003). Similarly, we can employ the gasliquid slug flow to prevent the blockage of SLNs within microchannels, which is expected to be helpful
to achieve the continuous preparation. Based on these fundamental
principles, LFGDM is developed by the combination of LFM (Zhang
et al., 2008b) and gas displacing method using slug flow (Kuboa and
Yonemoto, 1999; Cabassud et al., 2001; Cui et al., 2003).

Fig. 1 shows schematically the formation process of SLNs by

LFGDM. The microchannel system required for LFGDM has a crossjunction for liquid flow-focusing purpose and a T-junction for gas
displacing. It can be obtained by modifying the previous microchannel system using in LFM (Zhang et al., 2008b) with an additional Tshaped branch channel, which is employed to inject inert gas into the
flow-focusing streams of lipid solution and aqueous phase upward.
The rationale of LFGDM includes two aspects. One is the liquid flowfocusing process for the formation of expected streams of lipid and
aqueous solutions and the other is the gas displacing process for the
free passage of liquid suspension containing SLNs through the microchannel. During the former process, the lipid solution enters into
the main microchannel and the aqueous solution is introduced simultaneously through two branch channels. These solution streams
meet at the cross-junction. The flow of lipid solution is then focused
to occupy the center region, surrounded by the aqueous phase and
flows stably along the main microchannel. The water-miscible organic solvent in the lipid solution diffuses into the aqueous stream
and the local supersaturation of lipid occurs, inducing the formation of SLNs. During the latter process, the upward liquid streams
were divided by bullet-shaped gas bubbles with sizes lager than
the diameter of the microchannel, so called Taylor bubbles and slug
flow of gasliquid-SLNs suspension appears. This type of flow pattern is characterized by the intermittent occurrence of liquid slugs
and Taylor bubbles surrounded with a thin liquid film. The mass
transfer of solvent from the lipid solution stream into the aqueous
stream around it is enhanced by the complex mixing induced by slug
flow, which also contributes a positive role to the formation of more
homogenous lipid concentration field and consequently SLNs with
narrower size distribution. The intermittent movements of Taylor
bubbles and liquid slugs are expected to prevent the deposit of SLNs
and thus ensure the liquid suspension passing freely through the
microchannel without any blockage and finally accomplish the continuous production of SLNs.
3. Experimental section
3.1. Materials
Softisan 100 from Sasol (China) Chemical Co. Ltd. (Nanjing, China)
was employed as the tested lipid. Poloxamer 188 was from BASF
(China) Co. Ltd. (Shanghai, China). Other chemicals used were of
analytical grade from local sources.

3.2. Experimental set-up

The experiment set-up is shown schematically in Fig. 2(a). The
microchannel system has a main channel and two junctions. The
main microchannel is served as the flow entrance for the lipid

Fig. 1. The schematic diagram of SLNs formation process by LFGDM in the microchannel system.

J. Yun et al. / Chemical Engineering Science 64 (2009) 4115 -- 4122

4117

Fig. 2. The schematic diagram of experimental set-up (a) and the main and branch microchannels in a stainless steel plate. (1) microchannel module, (2) syringe for lipid
solution, (3) syringe for aqueous phase, (4) tank for compressed nitrogen gas, (5) gas valve, (6) pressure transducer, (7) digital ocular, (8) digital inversion microscope, (9)
personal computer, (10) liquid container, (11) stirred collection unit and (12) soap graduated-capillary for gas flow rate.

solution. The upward cross-junction has two branches for coinstantaneous passing through the aqueous phase, while the downward Tjunction has a branch channel for the injection of inert gas. The liquid
solutions were supplied by two precision syringe pumps (Model 11
plus, Harvard Apparatus Inc., Holliston, USA) and the gas was supplied from a stainless steel tank equipped with a precision gas valve.
The microchannels were fabricated in a stainless steel plate with the
thickness of 200 m by wire electrical discharge machining and the
structure is shown schematically in Fig. 2(b). The sizes of the main
microchannel and the cross-junction were same as those reported
previously (Zhang et al., 2008b), while the width, the depth and the
length of the T-junction branch channel are 470 m, 200 m and
20 mm, respectively. The stainless steel plate with microchannels
was covered by two flat polypropylene plates (thickness of 2 mm)
and tightened together by screws.

