journal of

controlled
ELSEVIER
release
Journal of Controlled Release 38 (1996) 219-228

Liquid-liquid emulsification by rotor/stator homogenization

Yuh-Fun Maa *, Chung Hsu
Department of Pharmaceutical Research and Development, Genenteeh, Inc., 460 Point San Bruno Boulevard,
South San Franciseo, CA 94080, USA

Received 29 March 1995; accepted 15 August 1995

Abstract

Liquid-liquid emulsification is a critical step in the double-emulsion microencapsulation process ( W / O / W or O / W / O ) . This

study focuses on the preparation of the primary emulsion ( W / O or O / W ) using rotor/stator homogenization. These homogenized
emulsions were characterized based on the emulsion droplet size. Emulsion droplet size was mainly determined by the shear
forces generated in the turbulent zone within the gap between the spinning rotor and the stationary stator. It was found that the
size of these droplets decreases with increasing homogenization intensity and duration. The dependence of emulsion droplet size
on viscosity, total volume size, volume ratio of the continuous phase to the dispersed phase, and the rotor/stator design was also
investigated. The scaleability of rotor/stator homogenization is limited by the internal circulation determined by the rotor/stator
assembly. Experiments using a large-scale rotor/stator homogenizer were conducted and the circulation rate was estimated using
a simple flow model. As an alternative approach, an externally circulated flow-through homogenization process was used and
compared to the batch operation. The results derived from this study can serve as a basis for the evaluation of large-scale liquid-
liquid emulsification in a microencapsulation process.

Keywords: Liquid-liquid emulsification; Microencapsulation; Rotor/stator homogenization; Emulsion; Droplet size

1. Introduction two-step emulsification process which uses a water-in-

The generation of fine liquid-liquid emulsions is a
common practice in the food and pharmaceutical indus-
tries. To be more specific, liquid-liquid emulsification
is critical to the multiple-emulsion solvent extraction
technique used for the preparation of multi-phase
microspheres for sustained-release applications [ 1,2].
Encapsulating active agents such as water-soluble pro-
teins and polypeptides is currently drawing increasing
attention from researchers in this field due to their ther-
apeutic importance [3]. Incorporating these hydro-
philic macromolecules in organic polymer matrices,
either biodegradable or non-biodegradable, requires a
* Corresponding author. Tel. (415)-225-6349.
oil-in-water ( W / O / W ) double emulsion. The major
difference between the primary and the secondary
emulsion lies in the size of the emulsion droplets. The
primary emulsion is much finer ( 1/zm or smaller) than
the secondary emulsion (normally 20-100/~m). Until
now, the majority of microencapsulation studies have
focused on the secondary emulsification, including our
previous investigations on the development and the
scale-up of the secondary emulsification ( O / W or W/
O) using stirred tank mixers and static mixers [4,5].
However, there is only limited information available
on the effect of the primary emulsion on the properties
of the microspheres [6]. Also, the primary emulsion
was rarely characterized in most of the studies. This
study, therefore, will address the primary emulsion

