Marais et al

Trop J Pharm Res, June 2003; 2 (1) 125

Tropical Journal of Pharmaceutical Research, June 2003; 2 (1): 125-135

Pharmacotherapy Group,
Faculty of Pharmacy, University of Benin,
Benin City, Nigeria.
All rights reserved.

Available online at http://www.tjpr.freehosting.net

Research Article


Effect of compression force, humidity and
disintegrant concentration on the disintegration and
dissolution of directly compressed furosemide tablets
using croscarmellose sodium as disintegrant

Andries F. Marais
1
, Mingna Song
2
and Melgardt M. de Villiers
2

1
School of Pharmacy, Potchefstroom University for Christian Higher Education, Potchefstroom 2520, South Africa
and
2
School of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209, USA.

Abstract

Purpose: The effect of compression force, relative humidity and disintegrant concentration on
furosemide dissolution in directly compressed furosemide/Avicel-tablets was studied.
Methods: Mixtures of furosemide (12.5% w/w), Ac-Di-Sol (0, 0.625% to 10% w/w) and
Avicel PH200 (qs to 100% w/w) were prepared in a Turbula mixer at 69 rpm for 10 min.
Tablets were stored for 6 months under conditions similar to the four climatic zones
recognized by ICH. Tablet hardness, disintegration time and dissolution were measured.
Results: At the same compression force, disintegration time decreased as the disintegrant
concentration increased above 0.625% w/w but an increase in compression force resulted in
increased tablet crushing strength and apparent density, both of which prolonged the
disintegration time. This effect was less significant when the disintegrant concentration was
above 1.25%. However, storage under high relative humidity conditions (mediterranean or
subtropical, hot and humid climate) caused softening of tablets leading to the spontaneous
disintegration of tablets containing high concentrations of Ac-Di-Sol

.
Conclusion: Fast disintegration of tablets within 1-2 min is a prerequisite for improving the
dissolution of furosemide. This was attributed to an increase in the speed at which the
maximum surface area of the sparingly water-soluble drug is exposed to the dissolution
medium. Ac-Di-Sol

was an efficient disintegrant for furosomide tablets at low concentrations

of 1.25% - 10% because it rapidly released the hydrophobic drug particles from tablets.
However, tablets containing 10 % disintegrant must be protected from atmospheric moisture
because storage at 60-70 % relative humidity led to softening of tablets.

Keywords: Disintegration; Furosemide dissolution; Tablets; Compression Force; Relative
Humidity; Croscarmellose sodium

To whom correspondence should be addressed: E-mail: [email protected] Fax: +1 318 342-3255

Marais et al
Trop J Pharm Res, June 2003; 2 (1) 126
Introduction

For tablets containing sparingly water-
soluble drugs, the start of dissolution is often
delayed by the poor wettability of the tablet
surface and/or slow liquid penetration into
the tablet matrix. This property causes
increased disintegration time and retarded
drug release that can be overcome by the
addition of a disintegrant
1
. Various
compounds have been employed as
disintegrants in tablet formulations
1-3
. Direct
compression as a method of tablet
manufacture, however, puts many of the
traditional disintegrants at a disadvantage
due to: (1) high concentrations needed for
optimum disintegrating efficiency, (2) poor
disintegration in insoluble systems, (3)
susceptibility to high compression forces
which decreases the efficiency of a
disintegrant, (4) poor compression properties
and (5) decreased disintegration efficiency in
hydrophobic formulations
1-8
. A group of fast
or super disintegrants, including
croscarmellose sodium type A (Ac-Di-Sol

),
sodium starch glycolate (Primojel

and
Explotab

), and cross-linked polyvinyl-

pyrrolidone (Polyplasdone

XL), alleviate
most of these problems.