by syringes as those reported previously (Zhang et al., 2008b). N2

was injected from the supply of gas tank into the branch of the Tjunction, as shown in Fig. 3. In each run, the gas velocity was adjusted by the gas valve to a constant value to ensure the formation
of gas bubbles steadily. The images of flow behaviors in microchannels were captured by the digital inversion microscope system and
the effluent was collected by a stirred and sealed collection vessel
and used for further analysis. The gas flow rate was measure by a
soap graduated-capillary connected with the collection vessel. Both
preparations with and without injection of gas were performed at
various liquid velocities and lipid concentrations. The operation was
conducted at room temperature (27 C).

3.4. Measurement of flow behaviors

3.3. Preparation of SLNs
Typically, the lipid solution (Softisan 100 in ethanol) was pumped
into the main microchannel and the aqueous phase of poloxamer 188
(0.5%, w/w) was into the two branch channels of the cross-junction

The patterns of the liquid flow-focusing and gasliquid flow were

observed using a digital inversion microscope system, as reported
previously (Zhang et al., 2008b). The gas pressure at the T-junction
was measured using a pressure transducer (Type 511, Huba Control

AG, Wurenlos,
Switzerland).

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J. Yun et al. / Chemical Engineering Science 64 (2009) 4115 -- 4122

Fig. 3. Microscope images of the gasaqueous phase-lipid solution flow at the T-junction of the microchannel system. (ac) Rew = 53.2, ReG = 1.6, ReL = 5.7, 2 mg/mL lipid
in ethanol, (d) Rew = 186.2, ReG = 1.5, ReL = 5.7, 2 mg/mL lipid in ethanol and (e) Rew = 53.2, ReG = 1.5, ReL = 5.7, 6 mg/mL lipid in ethanol. The aqueous phase was 0.5%
Poloxamer in water and the gas was N2 .

3.5. Measurement of morphology and size distribution of SLNs

The particle morphology was examined using transmission
electron microscopy (TEM) (CM200, Philips, Eindhoven, The Netherlands). The size distribution of SLNs was tested by dynamic light
scattering (DLS) using a nanoparticle size distribution analyser (90
plus, Brookhaven Instruments Corporation, New York, USA). DLS
measurement was conducted at 90 scattered light and the temperature was 25 C, as detailed in our previous work (Zhang et al.,
2008b).
4. Results and discussion

Table 1
Summary of experimental parameters of lipid solution, aqueous phase (0.5% poloxamer 188) and gas (N2 ).
Lipid concentration
(mg/mL)

Uw (m/s)

UL (m/s)

UG (m/s)

Rew

ReL

ReG

2
2
2
2
2
6
6
6
6

0.197
0.295
0.394
0.492
0.590
0.197
0.394
0.492
0.590

0.030
0.030
0.030
0.030
0.030
0.030
0.030
0.030
0.030

0.088
0.096
0.085
0.094
0.088
0.093
0.085
0.094
0.095

53.2
79.8
106.5
133.0
159.6
53.2
106.5
133.0
159.6

5.7
5.7
5.7
5.7
5.7
5.7
5.7
5.7
5.7

1.6
1.7
1.5
1.7
1.6
1.6
1.5
1.7
1.7

4.1. Hydrodynamics of the gasaqueous phase-lipid solution flow in

the microchannel system
Fluid hydrodynamics with the present microchannels are
fundamental and important to the continuous formation of SLNs.
Therefore, the focusing flow patterns and slug flow behaviors were
explored and studied firstly. For this microchannel system, when
the lipid and aqueous solutions met at the cross-junction, the lipid
solution was focused and suppressed by the aqueous phase and
flowed along the center area of the channel, while the aqueous
solution took most of the main channel region. During the liquid focusing process, the water-miscible solvent (ethanol in this work) in
the lipid solution transferred continuously into the aqueous phase,
which induced the increase of lipid concentration in the lipid solution stream. The flow performance of liquid phases is similar as