0168-3659/96/$15.00 1996 Elsevier Science B.V. All rights reserved

S S D 1 0 1 6 8 - 3 6 5 9 ( 9 5 ) 001 23-9
220 E-F. Maa, C. Hsu / Journal of Controlled Release 38 (1996) 21 ~ 2 2 8
~ stationary
stator
~]~4 Shearing
rotor
Fig. I. Schematic representation of the configuration of a rotor/stator
homogenizer.
( W / O and O / W ) , particularly the characterization of
emulsion droplet size.
Modern emulsions have been prepared on an indus-
trial scale by a variety of emulsification equipment
based on a similar operating principle, agitation. Rotor/
stator homogenization belongs to this category but its
mechanism and parameter effects lack thorough inves-
tigation. The rotor/stator assembly consists of a rotor
of two or more blades and a stator with either vertical
or slant slots around the wall of the homogenizer cell.
The rotor is housed concentrically inside the stator
(Fig. 1 ). As the rotor rotates, it generates a vacuum to
draw the liquid in and out of the assembly, thereby
resulting in circulation. One of the two major forces
which can reduce the size of the dispersed droplets is
mechanical impingement against the wall due to high
fluid acceleration. Another force is the shear force tak-
ing place principally within the gap between the rotor
and the stator. At high rotational speeds, the flow in
this region is highly turbulent and contains eddies of
different scales. Obviously, homogenization intensity
(power) and the residence time that emulsion droplets
stay in the shearing field are the primary parameters for
controlling emulsion droplet size. Other parameters
that might affect the performance of rotor/stator
homogenization are the viscosity of the two liquids,
surfactant, rotor/stator design, volume size, and vol-
ume ratio of the two phases.
In this study, we investigated the effect of the oper-
ating parameters associated with rotor/stator homog-
enization on the size of the emulsion droplets to
understand the mechanism and optimize the operating
conditions for small-scale and large-scale emulsifica-
tion. To solve the problem of non-uniform mixing com-
monly occurring in large-scale emulsification, an
alternative homogenization system aided by an external
circulation was designed and was compared with the
batch system.
2. Materials and methods
2.1. Materials
Poly(methyl methacrylate) ( P M M A ) was pur-
chased from Aldrich Chemical Company. Its molecular
weight was determined by the supplier to be 25 000.
Analytical-grade methylene chloride (MeCI2)
obtained from Baxter was used as the solvent for the
preparation of an oil phase. Polyvinyl alcohol (PVA)
was used as an emulsifier and was provided by Air
Products and Chemicals, Inc. under the trade name of
Airvol 205. Bovine serum albumin (BSA) was used
as a model protein. It was provided in a powder form
of Cohn fraction V and was obtained from Interegen
Co. The reasons for using PMMA as a model polymer
are that PMMA and the commonly used biodegradable
polymer, poly(DL-lactic-co-glycolic acid), had similar
microencapsulation properties and PMMA is very
inexpensive [4,5].
2.2. Rotor/stator homogenizer
A Virtishear homogenizer (Virtis, Templest IQ)
consisting of a digital display microprocessor control,
an overhead drive, and a homogenizing shaft was used.
The shaft came in two sizes, 1 and 2 cm. The shaft tip
is a rotor/stator assembly capable of generating ultra-
fine and fine dispersions depending on the shaft size
(Fig. 1 ). The I-cm assembly (micro-tip) has a rotor
with four blades and a stator with 12 vertical narrow
rectangular slots around the wall. The 2-cm assembly
(macro-tip) has two blades and the stator has eight
slant slits around the wall. The rotational speed can be
steadily controlled in the range of 5000 and 25 000 rpm
for both shafts.
 Y.-F. Maa, C. Hsu /Journal of Controlled Release 38 (1996) 219-228
2.3. Batch homogenization by rotor/stator
The schematic representation of the homogenization
device was described previously [4,5]. The emulsion
vessel is a jacketed glass container with an inner cyl-
inder of 6 cm height (H) X 2.5 cm inner diameter (ID)
and a septum-capped side-port. The inner tube was
filled with 10-15 ml of the continuous phase (PMMA/
MeC12 solution or aqueous BSA solution). The dis-
persed phase (aqueous BSA solution or PMMA/
MeC12 solution) was injected into the continuous phase
through the side-port with a syringe while the rotor/
stator homogenizer was running. To homogenize an
emulsion 10 times the original volume of the continu-
ous phase ( 100 ml), a scaled-up version of the glass
device ( 10 cm H X 4 cm ID) and the macro-tip rotor/
stator were used. For batches 50 times (500 ml) and
100 times ( 1000 ml) the original size, a 11 glass beaker
(15 cm H 10 cm ID) was used, and the dispersed
phase was injected from the top of the beaker with a
long needle extending to the rotor/stator tip. The injec-
tion time was 10-60 s depending upon the volume of
the emulsion. Homogenization duration was timed
from the end of the injection (time zero).
A small sample of the emulsion (approximately 0.2
ml) was taken at predetermined time periods (0, 0.5,
1, 2, 3, 4 and 5 min) using a syringe through the side-
port at a distance of 0.3-0.5 cm from the rotor/stator
