European Journal of Pharmaceutical Sciences 45 (2012) 657–667

Contents lists available at SciVerse ScienceDirect

European Journal of Pharmaceutical Sciences

journal homepage: www.elsevier.com/locate/ejps

Particle engineering of benzoic acid by spherical agglomeration

Jyothi Thati a, Åke C. Rasmuson a,b,⇑
a
Department of Chemical Engineering and Technology, Royal Institute of Technology (KTH), SE-100 44 Stockholm, Sweden
b
Department of Chemical and Environmental Science, Materials and Surface Science Institute, Solid State Pharmaceuticals Cluster, University of Limerick, Limerick, Ireland

a r t i c l e i n f o a b s t r a c t

Article history: The influence of process conditions on the properties of benzoic acid spherical agglomerates, are inves-
Received 19 April 2011 tigated. Agglomerates are produced in a fed-batch agitated tank process. Benzoic acid is dissolved in eth-
Received in revised form 12 December 2011 anol and the solution is mixed with the bridging liquid, before being fed into an agitated aqueous
Accepted 9 January 2012
solution. A broader investigation has been performed using heptane as the bridging liquid, and in further
Available online 15 January 2012
experiments different bridging liquids are compared. The results show that the bridging liquid has an
influence on the product properties, with diethyl ether and ethyl acetate being at the extreme end with
Keywords:
no agglomerates formed at all. Using any of the other five solvents (chloroform, toluene, heptane, pen-
Spherical agglomeration
Bridging liquid
tane, or cyclohexane) spherical agglomerates are formed, as long as a sufficient amount of the bridging
Benzoic acid liquid is used. The results show that the particle size and strength increase with increasing amount of
Physico mechanical properties, size bridging liquid, and with decreasing temperature. At amount of bridging liquid producing optimum par-
distribution, particle morphology and ticle shape, the largest agglomerates are produced when using either cyclohexane operating at 5 °C, or
mechanical strength, elastic recovery, using toluene in a process at 20 °C. The highest particle fracture stress is obtained using toluene as the
compressibility bridging liquid regardless of temperature. The particle shape depends on the bridging liquid, and
becomes completely spherical when toluene or pentane is used. For four of the solvents the particle mor-
phology improves with decreasing temperature, but for cyclohexane the result is the opposite. By contin-
ued agitation beyond the completion of the feeding, particle size and strength gradually increases and
also the shape gradually becomes more spherical. High compressibility and low elastic recovery suggest
that the particles are favorable for direct tabletting. The results are analyzed and discussed against cap-
illary theory and granulation mechanisms.
Ó 2012 Elsevier B.V. All rights reserved.

1. Introduction
Spherical crystallization is a solvent exchange crystallization
method in which crystal agglomeration is induced during the crys-
tallization through the addition of a third solvent, termed the
‘‘bridging liquid’’. The process is performed in a three partially mis-
cible solvent system (good, poor solvent, and bridging liquid). Far-
nand et al. (1961) suggested that when two immiscible solvents
are present and one of the solvents preferentially wets the solid
surface, a collision between two wetted particles leads to the for-
mation of a liquid bridge between the particles. This liquid bridge
holds the particles together by interfacial tension effects and cap-
illary forces (Kawashima et al., 1984), and by further random col-
lisions large spherical agglomerates can form (Blandin et al.,
2000). Zhang et al. (2010) investigated the spherical crystallization
process by means of particle vision measurement and microscopy
⇑ Corresponding author at: Department of Chemical Engineering and Technology,
Royal Institute of Technology (KTH), SE-100 44 Stockholm, Sweden. Tel.: +46 8
7908227; fax: +46 8 105228.
E-mail address: rasmuson@ket.kth.se (Å.C. Rasmuson).
and found the process to be occur in three stages i.e., emulsion for-
mation; nucleation and crystallization; and spheronization.
Spherical crystallization is a useful particle design technique
that can be employed to improve the micrometric properties of
pharmaceutical powders. Important parameters are the amount
of bridging liquid added into the system (Bausch and Leuenberger,
1994; Blandin et al., 2005), the stirring rate (Bos and Zuiderweg,
1987; Tambo and Watanabe, 1979; Blandin et al., 2003), the tem-
perature (Kawashima et al., 1984; Zhang et al., 2010), feeding rate
(Sang et al., 2006; Kawashima et al., 1982), and the initial particle
size (Capes and Sutherland, 1967; Kawashima and Capes, 1976).
Hasan (2001) has explored the influence of solvent on the size dis-
tribution of spherical agglomerates. However, there is still a lack of
understanding of the underlying mechanisms, and hence also for
what properties the solvents should have to form an adequate sys-
tem. Accordingly, the selection of the solvent system is done by
trial and error.
In our previous work experiments were performed using benzoic
acid as a model compound. Benzoic acid normally crystallizes as
needles or flakes. Benzoic acid was dissolved in ethanol and was
fed to water used as the anti-solvent. Initially (Katta and Rasmuson,