those reported previously (Zhang et al., 2008b) and thus not shown
here. The experimental parameters carried out in this work are
summarized in Table 1.
Fig. 3 shows examples of the images of gasaqueous phase-lipid
solution flow at the T-junction of the microchannel system. The
equivalent diameter of the main channel Db (=4Lb Wb /2(Lb + Wb ),
where Lb is the length and Wb is the depth of the main channel)
is 257 m. The superficial flow velocity of lipid solution (UL ) based
on Db was maintained at 0.030 m/s and the Reynolds number of
the lipid solution ReL (=L UL Db / L , where the lipid solution density
L is 783 kg/m3 and its viscosity L is 1.07 mPa s) was 5.7. The superficial gas velocity was in the range of 0.0840.096 m/s and the
Reynolds number of gas ReG (=G UG Db / G , where the gas density G

J. Yun et al. / Chemical Engineering Science 64 (2009) 4115 -- 4122

4119

Fig. 5. Comparison of the size distributions of SLNs prepared by the liquid flow-focusing without gas displacing () (Rew = 159.6, ReL = 5.7) and by the liquid flow-focusing and gas displacing ( ) (Rew = 159.6, ReG = 1.7, ReL = 5.7). The aqueous phase
was 0.5% Poloxamer in water and the concentration of lipid was 2 mg/mL.

Fig. 4. TEM photographs of the SLNs prepared by LFGDM (a) (Rew = 53.2, ReG = 1.6,
ReL = 5.7) and by LFM without gas displacing (b) (Rew = 53.2, ReL = 5.7). The aqueous
phase was 0.5% Poloxamer in water and the concentration of lipid was 2 mg/mL.

is 1.22 kg/m3 and viscosity G is 0.018 mPa s) was 1.51.7. Both ReL
and ReG were very low and the laminar flow regime of each phase
was then expected.
As can be seen from Fig. 3(a), when the gas flow and the upward
stream of the aqueous liquid phase met at the T-junction, the bulletshaped gasliquid interface occurred firstly in the branch channel.
The interface moved quickly with the gas flow from the branch channel into the junction. The front interface of the gas was distorted,
changed their flow direction and elongated by the shear stress of the
liquid streams (Fig. 3(b)). Consequently generation of Taylor bubbles were observed. These bubbles were penetrated into the flow
streams of the liquid phases and moved along the main channel. At
the T-junction, most parts of the upward liquid flow streams were
distorted due to the entering of gas bubbles (Fig. 3(c)) and the mass
transfer of the solvent (ethanol) from the miscible lipid solution into
the aqueous phase was expected to be enhanced. At given velocities of gas and lipid solution, when the aqueous phase velocity Uw
increase from 0.197 to 0.688 m/s, both the flow areas occupied by
the lipid solution stream and by gas bubbles in the main channel
decreased, as shown in Fig. 3(d). The reason is that the drag force
on the lipid solution or gas babbles induced by the aqueous phase
flow is enhanced by the increase of the flow velocity of the aqueous phase. The flow behaviors at different lipid concentrations, e.g.,
2 mg/mL in Fig. 4(c) and 6 mg/mL in Fig. 3(e), are similar and more
other images are then not shown here. Under the present gas displacing conditions, the pressure drop between the inlet and outlet
of the main channel varied in the range of 0.460.74 atm.
4.2. Morphology of SLNs
Fig. 4(a) shows an example of TEM image of SLNs obtained by
LFGDM. The superficial velocities of the gas, the aqueous phase and
the lipid phase were 0.088, 0.197 and 0.030 m/s, respectively. The

