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Powder Technology 128 (2002) 188 194

www.elsevier.com/locate/powtec

Spherical agglomeration during crystallization of an active


pharmaceutical ingredient
Daniel Amaro-Gonzalez a, Beatrice Biscans b,*
a

Centro de Qumica Farmaceutica, Calle 200 y 21, Atabey, Playa, P.O. Box 16042, La Habana, C.P. 11600, Cuba
Laboratoire de Genie Chimique UMR 5503 CNRS/UPS/INPT, 5 rue Paulin Talabot, 31106 Toulouse Cedex1, France

Abstract
Lobenzarit disodium (LBD) salt is a drug used in the treatment of rheumatoid arthritis diseases. The objective of this work is to propose
and validate a method for selecting the best wetting agent allowing to obtain spherical agglomerates during crystallization. This method is
based on the so-called Washburns test (capillary rise of liquids in a granular medium). Crystallization tests carried out at different conditions
showed that the best results were obtained in the presence of n-hexane that was effectively found to be a better wetting liquid of the lobenzarit
crystals than the other solvents.
D 2002 Elsevier Science B.V. All rights reserved.
Keywords: Lobenzarit disodium salt; Crystallization; Spherical agglomeration; Washburns test; Wettability

1. Introduction
The direct compression is a modern method in tablet
manufacturing. Many processing steps (granulation, drying,
etc.) are limited in direct compression, and additionally, wet
technology cannot be used with sensitive agent (e.g., in
effervescent tablet-making) [1]. The direct compression of a
powder depends on its particle size and size distribution,
and in connection with this, on its flowability, consistent
with the production rates of modern compression technology and also on its bulk density. Some drug crystals exhibit
appropriately such properties, but many materials have very
poor flowability and compressibility [2]. For tablet-making
from the latter materials, possible solutions may be the use
of wet granulation [3] (if this is possible with regard to the
drug stability) or the use of direct tablet-making with
good excipients which promote direct compression
(though this might not be favorable in terms of powder
flow). Another solution is to generate directly, during the
crystallization step, spherical agglomerates of drug crystals

Abbreviations: LBD, lobenzarit disodium; ESD, emulsion solvent


diffusion; SA, spherical agglomeration; BSR, binder solid ratio; PTD,
pitched turbine.
* Corresponding author. Tel.: +33-5-34-61-52-23; fax: +33-5-34-61-5253.
E-mail address: Beatrice.Biscans@ensiacet.fr (B. Biscans).

with good flowability and compressibility properties. This


last possibility recently came into the forefront of interest
because the habit of the particles (shape, size, size distribution, specific surface area, etc.) can be changed by crystallization processes.
During the 1970 decade, Kawahima and Capes [4]
suggested to obtain the size enlargement of particles during
the crystallization step, controlling the crystals agglomeration with the goal to obtain spherical agglomerates with
controlled properties. This was possible by two methods:
the first one is known as spherical agglomeration (SA)
and consists of precipitating fine crystals of drug
substance then aggregating them using a nonmiscible
liquid (so-called the wetting agent);
the second method is referred as emulsion solvent
diffusion (ESD). In this method, a quasi emulsion is
formed by droplets of solvent containing the drug. The
continuous phase is a liquid in which the drug is
nonmiscible. Crystallization occurs inside the droplets
because of the counter diffusion of the solvents through
the droplets.
The two methods, SA and ESD, are both spherical
crystallization techniques. By using these techniques, spherical agglomerates with controlled diameters can be produced
[5].

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D. Amaro-Gonzalez, B. Biscans / Powder Technology 128 (2002) 188194

SA method proceeds in three steps. The first one is the


selection of the crystallization method to precipitate crystals
from solution, i.e., thermal methods (temperature decrease
or evaporation), physicochemical methods (addition of
another solvent, salting out) and chemical reaction. The
second step is the choice of the wetting agent that will be
nonmiscible with the solvent of crystallization. Finally, the
third step is the hardening of the agglomerates. In the
literature, there are many papers about the application of
this method, and possible mechanisms, but the methodology
for selecting wetting agent is not yet clear.
The active ingredient studied in this paper was the
lobenzarit disodium (disodium 5-chloro-2,2V-iminodibenzoate, Na2C14H8ClNO4). It is a drug designed for treatment
of rheumatoid arthritis. It exerts a prophylactic or therapeutic effect against development of spontaneous arthritis and
nephritis. This drug produces an improvement of immunological abnormalities and has a regulatory effect on the
antibody-producing system [6 8].
The aim of this work is to investigate the feasibility of
capillary test to select the wetting solvent during spherical
agglomeration process. A relative scale of the different solvents possible to carry out the spherical agglomeration was
found and the results were tested by SA experiments at the
laboratory scale.