0928-0987/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.ejps.2012.01.006
658 J. Thati, Å.C. Rasmuson / European Journal of Pharmaceutical Sciences 45 (2012) 657–667
2008), chloroform was used as bridging liquid and was added after
the anti-solvent crystallization, as described by Kawashima et al.
(1984). However, in further work it was found that the agglomera-
tion was much better if the bridging liquid was mixed into the feed
solution, and this method was adopted in the next study (Thati and
Rasmuson, 2011) in which toluene is used as the bridging liquid. In
this work it is found that with increasing amount of bridging liquid
the particle size and strength increases and morphology improves.
Particle size decreases and the fracture force increases with increas-
ing feeding rate but the morphology remains unchanged. It is also
found that, using toluene as opposed to chloroform as the bridging
liquid leads to improved product properties. The results further
show that along the course of the process the properties of the par-
ticles change gradually but substantially. Particle size and number
increases along with increasing feed amount. The spherical shape
does not appear immediately but develops gradually, and is shown
to be very much the result of the agitation of the slurry.
The present work has two objectives. The first objective is to
continue the investigation of the influence of processing conditions
using a different bridging liquid, i.e., heptane, having favorable
properties as judged from our previous experience of benzoic acid
and also being an acceptable solvent for industrial operation. In
particular the influence of the amount of bridging liquid and the
temperature is examined. The second objective is to investigate
the influence of the selection of the bridging liquid. Besides hep-
tane, six additional solvents were selected based on low solubility
in the anti-solvent (water). The contact angle of the bridging liquid
on benzoic acid powder compacts is determined, and product par-
ticles are investigated for particle size, morphology, and strength.
Compression characteristics for single agglomerates are compared
with data on bed compression.
2. Materials and methods
2.1. Materials
Benzoic acid (C6H5COOH) (99% purity; Merck) was used as a
model compound, ethanol as good solvent (99.7% purity purchased
from Solveco chemicals AB) and filtered, de-ionized water as the
anti-solvent. Bridging liquids used were heptane (99%, VWR),
cyclohexane (99.5%, VWR), pentane (95%, VWR), ethyl acetate
(99.8%, VWR), diethyl ether (99.5%, VWR), toluene (99–99.4% pur-
ity; Merck), and chloroform (99–99.4% purity; Merck). Properties
of solvents used as bridging liquid are listed in Table 4.
2.2. Experimental method
In the experiments, benzoic acid is dissolved in ethanol at 40 °C
to a concentration (0.375 g/ml) corresponding to saturation at
15 °C. This solution is cooled to 20 °C and the required amount of
bridging liquid is added. Then the mixture is fed by a syringe pump
(YA-12), at the selected feeding rate, onto the surface of 76 ml of
water agitated in a 250 ml jacketed crystallizer (6 cm in diameter)
by a three-blade marine propeller (2.5 cm in diameter). The agitator
is centrally located at fixed distance (1 cm) from the bottom of the
crystallizer and temperature is controlled by a heating/cooling cir-
culation unit (Julabo, FP50-HP). After the termination of the feeding
the agitation continues for a certain time, and then the agglomer-
ates are filtered, washed with water and dried at room temperature.
The dried particles are characterized for size, shape, and strength. In
addition, size and shape of crystals are occasionally examined.
2.3. Experiments
In all experiments the benzoic acid concentration in ethanol is
0.375 g/ml before mixing with the desired amount of bridging li-
quid, the volume of feed solution is 23 ml including the bridging
liquid (the amount of bridging liquid ranges from 13% to 18% of
the feed at different BSR (volume of bridging liquid/volume of ben-
zoic acid)), the feeding rate is 1.73 ml/min and the agitation rate is
600 rpm. Normally the agitation continues after the termination of
the feeding for up to a total processing time of 1 h.
A broader experimental program has been performed using
heptane as the bridging liquid in which volume of bridging li-
quid/volume of benzoic acid (BSR), time of continued agitation
after the termination of the feeding and temperature have been
studied. The work includes experiments at BSR at 0.72, 0.82,
0.92, 1.02, 1.12, 1.23 all performed at 5 °C. In the calculation of
the BSR, the volume of solid is determined as the weight of solid
originally dissolved divided by the density (q) of benzoic acid
(1316 kg/m3, Othmer, 1992). The influence of different times of
continued agitation were studied at 5 °C and using BSR = 1.02,
and other conditions being unchanged. The feeding is done at
1.73 ml/min and hence takes 13.3 min to complete, and the agita-
tion is continued for up to a total processing time of 30, 45, 60, 90,
or 150 min. Experiments were done at 5, 10, 20, and 30 °C to exam-
ine the influence of temperature. The influence of the bridging li-
quid is investigated using also pentane, cyclohexane, chloroform,
and toluene at 5 and 20 °C and at different BSR. (For pentane only
experiments at 5 °C were performed as boiling point is very low.)
2.4. Particle characterization
The dried spherical agglomerates were sieved with woven wire
test sieves of DIN 4188 standard. The sieving was carried out in
10 min intervals until the weight of the different fractions re-
mained constant. The particle size distribution is obtained from
measuring the weight of the sieve fractions and are presented as
cumulative over size mass distributions. The morphology of the
agglomerates from each sieve fraction was examined by optical
microscopy (Olympus SZX12) and scanning electron microscopy
(JEOL Carry Scope JCM 5700). The agglomerate strength was deter-
mined by compressing agglomerates in a material-testing machine
(Zwick 2.5/TS1S) using a 10 N load cell. Measurements were made
on 30 agglomerates randomly selected from each selected sieve
fraction of each batch. The diameter of each particle (d) before
the compression is determined at the time the extensometer is
touching the surface of the particle. The measured force–displace-
ment curves are recalculated into stress–strain (r–e) curves by Eqs.
(1) and (2):
F
r¼ 2
ð1Þ
ðp4d Þ
l
e¼ ; ð2Þ
d
where F stands for force (N), and l for linear displacement (m). For a
few agglomerates, the same particle was exposed to repeated com-
pression–release cycles (0.5 mm/min) to evaluate the elasticity of
the particles. Initial size (Hi) and the minimum size (Hc) of the
agglomerate at maximum compression was determined, as well
as the size of the particle after releasing the load (He) to determine
the elastic recovery (ER). The elastic recovery for each compres-
sion–release was calculated by Eq. (3) (Fichtner et al., 2007).
 