lipid concentration was 2 mg/mL. Fig. 4(b) displays the TEM image
of SLNs under the same conditions of liquid phases and flow velocities but without gas displacing, i.e., by LFM. As can be seen, the SLNs
obtained by LFGDM are also nearly circular in shape and the morphology is similar as those without gas displacing, indicating that
the gas flow has no obvious negative effects on the particle morphology and shape under the present gas flow conditions compared with
those obtained under the conditions without gas displacing. The total
numbers of 22 particles in Fig. 4(a) and 37 particles in Fig. 4(b) were
chosen randomly from the TEM photograph and used to calculate
the mean sizes of SLNs by these two methods. The results showed
that the sizes of particles produced by LFGDM are approximately in
the range of 100220 nm and the mean size is about 137 nm, while
the sizes of particles prepared by LFM without gas displacing are in
the range of 80210 nm and the mean value is 118 nm, indicating
that these particles prepared using both methods are very close. In
the case using acetone as the miscible solvent without gas displacing as reported in our previous work (Zhang et al., 2008b), the mean
size of SLNs prepared at the lipid phase velocity of 0.028 m/s and
the aqueous phase velocity of 0.169 m/s was about 115 nm and the
sizes were in the range from 70 to 160 nm, which are also similar
to those obtained using ethanol as the miscible solvent in this work.
The particle morphology of those SLNs using ethanol is also similar
as that using acetone (Fig. 5 in the work by Zhang et al., 2008b).
4.3. Diameters and size distributions of SLNs
In the microchannel system with a cross-junction, the mean diameter and size distribution of SLNs prepared by LFM without gas
displacing were found to be influenced by the aqueous phase velocity, the lipid velocity as well as the lipid concentration (Zhang et
al., 2008b). In the case of using gas displacing, gas bubbles were introduced into the flow streams of the upward aqueous phase and
lipid solution and then the gasliquid flow occurred along the main
channel. In order to evaluate the effect of process conditions on the
particle formation, the aqueous phase velocity and the lipid concentration under the gas displacing condition were considered here as
two influence parameters and the preparation of SLNs were then
carried out using 2 and 6 mg/mL lipid solutions at various aqueous flow velocities with the superficial gas velocity in the range of
0.0840.096 m/s and particle size distributions of the obtained SLNs
were studied.

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J. Yun et al. / Chemical Engineering Science 64 (2009) 4115 -- 4122

Fig. 6. Variation of the mean diameter (a) and polydispersity index (b) of SLNs with Reynolds number of the aqueous phase. The SLNs were prepared using 2 mg/mL lipid
solution by LFM (), by LFGDM ( ) (ReG = 1.51.7) and using 6 mg/mL lipid solution by LFM without gas displacing () by LFGDM () (ReG = 1.51.7), respectively. The
aqueous phase was 0.5% Poloxamer in water and ReL = 5.7.

Fig. 5 displays an example of particle size distributions with and

without gas displacing at the superficial velocity of aqueous phase
of 0.590 m/s, the superficial lipid solution velocity of 0.030 m/s and
the lipid concentration of 2 mg/mL. The superficial gas velocity in
the gas displacing was 0.088 m/s. Particle size distributions under
the conditions of other aqueous phase velocities and lipid solution
concentrations were similar and not shown here. It is seen that the
sizes of most SLNs obtained by LFM were about in the range of
50280 nm, while those produced by LFGDM were about in the range
of 70260 nm, indicating that a narrow or even a narrower size distribution had been achieved with gas displacing.
Fig. 6(a) shows the variation of the mean diameters with the
Reynolds number of the aqueous phase flow Rew (=w Uw Db / w ,
where w and w are the density and viscosity of the aqueous solution) under the conditions with and without gas displacing. As can
be seen, the mean diameters of SLNs produced by LFGDM for different lipid concentrations (2 and 6 mg/mL) were very close to those
produced by LFM under the same liquid flow conditions, indicating
that the gas displacement had no obvious negative effects on the diameters of SLNs. It is also seen that the mean diameters of SLNs obtained increased slightly with the increase of Rew , as those observed
for the SLNs produced without gas displacing. Moreover, the SLNs
obtained using ethanol as solvent by the present method were in the
range of 120200 nm and slightly smaller than those obtained using
acetone as solvent under the similar operation conditions reported
previously (Zhang et al., 2008b).
Fig. 6(b) shows the variation of the polydispersity index with the
Reynolds number of the aqueous phase flow Rew . As can be seen, the
polydispersity index values of the SLNs produced by LFGDM are in
the range of 0.140.19 and for the SLNs produced without gas displacing of 0.180.29, indicating that these SLNs have narrow particle
size distributions, as those produced using acetone as solvent (Zhang
et al., 2008b). The polydispersity index values of SLNs produced by
LFGDM were even smaller than those obtained by LFM under the
same liquid flow condition without gas displacing, indicating that
more uniform particles were obtained by the present method. Actually, for a given lipid velocity the suppression of the flow stream
of lipid solution increased with the increase of Rew or the aqueous
phase velocity. On the one hand, the solvent transfer from the lipid
solution was enhanced by increasing Rew , which accelerated the formation of local concentrated zones within the liquid slug regions On
the other hand, the solvent transfer from these concentrated zones
were also enhanced by the gas displacing. Therefore, local supersaturation zones with more homogenous concentration distributions