2. Theory
The method used in this work is the capillary rise of
liquid in columns of packed powder. This method, following Washburns equation, is based on Poiseuilles law [9]
relative to the liquid flow through capillary. For a Newtonian fluid, the rate of ascension m of the liquid (covered
distance h during a period t) in a cylindrical tube of R in
radius and L in length is related to the flowrate of the
liquid Q under the Laplace pressure exerted by capillary
effect, DP=(2c/R)cosh, where h is the wetting angle of the
liquid in contact with the tube wall, according to the
relation:


dh
Q
R2 2c
m
2
cosh  qgh
1
dt
pR
8gh R
where g is the viscosity of the liquid, c is its superficial
tension and q its density, and g is the gravitational
constant.
In the early stages, if the hydrostatic pressure can be
neglected, relation (1) becomes: dh/dt=(cR/4gh)cosh, which
gives after integration for the boundary condition h = 0 when
t = 0:
h2 cR
cosh

2g
t

In the case of a granular bed, the porous bed is considered as


bundle of parallel capillaries characterized by a mean

189

constant radius R and a tortuosity C. The liquid ascension


kinetics in this system is then:

h2 cRC
cosh

2g
t

The equation above is called Washburns equation [10].


Several restrictions apply to this relationship: (a) steadystate laminar flow, (b) zero velocity of the liquid at the solid/
liquid interface, (c) no externally applied pressure and (d)
negligible gravitational differences.
The wetting angle represents the angle of the liquid in
contact with the fictive capillaries made by the surface of the
particles in the bed.
During the experiments, the accuracy of the measurement
was improved by measuring the weight variation of the bed
instead of the liquid level progression [11,12]. The weight m
of the liquid in the bed is related to the liquid front height by:
m eqSh

where e is the porosity of the packed powder bed, q the


density of liquid and S the inner section of the bed.
Finally, after combination with Eq. (3):
m2 cq2 Se2

C Rcosh
t
g
2

In practice, a preliminary experiment is carried out with a


liquid (i) which is considered as a perfect wetting agent and
for which the contact angle is assumed to be zero (cosh = 1).
A second experiment is performed with a liquid (l) for which
the value of the contact angle is unknown. The ratio of both
relations, the one for the reference liquid (i) and the other for
the measured liquid (l), enables to calculate the contact angle:
  2 1
c q2 g m2l
mi
cosh i i2 l
6
t
cl ql gi t
The first part in the right of the relation depends only on the
physical properties of the liquids. The other values must be
determined experimentally and correspond in fact to the slope
of the curves m2 = f(t) for each liquid.
With the objective to select the wetting agent, it was
assumed that the best agglomeration solvent was the best
solvent on the wettability relative scale of the Washburns
test.

3. Experimental and methods


3.1. Materials
Lobenzarit disodium (LBD) was used as the raw material
(synthesis Laboratory of the Center of Pharmaceutical
Chemistry, Cuba) with purity of 99.5%.
The liquids used in this work are bi-distilled water,
hexane, octane, acetone, methanol, ethanol, isopropyl alco-