He  Hc
Elastic recovery ¼ ð3Þ
Hi  Hc
As a complement, also the corresponding compression charac-
teristics have been determined for a bed of particles. About 100–
150 mg of agglomerates were poured into a cylindrical steel cup
(8.2 mm in diameter) and the bed was compressed in the same
 J. Thati, Å.C. Rasmuson / European Journal of Pharmaceutical Sciences 45 (2012) 657–667
way as the single agglomerates. For single particle compression the
maximum force used is 1 N, which corresponds to a maximum
stress of 0.8 MPa based on the particle cross sectional area. For a
bed of the particles the maximum force used is 10 N, which corre-
sponds to a maximum stress of 0.19 MPa based on total bed cross
sectional area.
The compressibility (Fichtner et al., 2007) is calculated as:
qp  q0 Hi  Hc
Compressibility ¼ ¼ ;
qp Hi
where qp is the bulk density at the maximum load of 0.19 MPa
(10 N) and q0 bulk density of the uncompressed powder bed.
To determine the wetting ability of different solvents, contact
angle measurements were done on compacts of benzoic acid by
the sessile drop method, using a Goniometer (CAM200, KVS Instru-
ments Ltd.) attached to a microscope. About 200 mg of benzoic
acid particles with a size of 200–300 lm was compressed into
disks (10 mm diameter and 2 mm thick) in a hydraulic press using
different forces (20 and 50 kN). The powder was loaded into the die
using a funnel and the die assembly was kept in the hydraulic
press. The load was applied for 1 min and then the disks were re-
moved carefully from the die set. Equilibrium contact angles of
pure water, cyclohexane, heptane, pentane, toluene, chloroform,
ethyl acetate, and diethyl ether on the surface of benzoic acid com-
pacts were determined. Each drop (5–6 ll) was placed on the sur-
face of the compact, and the contact angles were measured on two
sides of each drop. The difference between each drop ranged from
0° to 2°. At least three measurements were done for each liquid. All
the organic solvents specified above spread out immediately on the
benzoic acid compact surface i.e., the contact angle is 0°, except for
water droplets where the contact angle becomes 43°. Muster and
Prestidge (2002) measured contact angles on both powder com-
pacts and single crystals and found no difference in the results. Be-
cause of the very low contact angles, experiments have been
conducted under the microscope in order to clarify whether the li-
quid is just sucked into the compact and not spreading out because
of low contact angle. The studies do support the view that in fact
the contact angles are very low and the solvents are spreading
out on the powder disk.
3. Results and analysis
3.1. Influence of processing conditions using heptane as bridging liquid
The results show that the amount of bridging liquid is one of the
most important parameters, and that there is a critical range of BSR
(volume of bridging liquid/volume of benzoic acid) outside of
which spherical agglomerates are not formed. At 5 °C the critical
range for water-ethanol-heptane system was found to be BSR from
0.72 to 1.23. When the BSR is less than 0.72 agglomeration was
incomplete. Above BSR = 1.23 the product contains very big
agglomerates and paste-like material. The product particle size dis-
tribution for the experiments with BSR in the range of 0.72 to 1.02
is presented in Fig. 1. For experiments with BSR = 1.12 and 1.23 the
product particles are too large (2–6 mm) to be characterized by the
sieving set used. In our previous work on toluene as bridging liquid
the suitable range of BSR was found to be 0.47–1.16 at 20 °C (Thati
and Rasmuson, 2011), and also in this case the particle size clearly
increases with increasing amount of bridging liquid.
The particle morphology (as observed by optical microscopy)
does not change dramatically with changing BSR in the range
0.72–1.23. This result differ from the corresponding work on tolu-
ene (20 °C) previously reported, where a significant change in par-
ticle morphology with BSR was observed. In Fig. 1 is shown SEM
pictures of the surface of particles produced using heptane. Overall
659
the crystals are in the size range below 100 lm and the overall
shape is somewhat plate-like and sometimes needle-like (width
2–30 lm, length 30–100 lm). At BSR = 0.82 and 0.93 the crystals
and the packing are essentially the same as at BSR = 0.72, however
at BSR = 1.02 the crystals are smaller and appear to be more packed
together than at BSR = 0.72. Table 1, shows that the fracture stress
of individual agglomerates increases with increasing BSR. The
same behavior is found when toluene is used as bridging liquid
ð4Þ (Thati and Rasmuson, 2011).
In Fig. 2 is shown that the average product agglomerate size
clearly increases as a result of continued agitation beyond the mo-
ment of termination of the feeding. The SEM photographs show
that after 30 min total processing time (roughly two times the time
of the feeding) nice 1 mm-sized agglomerates have formed but
they are far from spherical and maybe contain some larger internal
voids (as indicated by pore openings at the particle surface). Parti-
cles allowed to mature for double the time (60 min) under agita-
tion are still about 1 mm in size, but are much more spherical
and voids opening at the surface cannot be seen. The surface of
the particles matured for 90 min is shown in the third photograph,
and is essentially equal to the surface of particles agitated for
30 min. Table 1 shows that there is a steady increase in agglomer-
ate fracture stress with increasing agitation time. These findings
agree well with the previous results obtained using toluene as
the bridging liquid: during continued agitation, particle size in-
creases, particles become more spherical and the strength
increases.
As shown in Fig. 3 the product agglomerate size quite clearly in-
creases with decreasing temperature. At 5 °C the dominating parti-
cle size fraction is 1000–1250 lm whereas at 30 °C it is 250–
450 lm. The comparison in Fig. 3 is made at the optimum BSR
for each temperature. As shown in Table 2, with decreasing tem-
perature the yield (amount of agglomerated product/amount of
solute actually dissolved) increases, i.e., the amount crystallized in-
creases, and the reason should be a decreasing solubility. At an
increasing amount crystallized we expect the optimum BSR to in-
crease. The temperature does not show much influence on the par-
ticle morphology for this system. The surface of particles produced
at two different temperatures are shown in Fig. 3. The micrographs,
suggest that there is a fairly clear increase in crystal size with
increasing temperature. A reason for this is that the lower solubil-
ity at lower temperature will lead to a higher supersaturation, and
this should lead to a stronger nucleation and smaller product crys-
tals. As shown in Table 1, with increasing temperature the fracture
stress decreases, i.e., particles produced at low temperature are
stronger than those produced at high temperature. Further results
on the influence of temperature are presented in the chapter on the
influence of the solvent.
In general, product particle properties from experiments using
toluene as the bridging liquid (Thati and Rasmuson, 2011) have
superior properties compared to those produced using heptane.
This observation has motivated more work into the role of the sol-
vent and this is presented below.
3.2. Influence of the bridging liquid
Among the solvents used as bridging liquid toluene, chloroform,
cyclohexane, heptane and pentane lead to spherical agglomerates
under properly tuned process conditions. Diethyl ether and ethyl
acetate could not produce any spherical agglomerates but the crys-
tals aggregated into very loose flocs. In Fig. 4 is presented the size
distribution of the product agglomerates depending on the bridg-
ing liquid used for experiments at two different temperatures.
The comparison is made for the BSR giving the best morphology
for each solvent. Quite clearly, at 20 °C larger particles are obtained
using chloroform or toluene, while at 5 °C the particles are fairly
660 J. Thati, Å.C. Rasmuson / European Journal of Pharmaceutical Sciences 45 (2012) 657–667

Cumulative under size

1
0.8
0.6 1.02
0.4 0.92
0.82
0.2
0.72
0

00 0

0
50 0

00 0
80 0 0
45 0

63 0

00 0
20 0

00
12 25

14 40

16 60
10 0 0
45

63
0

8
2

-2
-1

-1

-1
0-
0-

0-

1
0-

0-
Particle Size (µm)

BSR=0.72 BSR=1.02

Fig. 1. Influence of BSR (heptane) on product particle size distribution and morphology (sieve size: 1000–1250 lm) at 5 °C: Benzoic acid conc. = 0.375 g/ml, N = 600 rpm,
feeding rate = 1.7 ml/min, experiment time = 60 min.

Table 1
Fracture stress for different BSR, experiment time, temperature: particle size 1000–1250 lm, Benzoic acid conc. = 0.375 g/ml, N = 600 rpm, feeding rate = 1.7 ml/min.