and smaller volumes formed and consequently the SLNs with more
uniform diameters were produced.
4.4. Formation mechanisms of SLNs by LFDGM
When the lipid solution met the two aqueous phase streams at the
cross-junction the flow-focusing occurred. The lipid solution took up
the channel center stream and the aqueous phase flowed around the
lipid solution stream and the focusing characteristics and mass transfer behaviors were same as those reported previously (Zhang et al.,
2008b). When the two liquid streams arrived at the T-junction, the
gas bubbles leave off, immerged into the flow streams and the liquid
streams were divided into series of liquid slugs by Taylor bubbles.
This process was characterized by the bubbles to fill the T-junction
followed by the bubble pinching off and the insurgent liquid squeezing the gasliquid interface receded, similarly as those observed in
other T-shaped microchannels (van Steijn et al., 2007). Along the
main channel, the space between the channel wall and Taylor bubbles was occupied by liquid film. Therefore, local concentrated lipid
zones could form both within the liquid film and the liquid slug regions due to the strong mass transfer induced by the gasliquid slug
flow and parameters of gasliquid slug flow play important roles to
the properties of SLNs.
During the formation process of SLNs within the present microchannel system, parameters of Taylor bubbles and the flow patterns in liquid slugs are crucial and thus needed to be estimated and
determined. Among them, the length and velocity of Taylor bubbles
are two key parameters. The reason is that the bubble length always
influences the size of the lipid stream zones formed and the bubble
velocity controls the depositing or clogging of SLNs within the microchannels. Thus these two parameters play a significant role in the
formation of SLNs with narrow size distribution and the free passage
of suspension through out the microchannel system.
Based on the experimental characteristics and theoretical models
of gasliquid slug flow in tubes (e.g., Ghosh and Cui, 1999; Yun and
Shen, 2003a,b) or T-junction microchannels (e.g., Garstecki et al.,
2006; van Steijn et al., 2007; Warnier et al., 2008), the length of Taylor
bubbles LTB generated by the T-junction in the present microchannel
can be determined by the width of the T-junction branch wG and the
flow rate ratio of dispersed (gas in this work) to the carrier fluids
(lipid solution and aqueous phase in this work)

LTB = wG 1 + 2

QG
QL + Qw


(1)

J. Yun et al. / Chemical Engineering Science 64 (2009) 4115 -- 4122

Fig. 7. Variation of the length of Taylor bubbles with Rew . The lipid concentration
was 2 mg/mL () or 6 mg/mL ( ).

where 1 and 2 are constants depending on the geometry of Tjunction. QG , QL and Qw are the flow rates of the gas, the aqueous
phase and the lipid solution, respectively. For LFGDM, Eq. (1) can be
re-written as


UG
(2)
LTB = wG 1 + 2
UL + Uw
where 1 = 2 = 1.5 (van Steijn et al., 2007). The velocity of Taylor
bubbles UTB can be calculated by
UTB =