D. Amaro-Gonzalez, B. Biscans / Powder Technology 128 (2002) 188194

190

hol, decane, cyclohexane, chloroform and dichloromethane


with purity between 99.5% and 99.7%.
The solubilities of LBD in these different solvents were
determined previously by a classical method of dissolution
[13]. The results are reported in Table 1.
The solubility of LBD in water increases when the
temperature increases, but the values are rather low (at 20
jC, the solubility is 0.043 g/g solution). In the organic
solvents, the reported values of solubilities change very
weakly with the temperature and are almost equal to zero.
According to these results and for the crystallization process, the supersaturation of LBD in aqueous solutions can be
created by evaporation or by addition of an organic solvent
miscible to this aqueous solution. For this study, evaporation
was selected to generate the primary crystals before spherical agglomeration.
3.2. Capillary rise
After crystallization of the primary crystals of LBD, a
wetting agent was added to the suspension to provoke
spherical agglomeration of the particles. The selection of
this liquid acting as a wetting agent was made according to
the wettability criterion previously presented (on the principle of the Washburns test) and given by the capillary rise
of different solvents in a bed of LBD particles.
The principle of the experimental set-up is illustrated in
Fig. 1. A glass cylinder (12 cm in length and 1cm in internal
diameter) equipped with a sintered glass filter of controlled
porosity at its lower extremity contained a fixed quantity of
LBD powder (2.5 g) previously sieved in the range 200
355 Am and having a density of 2.16 g/cm3. The filled tube
was submitted to a packing procedure (with an automatic
device HOSOKAWA) allowing to obtain a regular and
reproducible internal porosity in the bed. In the experiments,
the corresponding particles bed height was 5.2 cm, which
corresponds to an apparent density of 0.61 g/cm3 and to an
interparticular porosity (free volume/total volume) e = 0.72.
Then, the filled glass tube was attached to an electronic
balance Sartorius (1/100 000 of precision) which was connected to a processor control unit (Fig. 1). The studied

Table 1
Solubility values of lobenzarit disodium (10  3 g/g solution) in several
solvents
Temperature
(jC)

Solubility values in different solvents (10  3 g/g solution)


Water

Isopropyl
alcohol

Acetone

5
15
20
25
30
40
50
60

36.5
38.1
43.0
44.1
47.1
50.5

0.024

0.87

55.1

Methanol

Ethanol

0.25
1.10
0.025
0.030

0.84
0.83

0.06

0.94

0.92
0.91

0.24
0.23

1.15

Fig. 1. Principle of the experimental set-up for capillary rise measurements.

solvent was placed in a small tank under the powder bed and
was slowly brought in contact of the basis of the bed. The
cylinder was weighed as the liquid surface raised with a rate
depending on the wettability of the particles by the fluid.
The experimental data, mass and time, were collected every
second until the saturation of the bed of particles (no more
variation of mass).
3.3. Crystallization procedure
The initial primary crystals were produced by adiabatic
evaporation of an aqueous LBD solution, in a classical
laboratory batch, 1-l crystallizer, equipped with down flow
turbine (PTB45j, four blades). Then, after generation of a
population of small crystals, the system was put again at the
atmospheric pressure and a cooling period was imposed
during which the wetting agent was added with a syringe
and spherical agglomerates were produced. The time
elapsed from the introduction of the wetting agent to the
withdrawal of the agglomerates was around 40 min. At the
end of the experiments, the agglomerates were filtered,
washed with cooled water (5 jC) and dried at 80 jC. The
products were finally kept in dark and dry place.

Table 2
Range of the different operating parameters studied in the spherical
crystallization process
Operating parameters

Studied range

Solid mass fraction:


crystals/solvent (%)
Cooling temperature profile
(jC/min) between
60 and 20 jC
Stirring rate (rpm)
Tested wetting agents
BSR (volume solid/
volume wetting agent) (-)
Phase ratio / (organic phase/
aqueous phase) (%)

8.5 11.3
0.2 0.4

550 1053
n-hexane dichloromethane
0.72 1.79
38

D. Amaro-Gonzalez, B. Biscans / Powder Technology 128 (2002) 188194

For a given system (initial LBD solid particles/wetting


agent), the operating parameters studied were the stirring
rate (rpm), the amount of wetting agent poured into the
initial suspension, quantified by the ratio: BSR = volume of
wetting agent/volume of solid [14] and the cooling temperature profile (jC/min). Table 2 gives the range of these
different parameters in this study.

191

Table 3
Wettability measurements of the lobenzarit particles with different solvents
Solvent

c
(mN/m)

q
(g/ml)

g
(mPa s)

Slope
m2 = f(t)

n-Hexane
n-Octane
n-Decane
Cyclohexane
Chloroform
Dichloromethane

18.4
21.8
23.9
25.5
27.5
28.6

0.66
0.703
0.73
0.778
1.492
1.325

0.3
0.508
0.838
0.894
0.537
0.413

0.0024
0.0017
0.0009
0.0009
0.0045
0.0039

0.00
26.67
48.76
54.58
63.93
69.08

4. Results and discussion


4.1. Contact angles between organic solvents and lobenzarit
crystals
The curves m2 versus time were obtained for several
organic solvents during their ascension into the bed of
lobenzarit disodium (LBD) particles (Fig. 2), and their
slopes were determined for the stationary state. The comparative results of wetting of particles of LBD by several
solvents were reported in Table 3 (the measurements were
carried out at 25 jC).
According to these results, n-hexane was the best wetting
agent for LBD particles because when n-hexane is taken as
the reference solvent (assumption of perfect wetting), the
wetting angles obtained for the other organic solvents are all
positive.
For an agglomerate formed by irregular particles, the
capillary depression responsible for the particles cohesion in
funicular or capillary regime is given by the relation:
DPc C1