Bridging liquid Temperature (°C) Experiment time (min) BSR (volume of bridging liquid/volume of solid) Fractures stress (MPa)
Heptane/BSR 5 60 0.82 0.17
0.93 0.19
1.02 0.23
Heptane/experiment time 5 30 1.02 0.21
60 0.23
90 0.25
150 0.26
Heptane/temperature 5 60 1.02 0.23
10 0.93 0.18
20 0.93 0.14
Cyclohexane/temperature 5 60 1.02 0.32
20 0.93 0.17
Toluene/temperature 5 60 1.02 0.45
20a 0.93 0.3
Pentane 5 60 1.4 0.18
Chloroform 20b 60 0.93 0.2
a
Thati and Rasmuson (2011).
b
Katta and Rasmuson (2008).

large also in cyclohexane and heptane. The amount of bridging li-
quid required is higher at 5 °C, since the amount crystallized is
higher. For pentane as bridging liquid the BSR required to produce
spherical agglomerates is higher perhaps because the high volatil-
ity actually leads to some loss during mixing and feeding (pentane
boiling point = 36 °C).
Figs. 5–8 provide SEM pictures of product particles from exper-
iments using different bridging liquids. Fig. 5 shows particles pro-
duced using cyclohexane as bridging liquid at two different
temperatures. At 20 °C (5a) the particles from the lower sieve frac-
tion are not spherical, but the shape however improves with
increasing size. At 5 °C (5b) no particles are actually close to being
spherical. The particles also have voids opening at the particle sur-
face as shown in Fig. 5c. The photographs indicate a state where
primary agglomerates have merged together into larger secondary
agglomerates but the consolidation is rather premature. It appears
as if the particles have not been given sufficient time, under the
influence of the agitation, to age into a more spherical and dense
form. Fig. 6 show SEM pictures for experiments using heptane as
bridging liquid at 5 °C. The particles are more or less completely
spherical throughout the size range. At 20 °C the particles in gen-
eral are smaller, but the shape is essentially the same as those of
5 °C. In the low sieve fraction (0–250 lm), though, some particles
are single, needle like crystals, but the amount is less than 1% of
the total weight of particles. In Fig. 7 is shown particles using pen-
tane as the bridging liquid at 5 °C. There are no single crystals or
irregular particles, but all the particles are highly spherical agglom-
erates without any voids. The surface of the particles is very
smooth, and the crystals are very small compared to those pro-
duced using other bridging liquids. Fig. 8 shows particles produced
in toluene at 5 °C. Throughout the size ranges the product agglom-
erates are quite spherical. In our previous work at 20 °C using
 J. Thati, Å.C. Rasmuson / European Journal of Pharmaceutical Sciences 45 (2012) 657–667 661

Cumulative under size

1

0.8 150 min

90 min
0.6 60 min
0.4 30 min

0.2

00 00
20 00

45 0

63 30

0 0

50 50
00 00

00 00

0
45

80 -80

00
10 -10
2

12 -12
14 -14

16 -16
0-

0-

0-

-2
0
Sieve Size (µm)

(a) 30min (b) 60min (c) Surface 90min

Fig. 2. Influence of experiment time (heptane) on product particle size distribution and morphology (sieve size: 1000–1250 lm) at 5 °C: BSR = 1.02, Benzoic acid
conc. = 0.375 g/ml, N = 600 rpm, feeding rate = 1.7 ml/min.

1
Cumulative under size

0.8

0.6
30C
0.4 20C
10C
0.2 5C

0
50 0
0

00 0

00 0

00 0

0
25 0

25

40

60
10 0 0

00
80
45

63
2 5

-1

-1

-1

-2
0-

0-

1
0-
0-

0-
63
45

80

12

14

16

Sieve size (µm)

10°C (BSR=0.93) 30°C (BSR= 0.86)

Fig. 3. Influence of temperature (heptane) on product particle size distribution and morphology (sieve size: 1000–1250 lm): Benzoic acid conc. = 0.375 g/ml, N = 600 rpm,
feeding rate = 1.7 ml/min, at 5 °C and BSR = 1.02, at 10 °C, 20 °C and BSR = 0.93 and at 30 °C and BSR = 0.86.

toluene as the bridging liquid, all agglomerates were also highly
spherical (Thati and Rasmuson, 2011). With chloroform at 20 °C
(Katta and Rasmuson, 2008) only particles larger than 630 lm
are spherical agglomerates. The smaller particles are either thin,
irregularly shaped agglomerates or fragments from larger agglom-
erates. Fig. 8 also present the inside of crushed particles. In sum-
mary, it is clear that the bridging liquid has a distinct influence
on the product particle morphology. Completely spherical particles
were found at 5 and 20 °C using toluene as bridging liquid, and at
5 °C using pentane. However, comparing Figs. 7 and 8, it is clear
that the crystals in the spherical agglomerates are much smaller
in the case of pentane. Accordingly, the spherical shape of the
agglomerates can be obtained for different crystal sizes.
Table 1 compares the strength of the particles. The table shows
a decreasing fracture stress in the order: toluene > cyclohex-
ane > heptane > pentane at 5 °C, and at 20 °C a decreasing fracture
662 J. Thati, Å.C. Rasmuson / European Journal of Pharmaceutical Sciences 45 (2012) 657–667

Table 2
Influence of bridging liquid and temperature on the yield: Benzoic acid conc. = 0.375 g/ml, N = 600 rpm, feeding rate = 1.7 ml/min.

Bridging liquid Temperature (°C) BSR (volume of bridging liquid/volume of solid) Yield
Heptane 5 1.02 84
Cyclohexane 5 1.02 87
Pentane 5 1.4 85
Toluene 5 1.02 86
Toluenea 20 0.93 84
Chloroformb 20 0.93 85
Heptane 20 0.93 78
Cyclohexane 20 0.92 79
Heptane 10 0.93 81
Heptane 30 0.86 74
a
Thati and Rasmuson (2011).
b
Katta and Rasmuson (2008).

the bed is 15–30%, and decreases with increasing compressibility,

as shown in Fig. 9.