tip. Emulsion samples were diluted 200-fold with meth-
ylene chloride immediately after homogenization. The
emulsion droplet size was determined by a laser-based
particle size analyzer as described below. The validity
of this size characterization method will be discussed
later.
2.4. Flow-through homogenization by rotor/stator
A flow-through rotor/stator homogenization was
conducted using the apparatus presented in Fig. 2. In
this system the dispersion head (Virtis company)
which was sealed with two Viton O-rings houses the
tip of a 2-cm homogenization shaft. A Masterflex con-
sole drive peristaltic pump (5-600 rpm) equipped with
an easy-load pump head was used. The tubing was also
made of Viton (Masterflex, 0.25 inch). After the
homogenizer was turned on, the peristaltic pump cir-
culated polymer solution from the reservoir into the
inlet port of the dispersion head. Prior to the inlet, a tee
221
homogenizer
I
flow-through
outlet
shaft" [[ pump
tip inlet /"'x
injection of
protein aqueous polymer solution
solution reservoir
Fig. 2. Schematic representation for the flow-through dispersion head
homogenization method. A 2-cm homogenization macro-tip is
housed within a flow-through dispersion head. The system consists
of a solution reservoir, the inlet and outlet ports, and a septum capped
t e e for the injection of protein solution. The emulsion is circulated
by a peristaltic pump.
with a septum-cap arm was inserted for the injection of
aqueous protein solution. The homogenized solution
was returned to the reservoir through the outlet port
and circulated for a pre-determined time period. Emul-
sion samples of approximately 0.2 ml were taken
through the septum-capped port using a syringe. Other
conditions such as sampling time and total homogeni-
zation time were similar to those used in the batch
homogenization process. The use of a flow-through
homogenizer allows a continuous emulsification proc-
ess. This continuous process will be compared with the
batch process in terms of large scale emulsification.
2.5. Particle size and emulsion droplet size analysis
A laser-based particle size analyzer (Brinkmann,
Model 2010) was used to determine the size of the
emulsion droplets. The system was capable of detecting
particles in size ranging from 0.5 to 150/zm. The mean
diameter of the droplets was calculated from the vol-
ume-moment average of the particle size distribution,
i.e. (~d4dn) / (~d3dn). Each reported value represents
the average of at least two determinations. The proba-
bility volume density graph was used for identifying
the particle size distribution.
Samples for droplet size determination required dilu-
tion to prevent light scattering interference from other
222 Y.-F. Maa, C. Hsu / Journal of Controlled Release 38 (1996) 219-228
droplets. Surface solidification (due to protein precip-
itation or water extraction) occurred during dilution.
Several experiments were conducted to demonstrate
that the diluted droplets do not coalesce and that hard-
ening occurs only at the interface. It was found that
decreasing the volume ratio between MeC12 (the dilut-
ing solvent for the W / O emulsion) and the emulsion
from 200:1 to 40:1 does not affect the droplet size. The
droplet size did not change when acetone, a water-
miscible solvent which was supposed to facilitate water
extraction, was used as the dilution solvent. In addition,
the droplet size did not change significantly with dilu-
tion time. These observations suggest that emulsion
droplets were stable and that there was no coalescence
occurring. In another experiment, a water-saturated
MeCI 2 solution was used for dilution. The resulting
droplets had the same size as those hardened in the
water-free MeC12 solution, suggesting that the droplets
became hardened primarily at the surface. Furthermore,
a small amount of the emulsified sample was diluted
and stabilized at least 100-fold in MeC12 containing 2%
Tween 85 (emulsion stabilizer) prior to size analysis.
Particle sizes measured before and after dilution in the
presence of Tween were essentially identical, suggest-
ing that the hardened droplets do not coalesce. For the
O / W system, the diluent was pure water.
2.6. Viscosity determination
The viscosities of both the continuous and dispersed
phases (/~o and/z,~) were determined using Cannon-
Fenske capillary viscometers at 25C. Equations
describing the relationship between viscosity and con-
centration for PMMA/MeC12 solution and aqueous
polyvinyl alcohol (PVA) solution (the continuous
phase used in the O / W emulsion) at 25C have been
reported previously [4].
2.7. Interfacial tension determination
The interfacial tension between the aqueous and
organic phases was determined by a Surface Tensiomat
(Fisher, Model 21) equipped with a 6 cm circumfer-
ence platinum-iridium ring. Each data point represents
the average of three measurements.
3. Results and discussion
3.1. Batch homogenization by rotor/stator
Background
Intense agitation creates turbulent flow consisting of
turbulent eddies with a spectrum of eddy sizes. Hydro-
dynamic forces, mainly shear forces, arise through the
motion of turbulent eddies [7]. Turbulent eddies
smaller than the size of the dispersed liquid drops are
most effective in exerting shear forces on the surface
