Download Manipulation of powder characteristics by interactions at the solid

European Journal of Pharmaceutical Sciences 8 (1999) 283–290
Manipulation of powder characteristics by interactions at the solid–liquid
interface: 1-sulphadiazine
Y.E. Hammouda*, L.K. El-Khordagui, I.A. Darwish, A.H. El-Kamel
Department of Pharmaceutics, University of Alexandria, Alexandria, Egypt
Received 8 July 1998; received in revised form 23 January 1999; accepted 23 February 1999
Abstract
A solvent-treatment technique aiming at manipulating the properties of powdered materials is reported. Potentials of the technique were
assessed using sulphadiazine (SD). A suspension of the drug in a preselected solvent (5% aqueous ammonia solution) was stirred under
controlled conditions. The solvent was subsequently removed and the material dried. The effect of experimental variables such as stirring
speed and time, powder / solvent ratio and inclusion of additives (Tween 80, sodium chloride and PVP) on the properties of solvent treated
SD was assessed. Data obtained were compared with those for SD recrystallized under identical conditions. Solvent treatment of SD in the
absence of additives resulted in a limited change in crystal morphology as indicated by SEM. This was associated with improved
flowability and a limited reduction in dissolution rate relative to untreated SD. On the other hand, recrystallized SD exhibited superior
flowability but a considerably low dissolution rate. Solvent treatment of SD in the presence of 2% PVP produced a microgranular directly
compressible material.  1999 Elsevier Science B.V. All rights reserved.
Keywords: Solvent treatment technique; Sulphadiazine; Additives; Flow properties; Dissolution rate; Direct compression
1. Introduction
Modification of the characteristics of pharmaceutical
solids to solve formulation and processing problems
related to inadequate physico-technical properties is receiv¨
ing considerable interest (Hutenrauch,
1983; York, 1992).
Building the desired properties into the pure powdered
solid provides a great potential for reducing the number of
formulation components and processing operations to a
tolerable minimum, thus rendering production simpler and
more economic.
Crystallization techniques are the most widely used
solvent-based, pretreatment methods for the production of
pure chemicals with altered solid state properties. Crystals
with engineered properties (crystal habit, form, density,
order / disorder state, wettability, etc.) can be obtained by
changing the crystallization solvent (Gorden and Amin,
1984; Marshall and York, 1991) and conditions (Fachaux
et al., 1995), or by using alternative crystallization techniques. These include solvent change crystallization (Nath
and Khalil, 1984, Khan and Jiabi, 1998), spherical crystallization (Gat et al., 1997), solvation / desolvation (Fachaux et al., 1993), etc. Further, the presence of small
*Corresponding author. Fax: 120-3-483-3273.
amounts of additives and impurities in the crystallization
solvent may produce crystal lattice imperfections or crystal
habit changes, resulting in major effects on the physicochemical properties of powders, such as the dissolution
rate (Chow and Hsia, 1991; Femi-Oyewo and Spring,
1994).
Usually, solvent-induced changes in the solid state
properties of recrystallized materials are associated with
modifications of their physico-technical properties, such as
packing, flowability and compaction, (York, 1983, 1992;
Marshall and York, 1991). These changes involve interactions between solute and solvent molecules at the various
crystal / solutions interfaces (Bourne and Davey, 1976a,b;
Davey et al., 1982). By virtue of such interactions, the
surface characteristics may be altered, producing a change
in the growth kinetics of the crystals (Davey et al., 1982;
Berkovitch-Yellin, 1985; Marshall and York, 1989).
In the present study, a solvent treatment approach
aiming at modifying the solid state and probably the
physico-technical properties of powdered materials is
investigated. The method is based on possible solute /
solvent interaction at the solid / liquid interface. It involves
treatment of the powdered material with a limited amount
of a preselected solvent under controlled conditions and
subsequent removal of the solvent.
0928-0987 / 99 / $ – see front matter  1999 Elsevier Science B.V. All rights reserved.
PII: S0928-0987( 99 )00026-3
284
Y.E. Hammouda et al. / European Journal of Pharmaceutical Sciences 8 (1999) 283 – 290
The potentials of this solvent treatment approach were
investigated using sulphadiazine (SD), a large dose drug
with poor flowability and compressibility (Sakr et al.,
1978) and 5% ammonia solution as the treatment solvent.