4. Discussion

The results clearly show in support of our previous findings,

Fig. 4. Influence of bridging liquid on product particle size distribution: at 20 °C and
BSR = 0.93; at 5 °C and BSR: pentane 1.4; toluene, heptane and cyclohexane 1.02;
Benzoic acid conc. = 0.375 g/ml, N = 600 rpm, feeding rate = 1.7 ml/min, experiment
time = 60 min.
stress in the order: toluene > chloroform > cyclohexane > heptane.
The data also show a consistent trend that fracture stress decreases
at increasing temperature.
Table 2 shows that the yield of the process does depend on the
bridging liquid used, but the influence is not very strong. In Table 3,
the compression characteristics of single agglomerates and beds of
agglomerates are presented and compared. With the load of 1 N
the single agglomerates are compressed to 25–35% of the initial
size, and the elastic recovery is just a few per cent. The low elastic
recovery is partly explained by the fact that the agglomerates are
actually crushed during the compression. There is a variation
depending on the bridging liquid on the compressibility with par-
ticles using chloroform having the highest compressibility, and
particles using pentane having the lowest. The compressibility of
single agglomerates produced by using different bridging liquids
does not correlate with their fracture stress. With 10 N load, the
compressibility of a bed of agglomerates ranges from 33% to 47%,
with the highest compressibility for a bed of particles produced
using chloroform as the bridging liquid. The elastic recovery of
that during continued agitation, particle size increases, particles
become more spherical and the strength increases. Agitation leads
to a gradual consolidation of the agglomerates, reducing their
porosity (Thati and Rasmuson, 2011). It is clear that a certain time
period is required to create the spherical shape and this corre-
sponds to the findings of Morishima and Kawashima (1993), as
does the observation that the particle size increases with increas-
ing agitation time. The results further show that the spherical
agglomerates produced in this study have high compressibility
and are clearly very plastic in their compression. It is generally be-
lieved that to create strong compacts (Sandell, 1993), either a plas-
tic deformation or an extensive fragmentation of the particles must
occur. Accordingly the agglomerates in the present work are
potentially suitable for direct compression into tablets.
From a mechanistic viewpoint, in spherical crystallization the
crystals are initially clustered together as a result of surface ten-
sion and capillary forces associated with the liquid–liquid interface
between the water-rich bulk solution and the bridging liquid rich
solution in the aggregates. Fig. 10 (Butt and Kappl, 2009) shows a
schematic over the situation of two spherical particles kept to-
gether by interfacial and capillary forces. Liquid B is the bridging
liquid rich solution, and liquid A is the water rich bulk solution.
If the bridging liquid is favorably attracted to the surface of the so-
lid, as revealed by the bridging liquid efficiently wetting the parti-
cle surfaces, a concave meniscus forms between the liquids, i.e., the
contact angle HBðAÞ becomes less than 90° as shown in the figure. As
a result of this concave surface, the pressure on the B-liquid side is
less than the pressure on the A-liquid side. This pressure difference
leads to a pressure force (capillary forces) on the particles pushing
them together. In addition, the direct action of the interfacial ten-
sion of the liquid around the periphery of the meniscus contributes
to pull the particles together (Butt and Kappl, 2009). A relation be-
tween pressure difference, interfacial tension and contact angle
has been given by Gonzalez and Biscans (2002):
1p c
DP ¼ C 1 cos H ð5Þ
p D
where C1 is a constant depending on the specific surface area of the
particles, p is the porosity of the agglomerate, D is the mean diam-
eter of the agglomerate, c is the interfacial tension between the liq-
uids (water and bridging liquid) and H is the contact angle.
Accordingly, the wettability of the crystal surfaces by the bridging
liquid rich solution and the interfacial tension between the two
liquids are both of key importance. A too low interfacial tension
 J. Thati, Å.C. Rasmuson / European Journal of Pharmaceutical Sciences 45 (2012) 657–667 663

Fig. 5. Particle morphology of different sieve fractions using cyclohexane as bridging liquid: Benzoic acid conc. = 0.375 g/ml, N = 600 rpm, feeding rate = 1.7 ml/min,
experiment time = 60 min: (a) at 20 °C and BSR = 0.93, (b) at 5 °C and BSR = 1.02 (c) at 5 °C and BSR = 1.02, 1000–1250 lm.

Fig. 6. Particle morphology of different sieve fractions using heptane as bridging liquid at 5 °C: Benzoic acid conc. = 0.375 g/ml, N = 600 rpm, feeding rate = 1.7 ml/min,
experiment time = 60 min, BSR = 1.02.

between the liquids does not lead to spherical agglomeration even if
the wettability is good (Kawashima et al., 1984). However, it has
also been suggested that too high interfacial tension leads to a de-
crease in agglomerate size and strength (Hasan, 2001).
Blandin et al. (2005) adapted an equation from granulation for
the compressive strength in the capillary state (saturation = 1), to
characterize the strength of the spherical agglomerate in the
solution:
ð1  pÞ c
rcap ¼ 8
p Lp
where rcap is the compressive strength and Lp is the size of the crys-
tals, of the agglomerate. The model predicts that the agglomerate
strength is proportional to the interfacial tension, and inversely
proportional to crystal size. Of course, the strength of our dried
spherical agglomerates is different since solid bridges are formed
during the drying (Rhodes, 2008).
Gonzalez and Biscans (2002) selected the bridging liquid based
on low contact angle with the solid, and in case of granulation
Alderborn and Nyström (1996) stated that good wettability of
the drug by the bridging liquid is a precondition for agglomeration
based on capillary forces. In the present work, all the organic sol-
vents (ethanol, toluene, pentane, heptane, chloroform, cyclohex-
ane, ethyl acetate and diethyl ether) spread immediately when
ð6Þ
placed as a droplet on the surface of the benzoic acid compact,
i.e., the contact angle is close to 0°. Accordingly, all the solvents ful-
fill the basic requirements of good ability to wet the solid phase,
and there is no significant difference in this respect between the
solvents. However, out of the seven solvents investigated as
664 J. Thati, Å.C. Rasmuson / European Journal of Pharmaceutical Sciences 45 (2012) 657–667

Fig. 7. Particle morphology of different sieve fractions using pentane as bridging liquid at 5 °C: Benzoic acid conc. = 0.375 g/ml, N = 600 rpm, BSR = 1.4, feeding rate = 1.7 ml/
min, experiment time = 60 min.

Fig. 8. Particle morphology of different sieve fractions using toluene as bridging liquid at 5 °C: Benzoic acid conc. = 0.375 g/ml, N = 600 rpm, BSR = 1.02, feeding rate = 1.7 ml/
min, experiment time = 60 min. Inside of particles from toluene compared with particles using chloroform.

Table 3
Compression characteristics of agglomerates – different bridging liquids.

Sample Hi = initial size (lm) Hc = final size (lm) He = recovered size (lm) Elastic recovery (%) Compressibility (%)
Toluenea Single 1216 349.5 391 4 71.2
Bed 4856 3230.5 3690 28 33.5
Chloroformb Single 1244 276 308 3 77.8
Bed 4842 2583.5 3066 21 46.6
Cyclo hexane Single 1577 484 554 1.9 62.2
Bed 6787 4185 4608 16 38.4
Heptane Single 1081 260.5 280 2.4 75.9
Bed 7204 4076 4928 27 43.4
Pentane Single 2015 861.5 907 3.9 62.9
Bed 5914 3965.5 4594 32 32.9
a
Thati and Rasmuson (2011).
b
Katta and Rasmuson (2008).
 J. Thati, Å.C. Rasmuson / European Journal of Pharmaceutical Sciences 45 (2012) 657–667 665

35 are used as bridging liquid compared to using the alkanes, and the
best particles in terms of size, shape and strength are obtained
30
using toluene, regardless of temperature. According to Table 4, tol-
Elastic recovery (%)