of these liquid drops [7,8]. As the surface shear
exceeds the cohesive forces of the drops, they fragment
to smaller drops. Fragmentation continues until the bal-
ance between these forces is reached. Our previous
studies [4,5 ] using dimensional group analysis have
indicated that the droplet size is a function of the exerted
shear force, the interfacial tension and viscosity of the
emulsification system in both an agitated vessel and a
static mixer. The turbulence is expected to be much
more intensive in the rotor/stator homogenizer than in
an agitated vessel or a static mixer because emulsifi-
cation in the rotor/stator homogenizer is achieved by
rapid flow circulation and high shear force within the
narrow gap between the rotor and the stator (less than
0.5 mm). Factors that could influence the circulation
rate and shear force are the design of the rotor/stator
assembly, the rotational speed of the rotor, the total
volume and the viscosity of the emulsion. These para-
meters were investigated in this study.
Homogenization intensity effect
Fig. 3 shows the time course of emulsion droplet size
(EDS) decreases during homogenization at 5000 to
24 000 rpm using either a micro-tip or a macro-tip. In
each case, the emulsion consists of 10 ml of 0.4 g/ml
PMMA/MeC12 solution as the continuous phase and 2
ml of 0.2 g/ml aqueous BSA solution as the dispersed
phase. As seen in Fig. 3, all time-course profiles show
an initial size reduction period (transition) and a lev-
eling-off period (equilibrium). The transition period
for the micro tip system is prominent at low homoge-
nization intensity (5000 rpm) and narrows down to be
barely noticeable at 24 000 rpm. This also holds true
for the macro tip system.
When the relationship between the equilibrium
emulsion droplet size (from Fig. 3) and homogeniza-
tion intensity for both the macro-tip and micro-tip sys-
 Y.-F. Maa, C. Hsu / Journal of Controlled Release 38 (1996) 219-228
20 . . . . . .
15
o
0 1
Homogenization time(min)
Fig. 3. Profiles of the homogenization time vs. the emulsion droplet size for the emulsion of a 0.4 g/ml PMMA/MeC12 solution and a 0.2 g/ml
aqueous BSA solution at a volume ratio of 10:2 (ml:ml) homogenized by a micro and a macro-tip at different homogenization intensity from
5000 rpm to 24 000 rpm.
tems is plotted, the equilibrium emulsion droplet size
decreases with respect to the increase in homogeniza-
tion intensity by an exponential decay function to its
minimum. W e define this minimum droplet size as the
ultimate equilibrium emulsion droplet size ( U E E D S ) .
The occurrence of UEEDS probably can be explained
from the hydrodynamic point view. Turbulent eddies
are required to break the dispersed phase into droplets.
The scale of the turbulent eddies decreases with the
increase of homogenization intensity until a critical
point where the eddies are so small that their energy is
lost as heat through viscous dissipation [8]. At a
homogenization speed of 15 000 rpm in the micro-tip
system and l0 000 rpm in the macro-tip system, the
turbulent eddies reach this critical scale. Consequently,
homogenization at even higher speeds cannot generate
turbulent eddies of a size smaller than the critical scale
to further fragment the droplets. It is also interesting to
note that at the same angular velocity, the linear veloc-
ity of the homogenization tip in the macro system is
twice as fast as that in the micro system. The macro-tip
system reached the UEEDS at 10 000 rpm but the
micro-tip system achieved the UEEDS at 15 000 rpm
instead of 20 000 rpm perhaps due in part to the differ-
ence in rotor design (2-blade rotor for the micro-tip vs.
the 4-blade rotor for the micro-tip).
223
O 5K rpm (micro-tip)
. . . . . . I ' ' ' I"1 10K rpm (micro-tip)
A 15K rpm (micro-tip)
24K rpm (micro-tip)
~, 5K rpm (macro-tip)
" 10K tpm (macro-tip)
~ I5K rpm (macro-tip)
3 2 4 5 6
Curve fitting in the form of Dp = a (homogenization
intensity) *' gives b = - 1.72 for the micro-tip system
( R = 0 . 9 7 8 ) and b = - 1.14 for the macro-tip system
( R = 0 . 9 5 0 ) . In a previous study [4] on the effect of
the system parameters on the microsphere size using a
baffled, mixed tank, b was found to be - 1.12 for a
double 6-blade flat Rashton impeller system. Interest-
ingly, the b value for the macro-tip system is essentially
identical to the b value for the tank system. This sug-
gests that a macro-tip system, although different from
the mixed tank system in homogenization mechanism,
is able to produce the same homogenization effect as
the tank system.
Viscosity effect
Fig. 4 shows the effect of homogenization duration
on emulsion droplet size at different P M M A and BSA
concentrations with an organic to aqueous volume ratio
of 10:2 homogenized at 5000 rpm using the micro-tip
system. The viscosity of P M M A / M e C I 2 solution (the
continuous phase) at 0.2, 0.4 and 0.6 g / m l was deter-
mined to be 9.2, 44 and 313 cP, respectively. For aque-
ous B S A solutions (the dispersed phase) at 0.2, 0.3
and 0.4 g / m l , their viscosities are 4.3, 40 and 410 cP,
respectively. The emulsion size decreases with time for
each condition studied. A more viscous continuous
224 Y.-F. Maa, C. Hsu / Journal of Controlled Release 38 (1996) 219-228