This solvent system has been reported earlier (Hammouda
et al., 1984; El-Massik, 1987) to produce prismatic,
flowable and directly compressible SD crystals. The formation of SD prisms was assumed to be due to the
interaction of SD and ammonia solution, allowing the
ordered arrangement of SD molecules. Selection of the
system sulphadiazine / 5% ammonia solution in the present
study, would allow a direct comparison of the outcome of
the solvent treatment approach with that of crystallization.
2.3. Scanning electron microscopy ( SEM)
2. Experimental procedures
2.5. Flow properties of solvent-treated and recrystallized
sulphadiazine
Samples of SD powder, recrystallized SD and solventtreated SD in the absence or presence of 2% PVP were
examined using scanning electron microscope (Jeol, SEM
model JSM-25 SII, Tokyo, Japan).
2.4. X-ray diffractometry
X-ray diffraction pattern analysis of SD powder,
solvent-treated SD and recrystallized SD was carried out
using Siemens D-500 Diffractometer with Co-Rad radia˚ voltage 35 kV, current 20 mA at a
tion ( l51.784 A),
scanning rate of 28 / min and chart speed 1cm / min.
2.1. Materials
Sulphadiazine crystalline powder (SD) (ACF
Chemiefarma, Holland), polysorbate 80 and sodium chloride (BDH Chemicals Ltd, U.K.), ammonia solution
ˆ
(Rhone-Poulenc,
France), methylene blue, polyvinylpyrrolidone and hydrochloric acid (Sigma Chemical Corporation, U.K.), maize starch (B.P.) and croscarmellose sodium
(a gift from EL-Amyria Company, Egypt) were used in the
study.
2.2. Preparation of solvent-treated and recrystallized
sulphadiazine ( SD)
2.2.1. Solvent-treated sulphadiazine
Sulphadiazine powder was added to 5% aqueous ammonia solution as the treatment solvent in the required
ratio w / v (1:1.5 and 1:3). The slurry was stirred mechanically (at 100, 200 and 300 rpm) at room temperature
for the specified time (1 and 4 h). The ammonia-treated
undissolved powder was separated using a sintered glass
funnel, and left to dry at room temperature away from
light.
2.2.2. Recrystallized sulphadiazine
The dissolved SD in the filtrate was left to crystallize
out in a shallow crystallizer at room temperature away
from light. The crystals were then collected by filtration
and left to dry at ambient temperature.
Further, solvent-treated and recrystallized SD fractions
were obtained from 5% ammonia solution containing
Tween 80 (0.2% w / v), sodium chloride (0.5% w / v) and
PVP (0.1, 0.5 and 2.0 w / v%).
Sulphadiazine powder and both solvent-treated and
recrystallized SD fractions obtained under different experimental conditions were sieved and the particle size
range 250–400 mm collected.
2.5.1. The angle of repose
The angle of repose of all solvent-treated or recrystallized SD samples (250– 400 mm), was determined using
the method described by Train (1958).
2.5.2. Bulk density
The bulk density of solvent-treated or recrystallized SD
samples (250–400 mm) was determined using the method
described by Parrott (1970).
2.6. Measurement of the wetability of solvent-treated SD
The wetability of ammonia-treated SD in the absence
and presence of additives (0.2% w / v Tween, 0.5% w / v
sodium chloride and 2% w / v PVP) was measured accord`
ing to the method reported by Lefebvre
et al. (1988). Three
grams of solvent-treated SD powder were introduced into a
specially designed sintered glass tube, the bottom of which
was immersed in a saturated solution of SD at 1 mm above
the sintered glass. The solution was allowed to rise through
the SD powder bed. Wetting of the powder bed surface was
made evident with crystals of methylene blue placed on
top of the bed. The time necessary for the capillary rise of
the saturated SD solution through the SD powder bed
under standardized conditions (tw) was used as a parameter for comparison. The same procedure was also used to
determine the wetability of untreated SD powder (the
starting material). The results presented are the mean of
three measurements.
2.7. Preparation of SD tablets by direct compression
Attempts were made to directly compress solvent-treated
and SD crops (particle size 250–400 mm) into tablets after
mixing with 5% maize starch or croscarmellose sodium as
disintegrant using Erweka single punch tablet machine.
Y.E. Hammouda et al. / European Journal of Pharmaceutical Sciences 8 (1999) 283 – 290
Tablets (500 mg each) obtained from compressible SD
samples were subjected to dissolution rate testing, as
outlined under dissolution rate study.
2.8. Dissolution rate study
The dissolution rates of SD powder, solvent-treated and
recrystallized SD samples obtained under different experimental conditions were determined using the USP
dissolution apparatus (Type II). The dissolution medium
was 900 ml of 0.1 M hydrochloric acid stirred at 100 rpm.