25
20
15
10
5 polarity, solubility of the bridging liquid in water and solubility
0
0 20 40 60 80 100
Compressibility (%)
Fig. 9. Mechanical properties of single particles and particle beds: 1000–1250 lm,
Benzoic acid conc. = 0.375 g/ml, N = 600 rpm, feeding rate = 1.7 ml/min, experiment
time = 1 h, all the solvents are at 20 °C and BSR 0.93, pentane at 5 °C and BSR 1.4.
Single particles: N, toluene; N, pentane; , chloroform; j, cyclo hexane; j, heptane;
bed of the particles: D, toluene; D, pentane; e, chloroform; h, cyclo hexane; h,
heptane.
Fig. 10. Schematic over the capillary conditions between two spherical particles
(Butt And Kappl, 2009).
bridging liquid: toluene, chloroform, cyclohexane, heptane and
pentane lead to spherical agglomerates under properly tuned pro-
cess conditions, while diethyl ether and ethyl acetate could not
produce spherical agglomerates. Only very loose aggregates were
formed. Accordingly, it is clear that good wettability is not a suffi-
cient criterion for a solvent to work as bridging liquid in spherical
crystallization.
In the process, the binding liquid will influence on aggregation
and agglomeration of the crystals, but will also influence on crystal
nucleation and growth. In Table 4, physical properties of the sol-
vents are given. Strikingly, for diethyl ether and ethyl acetate is
that the interfacial tension with water is clearly lower than for
the other five solvents, and this may lead to that the interfacial ten-
sion forces and the capillary forces are not strong enough, and
hence explain why these solvents do not lead to agglomeration.
The solubility of these two solvents in water is also clearly higher.
For the other five solvents, spherical agglomerates are obtained
and their properties depend on the bridging liquid. Product parti-
cles are stronger and more spherical when toluene and chloroform
uene and chloroform has high interfacial tension against water, but
all the three alkanes have clearly higher values. The alkanes also
have lower solubility of benzoic acid and lower solubility in water.
We have explored to what extent size and fracture stress of the
product particles produced by using different bridging liquids,
more quantitatively can be correlated to properties of the pure
bridging liquid solvent like viscosity, interfacial tension to water,
of the solute in the bridging liquid. In granulation, an intermediate
viscosity of the binding liquid is favorable being a compromise be-
tween high deformation and reduced growth because of attrition
at low viscosity, and insufficient deformability reducing growth
by coalescence at high viscosity (Johansen and Schaefer, 2001).
The optimum viscosity increases with increasing primary particle
size (Kenningley et al., 1997). The interfacial tension between the
binding liquid rich phase and the water rich phase is important
for interfacial tension and capillary forces, as is discussed above.
Here we have simplified the analysis to just consider the interfacial
tension between the pure bridging liquid and pure water. Alander
and Rasmuson (2007), found the degree of agglomeration of para-
cetamol crystals in various solvents to correlate to the Reichardt
(2003) solvent polarity index, being a measure of the hydrogen
bonding ability of the solvent, and the work of Hasan (2001) sug-
gest that there is an optimum polarity, where too high or too
low polarity leads to smaller and weaker agglomerates. The solu-
bility of the binding liquid in water will influence on the amount
of binding liquid being available for binding crystals into agglom-
erates, and do reasonably correlate with the interfacial tension be-
tween the binding liquid and water. The solubility of benzoic acid
in the binding liquid will reflect to some extent differences in wet-
tability, but may also influence the supersaturation under which
the crystals are produced. Higher supersaturation will lead to fas-
ter nucleation and smaller crystals. As mentioned above the SEM
pictures reveals that e.g. the crystals are much smaller when using
pentane having a low solubility for benzoic acid, than using tolu-
ene that has a clearly higher solubility for the solute. The evalua-
tion shows that there is no real correlation of neither the product
agglomerate mean size nor the product agglomerate fracture stress
to bridging liquid viscosity, bridging liquid–water interfacial ten-
sion or bridging liquid polarity. The viscosity range covered is very
narrow, and is hardly a key factor in explaining the influence of the
bridging liquid in the present work. The correlation to interfacial
tension is shown in Fig. 11. With respect to the qualitative discus-
sion above we would have expected some correlation. However in
the process, the binding liquid will influence on many different as-
pects that are of importance for the formation of spherical agglom-
erates: crystal size and shape distributions, aggregation forces, rate
of solid bridge formation by crystal growth, etc. Hence, because of
this complexity we shouldn’t expect a simple relation to a specific

Table 4
Properties of solvents used as bridging liquid (by Bahramian and Danesh, 2004; Small wood, 1996).

Solvent Chloroform Toluene Heptane Cyclo hexane Pentane Diethyl ether Ethyl acetate
CHCl3 C7H8 C7H16 C6H12 C5H12 C4H10O C4H8O2
Boiling point (°C) 61.2 110.6 98.4 80.7 36 34.6 77.1
Viscosity g (CP) 5 °C 0.657 0.701 0.488 1.277 0.219 0.273 0.52
20 °C 0.573 0.596 0.425 0.9845 0.202 0.235 0.448
Interfacial tension solvent/water 5 °C 33.6 37.3 50.6 51 50.4
dyn/cm 20 °C 31.6 36.1 50.2 50.2 49 11 6.8
Solubility in water (25 °C) g/100 g 0.8 0.052 0.01 0.0055 0.004 6.9 8.3
Solubility of BA at 20 °C g solid/g solvent 0.1317 0.0877 0.0123 0.0135 0.0119
Polarity 25.9 9.9 1.2 0.6 0.9 11.7 23
666 J. Thati, Å.C. Rasmuson / European Journal of Pharmaceutical Sciences 45 (2012) 657–667

1400 0.4

Fracture stress (MPa)

1200 5C
20C 0.3
Mean size (µm)

1000

800 0.2
600
0.1
400

200
0
0 0 0.02 0.04 0.06 0.08 0.1 0.12 0.14
Solubility of benzoic acid (g/g)
0.4
0.35 5C Fig. 12. Influence of benzoic acid solubility in bridging liquid (at 5 and 20 °C) on
Fracture stress (MPa)