35 - -0 - - PMMA/BSA (0.2/0.2 g/mL)

- PMMA/BSA (0.6/0.2 g/mL)
-- ~.- - PMMA/BSA (0.4/0.2 g/mL)
30 '%
- -X- -PMMA/BSA (0.4/0.4 g/mL)
':~' " . 2 0 - - -]-- - P M M A / B S A (0.6/0.4 g / m L )
%
25 %

'~ 20
o
-, 15
o "0- ~0- -- -- - - 0 m --0

fi 10

. , . ,+ . . . . . . . + . . . . . . . + . . . . . . . + . . . . . . . +

, , , , I , . , , I , , , , I , , , , I . . . . I , , , ,

0 1 2 3 4 5 6
Homogenization time(min)
Fig. 4. Profiles of homogenization time vs. the emulsion droplet size for emulsions homogenized at 5000 rpm by a micro-tip at an organic:aqueous
volume ratio of 10:2. Emulsions used are PMMA/MeCI2 and aqueous BSA solutions at different concentrations (PMMA in g/ml; BSA in g/
ml): 0.2; 0.2, 0.4; 0.2, 0.6; 0.2 0.4; 0.4, and 0.6; 0.4.

phase has a slightly shorter transition period and was found to be proportional to / . L d i s p1e r s e d and to O.I

-- 0 . 4 3
smaller equilibrium emulsion droplet size than a less /Xconti . . . . . . Our previous liquid-liquid emulsification
viscous continuous phase. study [4,5] for preparing microspheres concluded that
0.22 -- 0 . 4 2
The relationship between the equilibrium emulsion microsphere size is proportional to /.Ldispersed~LLcont i. . . . .

droplet size (EDS) (data obtained from Fig. 4) and in a baffled, mixed tank, but proportional to
0.004 O.56
the viscosity of the two phases is shown in Fig. 5. Based /XdisperseJXco,,i, .... in a static mixer These emulsifica-
on the curve fitting in Fig. 5, the emulsion droplet size tion methods showed the same trend of EDS decreasing

- - O - - Dispersion phase (PMMA/MeCI) I

25 phase (aqueous BSA)
[] - Dispersed
I
I []
20

"\=.~ J I

15
f ..... y = 61.803 * x ^ ( - 0 . 4 2 9 1 4 ) R= 0 . 9 9 6 9 5
g LO - y = 10.804 * x ^ ( 0 . 1 0 5 5 1 ) R = 0 . 9 8 0 0 7

= 10

'~ 5
5
, i . , I , , , , I . , , . I , i , , I , , . .