1e c
cosh
e D

where C1 is a constant depending of the specific surface area


of the particles, e is the porosity of the agglomerate, D is the

Fig. 2. Recorded curves m2 versus time, during the ascension of different


organic solvents on an LBD particles bed.

mean diameter in surface of the agglomerate, c is the


interfacial tension between both liquids and h is the contact
angle.
This relationship shows that with hexane used as a
wetting agent, the DPc value is higher than for the other
solvents and consequently, the cohesion between the
agglomerated particles is more favorable due to higher
values of c and cos h.
4.2. Validation of the selection of the wetting agent for
spherical agglomeration
The feasibility of spherical crystallization of LBD was
studied by carrying out experiments according to the previous described procedure and the conditions given in Table
2. Two different organic solvents were chosen on the
wettability scale as the best one (hexane) and the worst
one (dichloromethane). Initially, the particles of lobenzarit
generated by evaporation crystallization had spread size
distribution between 1 and 600 Am and their mean size
was around 20 Am. They had irregular shape and poor
properties of compression. The wetting agent was added in
this initial stirred and cooled suspension.
Both experiments (with n-hexane on one hand and with
dichloromethane on the other hand) were carried out in the
same conditions. The experiment carried out with n-hexane
as wetting agent led to well-shaped spherical agglomerates.
On the contrary, the experiment carried out with dichloromethane gave weak agglomerates with irregular shape.
Fig. 3 shows the shape and the size distribution of
agglomerates obtained by adding droplets of n-hexane in
the stirred and cooled suspension of LBD crystals. Fig. 3a
is a SEM view of the grains obtained with hexane as
wetting agent. The agglomerates are large, spherical and
dense with excellent physicomechanical properties. Their
size distribution reported in Fig. 3b is narrow around 800
Am.
Fig. 4 reports respectively the SEM picture (Fig 4a) and
the size distribution (Fig 4b) of particles obtained with
dichloromethane as wetting agent. In this case, the agglomerates are soft and fragile. The size distribution is in a
smaller range and spread. This first result suggests that the
relative wettability scale given by the Washburns method
could be a good indicator for the choice of wetting liquid for
spherical crystallization.

192

D. Amaro-Gonzalez, B. Biscans / Powder Technology 128 (2002) 188194

and their size distribution, 40 min after the addition of


hexane in the suspension.
Table 4 shows the evolution of the final mean size of the
agglomerates for experiments carried out at various quantity
of hexane, different stirring rates and cooling profiles. For
experiments 1 to 4, the quantity of wetting agent (expressed
as the ratio BSR, volume of solid/volume of wetting agent)
had an influence on the mean size of the final agglomerates.
A maximum was obtained for a value of BSR around 1.43.
Moreover, when the quantity of the wetting agent was too
small (BSR < BSRmin), there was no significant agglomeration (experiment 1). On the contrary, when too
much wetting agent was introduced into the suspension
(BSRmax < BSR), the agglomerates became soft and pasty.
Therefore, it seems that from a process point of view, a
critical range of BSR existed for which the agglomeration
process was efficient. For the studied system, BSRmin = 1.08
and BSRmax = 1.43.
As reported in Table 4, the mean size of the final
agglomerates depends also on the stirring rate of PTD
turbine, but this effect was more pronounced for low

Fig. 3. Spherical agglomeration of LBD with n-hexane as a wetting agent.


(a) SEM visualization of the obtained agglomerates; (b) agglomerate size
distribution.