20C agglomerate fracture stress: 1000–1250 lm, Benzoic acid conc. = 0.375 g/ml,
0.3
N = 600 rpm, feeding rate = 1.7 ml/min, experiment time = 1 h; at 5 °C: , pentane;
0.25 j, heptane; N, toluene; at 20 °C: h, heptane; +, cyclo hexane; D, toluene; x,
chloroform.
0.2
0.15
0.1 influence of primary particle size is discussed in terms of the rela-
0.05 tion between the capillary, viscous and frictional forces (Iveson and
0
Litster, 1998). All the forces, increase with decreasing particle size.
20 25 30 35 40 45 50 55 The increasing number of inter-particle contacts and decreasing
Interfacial tension (dyn/cm) average gap between particles, increase inter-particle friction
forces and viscous forces. Capillary forces increase because of the
Fig. 11. Influence of bridging liquid/water interfacial tension on agglomerate mean increasing liquid bridge curvature between particles as a result of
size and fracture stress at 5 and 20 °C Benzoic acid conc. = 0.375 g/ml, N = 600 rpm, the decreasing pore size. For coarse particle systems, inter-particle
feeding rate = 1.7 ml/min, experiment time = 60 min, at 20 °C: BSR = 0.93; at 5 °C
frictional forces are insignificant and so the lubrication effect is
BSR heptane, cyclohexane, toluene = 1.02, pentane 1.4.
negligible. For smaller more broadly sized particles, the frictional
forces dominate and adding more liquid decreases particle
strength. From the SEM micrographs of the particles from different
pure bridging liquid property, and in fact that is the overall conclu-
solvents, it can be observed that the crystal width ranges from 6 to
sion we have drawn.
70 lm and length from 20 to 170 lm. When heptane is used as
The temperature is found to have a significant influence on the
bridging liquid (at 20 °C and BSR 0.93) the size of the crystals
product properties, in that a lower temperature leads to larger and
ranges from 10 to 70 lm in width and from 20 to 140 lm in length.
stronger agglomerates. The temperature influences many of the
When toluene is used as bridging liquid (Thati and Rasmuson,
important conditions for spherical crystallization. The viscosity of
2011), the crystal dimensions range from 7 to 20 lm in width,
the solvents increases with decreasing temperature, however this
and from 20 to 140 lm in length. Accordingly, because of fairly
is not likely to be of governing importance since at constant tem-
wide crystal size and shape distributions we cannot distinguish a
perature there is no clear correlation to viscosity of the bridging li-
clear difference that can explain differences in properties, and
quid. In addition, the change in viscosity with temperature is not
there is no big difference in the amount of bridging liquid required.
able to systematically capture the influence of temperature on
We have not observed that the crystals have an overall preferred
the product properties. As shown in Table 4, the interfacial tension
orientation in the agglomerates (in example indicating spherulitic
between the bridging liquid and water do not change much with
growth (Beck and Andreassen, 2010)), besides the fact that at the
temperature, and hence cannot explain the influence of tempera-
surface they seem to orient along the surface, which we interpret
ture. A higher solute concentration in the bridging liquid rich solu-
as being due to the action of the agitation.
tion retained after filtration, is expected to lead to formation of
According to Kawashima et al. (1982), the probability of cohe-
stronger solid bridges in the drying and hence lead to stronger
sion of the particles is proportional to concentration of the bridging
dry product agglomerates (Rhodes, 2008). The solubility of the
liquid in the system. The bridging liquid collects the crystals by
bridging liquid in water and of benzoic acid in the solution are ex-
capillary action and increasing BSR leads to larger agglomerates.
pected to decrease with decreasing temperature. However, as
Increasing the amount of bridging liquid also induces a higher
shown in Fig. 12, at constant temperature, 5 °C, the product parti-
deformability of the agglomerates which lead to more energy dis-
cle strength actually tends to decrease with decreasing benzoic
sipation during collisions (Blandin et al., 2005). Accordingly,
acid solubility in the bridging liquid, and at 20 °C there is at least
bouncing of colliding particles is reduced and agglomeration be-
no clear increase. Accordingly, these properties neither explain
comes more likely, leading to bigger agglomerates. The degree of
the influence of temperature. At present, the hypothesis is that
saturation (s) of the pores of the agglomerate by bridging liquid
the influence of temperature is the result of an influence on the
can be estimated by Eq. (7) below, using an effective BSR based
crystal size and shape distribution generated. All the agglomerates
on the amount of actually crystallized benzoic acid and the mean
contain a size distribution and a shape distribution of crystals, the
agglomerate porosity (p) (Thati and Rasmuson, 2011).
shape varying from more needle-like to more plate-like shapes.
The crystal size and shape influences the capillary structure in
the agglomerates and may thus influence on the formation of  
BSRð1  pÞ vol of bridging liquid
agglomerates and their final properties. Previous studies (Kawashi- s¼ ð7Þ
p vol of voids
ma and Capes, 1976; Blandin et al., 2005; Subero et al., 2006;
Zhang et al., 2010) suggest that the crystals are more closely com- For toluene as bridging liquid at 20 °C, s receives a value of
pacted, require less amount of bridging liquid and adhesion forces about 1.1. With the uncertainties involved this value can be inter-
are stronger when the crystals are smaller. In granulation, the preted as if the amount of bridging liquid should be sufficient to fill
 J. Thati, Å.C. Rasmuson / European Journal of Pharmaceutical Sciences 45 (2012) 657–667
up the pore volume of the solid phase. More bridging liquid than
that will tend to aggregate the solid mass into a paste instead of
into discrete particles.
5. Conclusions
Spherical agglomerates of benzoic acid can be prepared by
using chloroform, toluene, cyclohexane, heptane or pentane as
bridging liquid. Ethyl acetate and diethyl ether are not suitable
as bridging liquid since no spherical agglomerates are formed. Re-
sults suggest that good wettability between the bridging liquid and
the solid, and low solubility of the bridging liquid in the anti-sol-
vent are important properties of a suitable bridging liquid solvent.
In addition, the interfacial tension between the bridging liquid and
the anti-solvent plays a governing role, and should be high. The re-
sults show that successful spherical agglomeration requires a cer-
tain minimum volume of bridging liquid, but too much leads to
formation of a paste instead of individual agglomerates. The