0 100 200 300 400 500

Viscosity (cps)
Fig. 5. Curve fittings for the emulsion droplet size (from Fig. 8) as a function of solution viscosity for continuous phase (PMMA/MeCI2) and
the dispersed phase (aqueous BSA solution).
 E-F. Maa, (2. Hsu /Journal of Controlled Release 38 (1996) 219-228
24
22
k []
20
~- 18
14
12 , . . , I , , .
0 l
Fig. 6. Profiles of the homogenization time vs. the emulsion droplet size for emulsions of a 0.4 g/ml PMMA/MeCI, solution and a 0.2 g/ml
BSA aqueous solution homogenized at 5000 rpm by a micro-tip at an organic to aqueous volume ratio of 10/1, 10/2 and 10/5.
with increasing viscosity of the continuous phase and
with decreasing viscosity of the dispersed phase. The
absolute value of the coefficient for/Xco,1,....... in all of
the systems is higher than that for/Xdi~per~eJ, indicating
that the viscosity of the continuous phase has a more
dominating effect than the viscosity of the dispersed
phase. Interestingly, the coefficient for/x~o,,, ...... in the
micro-tip system is essentially identical to the coeffi-
cient for/Z~o,,~...... in the baffled, mixed tank system,
suggesting the viscosity of the continuous phase might
play a similar role in affecting the EDS in these two
systems. Intuitively, dispersing a more viscous solution
under the same agitation conditions requires higher
input power. This viscosity effect can be explained
from the hydrodynamic point of view. The turbulent
shear stress (~.~t>) carried by eddies on the surface of
the dispersed phase was expressed by Bird et al. [9]
as:
"r~'~ = #~'>dv/dl
where/x C'~ is the eddy viscosity and dv/dl, i.e. shear
rate, represents the velocity change over the turbulence
of scale 1./Z '~ is a complex function of several molec-
ular parameters including a linear relationship with the
viscosity of the continuous phase. This means that the
shear stress increases with increasing viscosity of the
continuous phase, resulting in smaller emulsion
droplets.
225
I
10/1 (organic:aqueousvolumeratio) I
10/2 (organic:aqueousvolumeratio)
o)
I
. I , ~ , . I . , . , I . . . . I . . . .
2 3 4 5
Time(min)
The effect of ]-Ldispersed o n the emulsion droplet size
appears straightforward. The viscoelastic force of the
dispersed phase is another force that can resist droplet
fragmentation. Solution viscosity is a direct measure of
the fluid viscoelastic force and the transfer of momen-
tum during fluid flow. Causing a viscous solution to
flow requires higher energy and so does fragmenting
viscous liquid drops. Thus, droplet size increases as the
viscosity of the dispersed phase increases. There is no
clear similarity among the micro-tip homogenizer,
mixed tank, and static mixer in the extent of the effect
of the dispersed phase viscosity on EDS. However,
]-dispersed consistently has less of an effect on the emul-
sion droplet size than/Xco,t~.....
Emulsion volume and volume ratio effects
The effect of the volume ratio between the continu-
ous phase (PMMA/MeC12 solution) and the dispersed
( 1) phase (aqueous BSA solution) on EDS is shown in
Fig. 6. Emulsions of three different volume ratios, 10:1,
10:2 and 10:5, were prepared by homogenization at
5000 rpm using a micro-tip assembly. For comparison,
injection lasted about 10 s regardless of the actual vol-
ume of the BSA solution. As seen in Fig. 6, an identical
equilibrium emulsion droplet size (approximately 13
/zm) was obtained in all three cases. The transition
period of the time course profile, however, increased
with decreasing volume ratio. This trend is consistent
226 Y.-F. Maa, C. Hsu / Journal of Controlled Release 38 (1996) 219 228

4 ' ' " ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' '

< O 10/2 (organic:aqueous) in m L , injection tO sec I

k I [] 100/20 (organic:aqueous) in mL, injection 3 0 sec

=3t B
I
O
X
5 0 0 / 1 0 0 (organic:aqueous) in m L , injection 3 0 sec
1 0 0 0 / 1 0 0 (organic:aqueous) in m L , injection 6 0 sec
I
c

~ 1

0 , , , , I , , , , I , , , , I , , , , I

0 1 2 3 4
Homogenization time(min)
Fig. 7. Profiles of the homogenization time vs. the emulsion droplet size for emulsions of a 0.4 g/ml PMMA/MeCI2 solution and a 0.2 g/ml
aqueous BSA solution homogenized at 15 000 rpm by a macro-tip at an organic to aqueous volume ratio of 10/2 (ml:ml) with an injection
duration of 10 s, 100/20 with an injection duration of 30 s, 500/100 with an injection duration of 30 s and 1000/100 with an injection duration
of 60 s.

