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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
0032-5910/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 3 2 - 5 9 1 0 ( 0 2 ) 0 0 1 9 6 - 1
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
189
h2 cRC
cosh
2g
t
C Rcosh
t
g
2
190
Table 1
Solubility values of lobenzarit disodium (10 3 g/g solution) in several
solvents
Temperature
(jC)
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
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
8.5 11.3
0.2 0.4
550 1053
n-hexane dichloromethane
0.72 1.79
38
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
1e c
cosh
e D
192
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
193
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:
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
S
t
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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