A
(UL + Uw + UG )
ATB

(3)

where A and ATB are the cross-section areas of the main microchannel
and the Taylor bubbles. Warnier et al. (2008) reported the ratio value
in rectangular microchannels ATB /A 0.820.84.
For the lipid solutions of 2 and 6 mg/mL in this work, the lengths
of Taylor bubbles given by Eq. (2) at different Rew are shown in
Fig. 7. It is seen that the bubble lengths estimated were about in
the range of 7801000 m and decreased with the increase of Rew .
These bubbles have lengths more than 2 to 3 times of the main channel and thus could segment the liquid streamlines effectively into
slugs, where most of the SLNs were formed. Fig. 8 shows the variation of UTB given by Eq. (3) with Rew under the same conditions as
Fig. 7. As can be seen, the estimated values of UTB were in the range
of 0.380.98 m/s and increased with the increase of Rew . Therefore,
under the present condition the bubble velocities were high enough
to prevent the deposit or blockage of SLNs.
Different from that in the liquid flow-focusing case, the mass
transfer of solvent from the local concentrated lipid zones within liquid slugs were influenced by the liquid flow patterns. For gasliquid
slug flow in microchannels, there were different flow patterns inside
the liquid slugs, depending on the capillary number Ca (Thulasidas
et al., 1997). For a large Ca a complete bypass flow inside the liquid
slug could be observed, while for a very small Ca ( < 0.1) counter
rotating vortices could be observed (Warnier et al., 2008).
In the present microchannel system, Ca within the main channel
can be determined as
Ca =

w UTB
w

(4)

where w and w are the viscosity and surface tension of the aqueous phase. The surface tension of the poloxamer solution is about
40 mN/m (Alexandridis et al., 1994; Elversson and Millqvist-Fureby,

4121

Fig. 8. Variation of the velocity of Taylor bubbles with Rew . The lipid concentration
was 2 mg/mL () or 6 mg/mL ( ).

2006; Pornsunthorntawee et al., 2008) and the viscosity is 0.95 mPa s.

Therefore, the values of Ca is in the range of 0.0090.023, which were
much low and the bypass flow patterns could not occur inside the
liquid slugs but the toroidal vortices could be formed. The liquid circulation within slugs could improve the mass transfer of solvent and
thus led to more uniform lipid concentration field. With the increase
of distance away from the T-junction, the miscible solvent (ethanol
in the present work) transferred quickly into the aqueous phase and
water diffused into the lipid solution at the same time, due to the
effects of both gas bubbles and liquid recirculation within the slugs.
After the local supersaturation zone was formed, SLNs was finally
obtained. Because of the more efficient mass transfer and uniform
lipid concentration field under the conditions of gas displacing, the
SLNs formed had narrower size distributions compared with those
by LFM.

5. Conclusions
Continuous production of SLNs without particle blockage can be
achieved by LFGDM in the microchannel system with cross and Tshaped junctions. The complex slug flow of gasaqueous phase-lipid
solutionSLNs is formed by injecting the gas through the T-junction
into the main channel. Under the present conditions, the focused liquid streams of the aqueous phase and lipid solution can be divided
effectively into liquid slugs by Taylor bubbles. Due to the small capillary number (0.02) considered in this case, the liquid circulation
patterns are expected within these liquid slugs, which improve the
mass transfer of solvent and led to a more uniform local lipid concentration field within a given slug. Therefore, the SLNs with even
a narrower size distribution can be obtained compared with those
by LFM without gas displacing. By LFGDM, most of the mean diameters of the SLNs obtained are in the range of 120200 nm under the
present operation conditions and increasing the flow velocity of the
aqueous phase can decrease the mean diameters.
Compared with other preparation methods like high pressure
homogenization, microemulsion and supercritical fluid technology,
the present method is simple and without overcritical operations
like high speed, toxicological solvents and high pressure. Therefore,
it is expected to be applied in the preparation of SLNs with small
sizes and a narrow diameter distribution.

4122

J. Yun et al. / Chemical Engineering Science 64 (2009) 4115 -- 4122

Acknowledgments
The work was financially supported by National Natural Science
Foundation of China under Grant no. 20606031. The financial support
partially by Zhejiang Provincial Natural Science Foundation of China
under Grant no. Y406164 is also acknowledged.
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