with that found in preparation of the P M M A micros-
pheres using a P V A solution as the continuous phase
(data not shown).
The effect of emulsion volume on EDS was inves-
tigated for the macro-tip system by increasing the total
emulsion volume from 12 ml (10 ml of 0.4 g / m l
P M M A and 2 ml of 0.2 g / m l B S A solution) to 120 ml
(100:20), 600 ml (500:100), and 1100 ml
(1000:100), i.e. 10, 50 and 100 fold increase in the
continuous phase, respectively. Injection duration var-
ied from 10 to 60 s depending on the injection volume
of the dispersed phase. The profiles of EDS vs. duration
of homogenization operated at 15 000 rpm are pre-
sented in Fig. 7. The equilibrium emulsion droplet size
is consistently around 1.0-1.5 p,m regardless of the
difference in the total emulsion volume. However, the
homogenization time required to yield the EDS (i.e.
the transition period) changes depending on the total
volume and how long the injection lasts. When the
injection duration is added to the zero time point, it
shows a trend that the transition period increases with
increasing emulsion volume probably because a larger
volume needs a longer time to process.
Flow circulation model
Flow circulation through the tip of the rotor/stator
homogenization system is contributed by the pressure
difference due to the vortex and centrifugal forces.
Exact solutions of this fluid dynamic problem are com-
plex and difficult to solve. Nevertheless, the difference
in circulation rates between the micro-tip and macro-
tip assemblies can be estimated. The total area of the
opening (A) and the radial velocity (L,) at the opening
as a result of the pressure difference ( A p ) within the
vortex must be obtained. The Ap can be approximated
by a simplified system which contains a cylindrical
container of radius R rotating at an angular velocity of
g2. This is a typical vortex system in which the shape
of the free surface of the fluid is parabolic (Ref. [9],
pp. 98-100). The pressure profile can be expressed as:
A p = p - - p o = -- pg( z-- zo) + p12Zr2/2 (2)
where p is the pressure within the fluid, z the height
from the bottom of the container, r the distance from
the axial line, Po and Zo the pressure and height at the
lowest point of the free surface, respectively, p the fluid
density, and g the gravity constant. Apparently, Ap
increases as the fluid is closer to the wall. This simpli-
fied system differs from the actual system within the
homogenizing cell (Eq. 2) mainly in two aspects. Our
system generates an upside-down vortex and has open-
ings around the wall. The radial velocity is not zero in
the actual system.
A p in Eq. 2 changes with P, i.e., the ratio of pressure
drops for the 2-cm (macro-tip) and 1-cm (micro-tip)
 Y.-F. Maa, C. Hsu / Journal of Controlled Release 38 (1996) 219 228 227

7 . . . . I . . . . I . . . . I . . . . I . . . .

FTDI-I (500/100 in mL, 0.6 L/min circulation)

6 FFDH (1000/100 in mL, 0.6 L/rain circulation)
~ ~ . . ~ A ~ FrDtt (1000/100 in mL, 1 L/rain circulation) .
,_.= 5
"3 ~O
4
m_
o
E 3 U
.....

2
~a
1 v~ O O

0 . . , , I , . . , I , . , , I . . . . I , , , ,

0 1 2 3 4 5
Homogenizationtime(min)
Fig. 8. Profiles of the homogenization duration vs. the emulsion droplet size for emulsions of a 0.4 g/ml PMMA/MeCIe solution and a 0.2 g/
ml aqueous BSA solution homogenized at 15 000 rpm by a macro-tip at an organic to aqueous volume ratio of 1000/100 (ml:ml) by a batch
operation, 500/1000 by FI'DH homogenization method circulated at 0.6 l/min, 1000/100 by FTDH homogenization circulated at 0.6 and 1 1/
min.