At specified time intervals, up to 90 min, 5 ml samples
were withdrawn and analyzed spectrophotometrically at
lmax 244 nm after suitable dilution with 0.1M hydrochloric
acid. Experiments were run in triplicate.
3. Results and discussion
Recrystallization of SD microcrystalline powder from
5% ammonia solution was reported earlier (Hammouda et
al., 1984) to result in a change of the crystal habit.
Prismatic crystals with better flowability and compressibility were obtained. Polymorphism and possible formation of a detectable ammonium salt of SD were ruled out.
Interaction of SD with ammonia in solution was assumed
to have resulted in an ordered arrangement of SD molecules and formation of crystals with different solid state
properties.
The effect of solvent treatment on the properties of
powdered SD is the subject of the present study. Solvent
treated and recrystallized sulphadiazine samples (250–400
mm) were obtained using 5% ammonia solution as a
treatment or recrystallization solvent respectively.
285
sharp and major peak in the starting material and recrystallized form. On the other hand, appearance of new
peaks in the X-ray diffraction pattern at 2u 5308 to 328 and
498 of recrystallized SD indicates increased crystallinity.
Minor changes in the X-ray diffraction pattern of solvent
treated SD may be due to the unsuitability of X-ray
powder diffractometry to identify changes that take place
only at the particle surface for a small distance into the
crystal (York, 1983).
3.2. Effect on flow properties
The effect of treatment conditions on the values of the
angle of repose and bulk density of solvent treated
compared to recrystallized SD samples is shown in Table
1. SD powder exhibits poor flow properties (angle of
repose574.6 and bulk density 0.31). Solvent treatment
resulted in a limited improvement of SD flowability as
indicated by the decrease in the angle of repose and the
slight increase in bulk density. On the other hand, recrystallization resulted in a marked improvement of SD
flowability. Changes in the flow properties of both solvent
treated and recrystallized SD were only slightly affected by
the change in the drug:solvent ratio, stirring rate and
stirring time (Table 1). Bulk density and angle of repose
are functions of particle shape and surface smoothness
(Carstensen et al. 1993). As solvent treatment did not
affect the crystal shape of SD (Fig. 1), improved flowability can be attributed to the reduction in surface roughness
and edge sharpness leading to reduction in inter-particle
friction.
3.3. Effect on dissolution rate
3.1. Effect on solid state properties
Fig. 1 shows the scanning electron micrographs of SD
(control), solvent treated and recrystallized SD samples.
Control SD crystals are tabular with rough edges and
surface irregularities. Treating SD with 5% ammonia
solution did not appreciably affect the crystal shape. A
slight decrease in surface roughness and edge sharpness
can be observed. This may be attributed to the deposition
of SD from the treatment solvent onto the surface of the
original SD particles. Recrystallization expectedly produced well formed, longer prismatic crystals with
smoother surfaces and more rounded edges.
X-ray diffractograms of these samples are shown in Fig.
2. Minor changes could be observed in the X-ray diffraction pattern of solvent treated SD with respect to that of
control SD crystalline powder. A small peak at 2u 158
instead of a sharp clear peak in the original powders and
recrystallized SD coupled with the disappearance of the
peak at 2u 178. Also there is a peak splitting into two
peaks in the region of 2u 5248 to 268 instead of one single
The dissolution profiles of SD (control), solvent treated
SD and recrystallized SD in 0.1 M HCl are shown in Fig.
3. Results show fast dissolution of SD (control), 100%
dissolution was attained in 10 min. Treatment of SD with
5% ammonia solution reduced the initial dissolution rate,
while recrystallization from the same solvent expectedly
suppressed the dissolution process (50% dissolution in 90
min). The reduction in initial dissolution rate of solventtreated SD points to a greater dissolution resistance of the
surface layers of SD particles. This might imply a higher
degree of crystallinity and / or a lower degree of wetting or
surface hydrophilicity of these layers.