Therefore, this wettability scale is an interesting tool


for defining the spherical crystallization system, but of
course, other process conditions and specially hydrodynamics can have a non-negligible influence on the spherical grains properties. In the following section, the
spherical crystallization experiments were carried out in
the presence of n-hexane selected as wetting agent. From
a pharmaceutical point of view, n-hexane could be discussed even if the quantity of the residual content after
drying was negligible, but this study was focused on the
methodology. The influence of some parameters is discussed in order to try to understand the mechanism of
formation of the agglomerates and the role of the wetting
agent.
4.3. Effect of the operating parameters
Three main parameters were studied: the wetting liquid
quantity, the stirring rate and the cooling rate. The criteria of
quality for the formed agglomerates were their filterability

Fig. 4. Spherical agglomeration of LBD with dichloromethane as a wetting


agent. (a) SEM visualization of the obtained particles; (b) particle size
distribution.

D. Amaro-Gonzalez, B. Biscans / Powder Technology 128 (2002) 188194


Table 4
Spherical crystallization experimental conditions for LBD particles with
hexane
Experiment
no.

Stirring
rate (rpm)

Cooling rate
(jC/min)

Volume
ratio
BSR

Mean size of
the agglomerates
(Am)
only few
agglomerates
335
500
1084
655
1827
586
771
952
967

550

0.2

0.72

2
3
4
5
6
7
8
9

550
550
550
770
1053
550
770
1053

0.2
0.2
0.2
0.2
0.2
0.4
0.4
0.4

1.08
1.43
1.79
1.43
1.43
1.43
1.43
1.43

cooling rate (DT/Dt = 0.2 jC/min, experiments 3 5 6). In


that case, the maximum size was obtained for 770 rpm. As
it is well known in agglomeration studies, the probability
of collision between crystal particles and droplets of
hexane was favored by high agitation level, but an
excessive increase of the stirring rate can lead to the
breakage of the agglomerates or a too short contacting
time. On the other hand, the variation of temperature
(during cooling) affects the crystallization kinetics, but

193

also the formation of drops. Finally, those feasibility trials


showed that the process parameters are highly coupled and
the properties of the spherical grains depend on a combination of their effects. Some attempt to explain the
mechanisms involved in spherical crystallization was made
in conclusion.

5. Conclusion
As expected from the obtained relative wettability scale,
n-hexane was a possible wetting agent allowing to obtain
spherical agglomerates of lobenzarit disodium salt with an
enhanced narrow size distribution. However, two other
important parameters must be taken into account to conclude on the feasibility of spherical crystallization: the
stirring rate and the temperature.
In fact, the spherical agglomeration process of lobenzarit
disodium involves three steps:


the dispersion of the wetting liquid in the suspension and


the formation of droplets of defined size distribution
inside the particles population;
 the wetting phase during which the particles collide and
adhere on the droplets to finally enter inside the droplets
and agglomerate;

Fig. 5. Schematic presentation of the possible mechanisms of spherical agglomeration. Case 1: The average diameter of the droplets is nearly the same as the
one of the crystals. Case 2: The average diameter of the droplets is higher than the crystals diameter.

194


D. Amaro-Gonzalez, B. Biscans / Powder Technology 128 (2002) 188194

the consolidation spheronization of the agglomerate due


to cooling crystallization and influence by the collisions
between particle particle and/or particles parts of the
crystallizer.

All these phenomena take place simultaneously. Fig. 5


proposes two possible mechanisms depending on the relative
size of the droplets and solid particles and on the physicochemical properties of the system. In the first case, the
average diameter of the droplets is nearly the same as the
one of the crystals. The small binding liquid droplets coat the
solid particles and enable them to agglomerate as irregular
flocs. In the second case, the average diameter of the droplets
is larger than the primary crystals, and the large binding liquid
droplets act as collectors and are covered by solid particles,
which then penetrate and fill the interior of the droplets.
These agglomerates maintain more or less their spherical
structure and the hydrodynamics conditions lead to a good
dispersion and consolidation. Both mechanisms can occur in
some case when not all droplets are larger than the particles.
For the present study, and taking into account the
operating conditions, the second case (large droplets) is
more probable.
Notations
D
mean diameter in surface of the agglomerate (m)
g
gravitational constant (m s  2)
h
distance of penetration of the liquid (m)
L
tube length (m)
m
mass of liquid (kg)
P
pressure (Pa)
Q
liquid flowrate (m3 s  1)
R
tube radius (m)

S
t

inner section of the bed (m2)


time (s)

Greek symbols
e
porosity of the bed and of the agglomerate
c
interfacial tension between the liquids (N/m)
g
liquid viscosity (kg m  1 s  1)
q
liquid density (kg m  3)
h
contact angle between the solid and the liquid
m
ascension rate of the liquid (m s  1)

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