equals 4:1. If Zip is completely converted to velocity, enization systems when large rotor/stator homogeni-
A L, is proportional to zip0.5 according to the energy zation tips are used.
balance equation [9]. Therefore, the ZIt, ratio between
the macro-tip and the micro-tip is proportional to the r 3.2. Continuous-flow homogenization by rotorZ~tator
ratio, i.e. 2:1. The total opening area is 5 cm 2 for the
stator in the macro-tip system and 1.2 cm 2 for the stator External-circulation-aided homogenization offers an
in the micro-tip system. Since the circulation rate ( Q ) alternative homogenization method (Fig. 2). The con-
is proportional to the product of A and t,, the ratio of tinuous phase ( P M M A solution) in the reservoir was
pumped into a flow-through dispersion head ( F T D H )
( Q . . . . . ) . . . . . and (Qmicro) vortex is approximately 10:1.
which housed a macro-tip assembly for emulsification.
This ratio might be greater if the centrifugal force
Aqueous BSA solution was injected through a tee prior
( C F ) is considered. Assuming another simplified con-
to the inlet port. The emulsion returned to the reservoir
dition where C F is mainly caused by the deflection of
to form a closed-loop. Changes in EDS as a function
the fluid in the radial direction by the legs of the rotor,
of the homogenization duration for emulsions homog-
the resulting circulation rate is the product of the radial
enized by the FTDH method are shown in Fig. 8. All
velocity and the area of the plane generating the radial
the emulsions have the same composition (0.4 g / m l of
velocity. The ratio of ( Q . . . . . )CF and (Qmicro)CF w a s PMMA/MeC12 solution and 0.2 g / m l of aqueous BSA
calculated to be 5:1 for the C F effect alone; therefore, solution). P M M A solution was homogenized with 100
( Q ...... )to,al:(Q,nicro)total is at least 50:1 when both the ml of BSA solution at a pumping rate of 0.6 l / m i n for
vortex and C F factors are combined. A separate circu- the 0.5 and 1 1 batch and 1 l / m i n for the 1 1 batch at
lation experiment indicated that the micro-tip could 15 000 rpm. For comparison, the profile for a 1 I batch
circulate 50 ml of 0.4 g / m l P M M A solution satisfac- homogenization using the macro-tip at 15 000 rpm
torily, but was unable to homogeneously emulsify the (from Fig. 7) is also included in Fig. 8. The equilib-
volume of 100 ml. However, the macro-tip assembly rium emulsion droplet sizes by the FTDH method are
could successfully homogenize 21 of the same solution 2, 3, and 4.6/xm for the 1 1 batch at a pumping rate of
(data not shown). This suggests that our simplified 1 l/min, 0.5 1 batch at 0.6 l/min, and 1 I batch at 0.6 1/
theoretical calculation can explain large-scale h o m o g - min, respectively. These sizes were consistently larger
228 IL-F. Maa, C. Hsu / Journal of Controlled Release 38 (1996) 219-228
than those prepared by the batch method which pro-
duced droplets of around 1 /zm. The size of emulsion
droplets prepared by the FTDH method was determined
by the circulation rate and the total emulsion volume.
Emulsion droplets spent less time in the rotor/stator
gap for emulsions of large volume regardless of the
circulation rate because the emulsification time is deter-
mined by the ratio between total volume and the gap
volume. Since emulsion droplets are stable within
hours because PMMA is a good emulsifier, the coales-
cence of droplets in the hold tank during circulation is
not a concern. Also, the droplet size was primarily
determined at the early stage ( mainly in the first 1 min).
Droplets were hardened due to solvent extraction at the
surface and became difficult to be further fragmented
during the later stage of homogenization. Therefore,
smaller droplets were obtained for emulsion of a
smaller volume at a higher external circulation rate.
Since the macro-tip system was estimated to be able to
circulate the emulsion at a rate greater than 1 1/min
internally as mentioned in the earlier section, it pro-
duced smaller emulsion droplets in the batch process
than the FTDH method did using the circulation rate of
1 l/rain. It is feasible to use the FTDH method for large-
scale homogenization but it is efficient only at fast
circulation rates.
4. Conclusions
Process parameters that could affect the emulsion
droplet size during rotor/stator homogenization were
investigated. The change of emulsion droplet size
(EDS) was found to be kinetic, reducing initially and
then reaching a constant, equilibrium value. The emul-
sion droplet size decreased with increasing homoge-
nization intensity using both the micro- and
macro-tips. An ultimate equilibrium emulsion droplet
size of around 1 /xm was obtained when the homoge-
nization intensity exceeded 10 000 rpm with the macro-
tip system. The EDS decreased with increasing
viscosity of the continuous phase and with decreasing
viscosity of the dispersed phase. Changes in the emul-
sion volume ratio between the two phases showed no
significant effect on the equilibrium EDS. Homogeniz-
ing emulsions with volumes up to 1 1 using a macro-
tip assembly was successful. A flow-through dispersion
head ( F T D H ) method was evaluated to compare with
the batch operation and was shown to be feasible for
homogenizing large emulsion volumes if a fast external
circulation is provided. The results derived from this
study can serve as a basis for the evaluation of large-
scale liquid-liquid emulsification in a microencapsu-
lation process.
Acknowledgements
The authors are grateful to Dr. Tom Patapoff and
Mr. Andrew Walsh for their suggestions during the
preparation of this manuscript.
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