Wetability measurements of SD (control) and solvent
treated samples using a liquid penetration technique
`
(Lefebvre
et al., 1988), indicated a marked decrease in
wetability of the treated samples (Table 2). The time
required for complete wetting (T w ) of a sample bed was 15
min and 40 min for SD (control) and solvent treated SD
respectively. Wetability of powdered materials is a function
of their chemical and crystal structures (Lerk et al., 1977),
286
Y.E. Hammouda et al. / European Journal of Pharmaceutical Sciences 8 (1999) 283 – 290
Fig. 1. Scanning electron micrographs of (a) untreated SD, (b) solvent-treated SD, (c) recrystallized SD using 5% ammonia and (Magnification power 700),
(d) solvent-treated SD using 5% ammonia–2% PVP (Magnification power 300).
and their pretreatment history (Hansford et al., 1980;
Chow et al., 1995). As molecules contain regions which
are hydrophobic and regions which are hydrophilic, the
outer face of a crystal will be influenced by the liquid from
which it was crystallized, with possible internalization of
the functional groups which are less attracted to the liquid
Y.E. Hammouda et al. / European Journal of Pharmaceutical Sciences 8 (1999) 283 – 290
287
Fig. 2. X-ray diffraction pattern.
(Buckton, 1995). Wetability and dissolution rate data of
solvent treated SD tend to indicate that the orientation of
SD molecules in the ammonia solution during treatment,
resulted in the deposition of a less hydrophilic and less
wetable surface layer. The relatively slow dissolution of
this surface layer appears to be followed by rapid dissolution of the layers underneath.
3.4. Effect of additives
Additives or impurities even in trace amounts can exert
major effects on the physicochemical and solid state
properties of solids (York, 1983). In the present study, the
effect of inclusion of Tween 80 (0.2% w / v), NaCl (0.5%
w / v) and PVP (0.1, 0.5 and 2% w / v) in the treatment
Table 1
Effect of treatment conditions on the angle of repose and bulk density of solvent treated and recrystallized SD
Treatment condition
SD:
100
SD:
100
100
200
200
300
5% Ammonia 1:1.5
rpm, 1 h
5% Ammonia 1:3
rpm, 1 h
rpm, 4 h
rpm, 1 h
rpm, 4 h
rpm, 1 h
Bulk density (g / cm 3 )6SD
Angle of repose (8)6SD
Solvent treated
Recrystallized
Solvent treated
Recrystallized
51.660.6
–
0.3860.005
–
53.160.4
52.660.5
52.660.8
53.760.6
52.860.5
37.660.3
35.760.4
36.860.4
37.260.4
36.960.3
0.3860.004
0.3860.004
0.3660.003
0.3560.002
0.3760.003
0.6160.01
0.6160.01
0.6260.01
0.5560.01
0.5960.01
288
Y.E. Hammouda et al. / European Journal of Pharmaceutical Sciences 8 (1999) 283 – 290
Fig. 3. Percent dissolution of untreated, solvent-treated and recrystallized
SD using 5% ammonia.
Table 2
Time for complete wetting (T w ) of solvent treated sulphadiazine in
absence and presence of additives.
Treatment
T w (min)6SD
SD: 5% Ammonia 1:3
SD: 5% Ammonia 1:3
0.2% w / v Tween 80
0.5% w / v NaCl
2.0% w / v PVP
Untreated
40.062.0
0.5 60.0
30.061.0
5.0 60.5
15.061.0
solvent, on the properties of SD was assessed. It is worth
noting that only trace amounts of the additive would
remain in the treated powder after separation of the
solvent.
Tween 80 slightly improved the flow properties of
solvent treated sulphadiazine (Table 3) and enhanced
dissolution (Fig. 4). About 94% dissolution was attained in
10 min. Dissolution enhancement can be associated with
the marked increase in wetability (Table 2). The time
required for complete wetting decreased from 40 min. to
0.5 min. in the presence of Tween 80. Faster dissolution of
Fig. 4. Effect of additives on the percent dissolution of solvent-treated
SD using 5% ammonia.
crystals treated with trace amounts of surfactants has been
attributed to increased wetability and or crystal structure
defects caused by the uptake of the surfactant onto the
crystal (Chiou et al., 1976). The presence of Tween 80 did
not appreciably affect the flow properties (Table 3) or the
dissolution rate (Fig. 5) of recrystallized SD. It can be
speculated that Tween 80, being nonionic, failed to disturb
the arrangement of SD molecules in ammonia solution.
This arrangement appears to involve the ammonia / SD
dipole structure, resulting in dissolution retardation.
Sodium chloride (0.5% w / v) slightly influenced the flow
properties of solvent treated SD (Table 3) but increased its
dissolution rate (Fig. 4). Dissolution enhancement was not
associated with a corresponding increase in wetability
(Table 2). The time for complete wetting of a sample bed
decreased from 40 min for solvent treated SD to 30 min
for NaCl-solvent treated SD. An increase in the dissolution
rate of recrystallized SD was also observed (Fig. 5).