amount required in this study corresponds approximately to the
amount needed for completely filling the pore structure of the
agglomerates. Until a paste is formed, the agglomerate size and
strength increase with increasing amount of bridging liquid. In
all solvents where agglomerates were successfully formed, except
for cyclohexane, the particle shape improves with decreasing tem-
perature, and the agglomerates become larger and stronger. The
hypothesis is that the temperature effect relates to the influence
of temperature on the size and shape distributions of the crystals,
building up the agglomerates. Spherical, strong agglomerates are
formed regardless of temperature, using toluene. Very nice spher-
ical agglomerates are also obtained using pentane at 5 °C, but in
general toluene and chloroform produce stronger and more spher-
ical particles than the alkane solvents. It appears as if capillary and
interfacial tension forces governs the formation of the agglomer-
ates, and continued agitation beyond the moment of termination
of the feeding, clearly contributes to the generation of the spherical
shape, and increases particle strength. The spherical agglomerates
produced in this work as well as beds of agglomerates are highly
compressible with a quite limited elasticity.
Acknowledgments
Dr. Denise Croker, Peigao Zhong, Anthony Maher, Marcus
ÓMahony are acknowledged for the assistance and help during
some of the experimental work performed at the Materials and
Surface Science Institute, University of Limerick, Ireland.
References
Alander, M.E., Rasmuson, C.A., 2007. Agglomeration and adhesion free energy of
paracetamol crystals in organic solvents. AICHE 53 (10).
Alderborn, G., Nyström, C., 1996. Pharmaceutical powder compaction technology.
Uppsala University, Uppsala, Sweden.
Bahramian, A., Danesh, A., 2004. Prediction of liquid–liquid interfacial tension in
multi-component system. Fluid Phase Equilib. 221, 197–205.
Bausch, A., Leuenberger, H., 1994. Wet spherical agglomeration of proteins as a new
method to prepare parenteral fast soluble dosage forms. Int. J. Pharm. 101, 63–
70.
667
Beck, R., Andreassen, J., 2010. Spherulitic growth of calcium carbonate. Cryst.
Growth Des. 10, 2934–2947.
Blandin, A.F., Rivoire, A., Mangin, D., Klein, J.P., Bossoutrot, J.M., 2000. Using in sity
image analysis to study the kinetics of agglomeration in suspension. Part. Part.
Syst. Charact. 17, 16–20.
Blandin, A.F., Mangin, D., Rivoire, A., Klein, J.P., Bossoutrot, J.M., 2003.
Agglomeration in suspension of salicylic acid fine particles: influence of some
process parameters on kinetics and agglomerate final size. Powder Technol. 130
(1–3), 316–323.
Blandin, A.F., Mangin, D., Rivoire, A., Klein, J.P., Bossoutrot, J.M., 2005. Modeling of
agglomeration in suspension: application to salicylic acid microparticles.
Powder Technol. 156, 19–33.
Bos, A.S., Zuiderweg, F.J., 1987. Size of agglomerates in batch wise suspension
agglomeration. Chem. Eng. Res. Des. 65, 187.
Butt, H., Kappl, M., 2009. Normal capillary forces. Adv. Colloid Interface Sci. 146.
Capes, C.E., Sutherland, J.P., 1967. Formation of spheres from finely divided solids in
liquid suspension. I&EC Proceed Des. Dev. 6 (1), 146–154.
Farnand, J.R., Smith, H.M., Puddington, I.E., 1961. Spherical agglomeration of solids
in liquid suspension. Can. J. Chem. Eng. 39 (4), 94–97.
Fichtner, F., Rasmuson, Å., Ålander, E., Alderborn, G., 2007. Effect of preparation
method on compactability of paracetamol granules and agglomerates. Int. J.
Pharm. 336 (1), 148–158.
Gonzalez, D.A., Biscans, B., 2002. Spherical agglomeration during crystallization of
an active pharmaceutical ingredient. Powder Technol. 128 (2).
Hasan, O.S., 2001. Effect of solvent composition on the spherical crystallization of
salicylic acid. UMI, USA.
Iveson, S.I., Litster, J.D., 1998. Fundamental studies of granulation consolidation Part
2: quantifying the effects of particle and binder properties. Powder Technol. 99,
243–250.
Johansen, A., Schaefer, T., 2001. Effects of interactions between powder particle size
and binder viscosity on agglomerate growth mechanism in a high shear mixer.
Eur. J. Pharm. Sci. 12, 297–309.
Katta, J., Rasmuson, Å.C., 2008. Spherical Crystallization of benzoic acid. Int. J.
Pharm. 348, 61–69.
Kawashima, Y., Capes, C.E., 1976. Further studies of the kinetics of spherical
agglomeration in a stirred vessel. Powder Technol. 13 (2), 279–288.
Kawashima, Y., Karachi, Y., Takenaka, H., 1982. Preparation of spherical wax
matrices of Sulfamethoxazole by Wet Spherical Agglomeration Technique Using
a CMSMPR Agglomerator. Powder Technol. 32, 155–161.
Kawashima, Y., Okumura, M., Takenaka, H., 1984. The effects of temperature on the
spherical crystallization of salicylic acid. Powder Technol. 39, 41–47.
Kenningley, S.T., Knight, P.C., Marson, A.D., 1997. An investigation into the effects of
binder viscosity on agglomeration behavior. Powder Technol. 91, 95–103.
Morishima, K., Kawashima, Y., 1993. Micromeritic characteristics and
agglomeration mechanisms in the spherical crystallization of bucillamine by
the spherical agglomeration and the emulsion solvent diffusion methods.
Powder Technol. 76, 57–64.
Muster, H.T., Prestidge, A.C., 2002. Application of time dependent sessile drop
contact angles on compacts to characterize the surface energetics of
sulfathiazole crystals. Int. J. Pharm. 234.
Othmer, K., (1992). Kroschwitz, J.I., Howe – Grant, M., (Eds.), Encyclopedia of
Chemical Technology, vol. 4, fourth ed. John Wiley & Sons, New York.
Reichardt, C., (2003). Solvents and solvent effects in organic chemistry. VCH
publishers, ISBN 10 3527306188.
Rhodes, M., (2008). Introduction to Particle Technology. ISBN 9780470014271.
Sandell, E., 1993. Industrial Aspects of Pharmaceutics. Swedish Pharmaceutical
Press, Stockholm, Sweden, p. 142.
Chang, Sang M., Kim, Jong-Min, Kim, In-Ho, Shin, Dong-Myung, Kim, Woo-Sik, 2006.
Agglomeration control of L-Ornithine Aspartate crystals by operating variables
in Drowning-out crystallization. Ind. Eng. Chem. Res. 45, 1631–1635.
Small wood, I.M., (1996). Handbook of Organic Solvent Properties, Elsevier, ISBN
978-0-340-64578-9. Electronic ISBN 978-0-0805-2378-1.
Subero, C.C., Mangin, D., Rivoire, A., Blandin, A.F., Klein, J.P., 2006. Agglomeration in
suspension of salicylic acid fine particles: analysis of the wetting period and
effect of the binder injection mode on the final agglomerate size. Powder
Technol. 161, 98–109.
Tambo, N., Watanabe, Y., 1979. Physical aspect of flocculation process. I.
Fundamental treatise. Water Res. 13 (5), 429–439.
Thati, J., Rasmuson, Å.C., 2011. On the mechanisms of formation of spherical
agglomerates. Eur. J. Pharm. Sci. 42, 365–379.
Zhang, H., Chen, Y., Wang, J., Gong, J., 2010. Investigation on the Spherical
Crystallization Process of Cefotaxime Sodium. Ind. Eng. Chem. Res. 49 (3),
1402–1411.