Sodium chloride probably reduced the interaction of
ammonia with SD through ion-dipole interaction, thus
opposing the effect of ammonia on the orientation of SD
Table 3
Effect of additives on the angle of repose and bulk density of solvent treated and recrystallized SD using 5% ammonia solution as solvent
Additive
No additive
0.2% w / v Tween 80
0.5% w / v NaCl
0.1% w / v PVP
0.5% w / v PVP
2.0% w / v PVP
Bulk density (g / cm 3 ) 6SD
Repose angle (8)6SD
Solvent treated
Recrystallized
Solvent treated
Recrystallized
53.160.4
52.860.7
52.161.1
48.661.0
49.261.2
39.360.7
37.660.3
37.160.3
38.760.6
37.660.7
37.561.0
35.760.5
0.3860.004
0.4260.003
0.3960.004
0.4060.004
0.3760.003
0.5060.005
0.6160.01
0.6660.01
0.6760.02
0.5660.01
0.6560.02
0.7760.02
Y.E. Hammouda et al. / European Journal of Pharmaceutical Sciences 8 (1999) 283 – 290
Fig. 5. Effect of additives on the percent dissolution of recrystallized SD
using 5% ammonia.
molecules during solvent treatment or recrystallization and
its dissolution-suppressing effect. This could explain the
dissolution enhancement observed in Figs. 4 and 5.
Retardation of SD dissolution by ammonia has been
reported earlier for recrystallized SD (El-Massik, 1987)
and observed in this study for both solvent treated and
recrystallized SD (Figs. 4 and 5).
PVP effectively decreased the angle of repose and
increased the bulk density of solvent-treated SD, the
largest changes being obtained with 2% PVP (Table 3).
Scanning electron micrographs (Fig. 1,d) indicated the
formation of SD microgranules with round edges, which
may account for the marked increase in flowability. The
small amount of polymer interacting at the surface layers
of solvent-treated SD did produce a free flowing microgranular material. However, inclusion of 2% PVP in the
ammonia solution resulted in a limited decrease on dissolution rates of both solvent-treated and recrystallized SD
(Fig. 4 and 5 repectively), probably due to the binding
properties of PVP (Adeyeye and Barabas, 1993).
289
tablets exhibited good in vitro and in vivo performance. It
appears that the degree of change induced by solvent
treatment of powdered materials varies with the inherent
physicochemical and solid state properties of the material
and the type of solvent used.
Additives in the treatment solvent did not improve the
tableting properties of SD with the exception of 2% PVP.
The microgranular material obtained with 2% PVP could
be successfully compressed into tablets. The material was
used to prepare 500mg tablets containing 5% starch as
disintegrant by direct compression. The tablets had acceptable hardness but exhibited poor disintegration and dissolution (Fig. 6). The use of croscarmellose (5%) in place of
starch resulted in tablets with a high dissolution rate, 100%
dissolution in 20 minutes (Fig. 6) and good overall in vitro
performance (hardness was 5 kg, disintegration time, 1
min.). These tablets obviously met the USP dissolution
limit for SD tablets (70% dissolution at 1h) and the rate of
drug release was comparable to the best sulphadiazine
release obtained from tablets prepared by fluidized bed
granulation (Erni and Ritschel, 1977).
In conclusion, the solvent-treatment technique proposed
in the present work offers promises as a simple, rapid and
economic technique for the improvement of tableting
properties of powders. It can be applied to manipulate the
surface crystal morphology of powders having poor
physico-technical properties with a limited effect on
dissolution. Improvement of the desired properties can be
further increased by using additives during solvent-treatment and / or a limited number of formulation excipients
during processing. This may have important practical
implications for the engineering of tablet excipients and
large dose drug substances for direct compression.
3.5. Preparation of SD tablets by direct compression
Although treatment of SD with 5% ammonia improved
its flow properties, attempts to compress the solvent treated
material using a single punch tablet machine failed to
produce tablets with acceptable properties. In another
study (Molokhia et al., 1997), however, application of the
solvent-treatment technique improved the flow properties
and compressibility of paracetamol, allowing its direct
compression into tablets after mixing with 15%w / w
Avicel and 5%w / w starch. The formulated paracetamol
Fig. 6. Dissolution profiles of SD tablets prepared by direct compression
and containing maize starch or croscarmellose as disintegrant.
290
Y.E. Hammouda et al. / European Journal of Pharmaceutical Sciences 8 (1999) 283 – 290
Acknowledgements
This paper has been presented at the AAPS Annual
Meeting and Exposition, October, 1996, Seatle,USA.
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