The effect and efficiency of some super
disintegrants have been studied in both wet
granulated
4, 5
and directly compressed
formulations
6-8
. The mechanism of action of
these disintegrants is that of water uptake
(liquid penetration) into the tablet which
cause the disintegrant particles to swell
9, 10
.
This results in a significant disintegrating
force inside the tablet, causing rupture of the
tablet structure
11, 12
. Factors affecting
disintegrant efficiency include tablet
solubility
5, 7, 13-16
, tablet hygroscopicity
5, 7
,
method of incorporation into wet granulated
formulations
4, 13, 14
, compression force
15-17
,
and storage under high relative humidity
18, 19
.
All of these factors are related to the
accessibility of liquid molecules to
disintegrant particles inside the tablet
20
.

The purpose of this study was to determine
the effect of the disintegrating efficiency of
croscarmellose sodium (Ac-Di-Sol

) in
directly compressed Avicel

(PH200), on the
dissolution rate of furosemide, a sparingly
water-soluble drug, as a function of
disintegrant concentration, compression
force and storage under different climatic
conditions. Furosemide was chosen because
the work of several researchers has shown
that excipients and processing factors
significantly affect its dissolution and
bioavailability
21-25
. The correlation between
disintegrant concentration and compression
force and two dissolution parameters - the
initial dissolution rate and extent of
dissolution was also investigated.

Materials and Methods

Materials

Furosemide (lot 14859, Adcock Ingram Ltd,
Wadeville, South Africa), Avicel

PH200 (lot
M439C, FMC International, Wallingstown,
Ireland) and Ac-Di-Sol

(lot T124, FMC

Corporation, Philadelphia, Pennsylvania,
USA) were used.

Mixture Composition and Preparation

Thirty-two gram mixtures, consisting of
furosemide (12.5% w/w), Ac-Di-Sol

(0,
0.625%, 1.25%, 5% or 10% w/w) and Avicel

PH200 (qs to 100% w/w) were prepared in a
Turbula

mixer (model T2C, WA Bachofen,

Basle, Switzerland) at 69 rpm for 10 min.

Tablet Preparation

Flat-faced tablets weighing approximately
160 mg were prepared from each mixture.
The mixture powder was placed manually
into a stainless steel die with an inner
diameter of 8 mm and compressed for 15
seconds at 77, 154, 231 and 203 Mpa,
respectively, on an automated hydraulic
press (Carver Inc., Wabash, In., USA).
Figure 1 is a schematic of the die set-up
used in this study. The tablets used for
determination of crushing strength were
manually pushed out from the die. In the
Marais et al
Trop J Pharm Res, June 2003; 2 (1) 127
dissolution studies the tablets were leveled
with the surface of the die. The open bottom
of the die was sealed with a stainless steel
pellet. The die was then firmly pushed down
in a stainless steel saucer, which fitted
tightly around the die.

Tablet Storage

The International Conference on
Harmonization (ICH) is developing stability
standards guidelines
26
. According to these
guidelines, manufacturers, when conducting
"real time" product stability studies, will use
actual packaging and storage conditions
according to the climatic zone in which the
product will be marketed. The four worldwide
Climatic Zones recognized by ICH are based
on observed temperatures and relative
humidities, both outside and inside rooms,
from which mean temperatures and average
humidity values are calculated
26
. Zone I
(21C/45% relative humidity, RH),
Temperate - includes the United Kingdom,
Northern Europe, Canada, and Russia. Zone
II (25C/60% RH), Mediterranean or
Subtropical - includes the United States,
Japan, and Southern Europe. Zone III
(30C/35% RH), Hot and Dry - includes
Australia, Argentina, and Egypt. Zone IV
(30C/70% RH), Hot and Humid - includes
Brazil, Ghana, Indonesia, Nicaragua, and the
Philippines. In this study tablets were stored
for up to six months under these conditions
in climatic chambers (Hot Pack
Temperature/Humidity Chamber, MOD,
435314). Tablets were stored uncovered in
glass Petri-dishes similar to the conditions
described as the open dish method for
stability testing
27
.

Dissolution Studies

Dissolution studies were performed in a six-





















Figure 1: Presentation of the cup and saucer system used for compressing the tablets and for
determination of drug dissolution from tablets
Marais et al
Trop J Pharm Res, June 2003; 2 (1) 128
station Erweka

dissolution apparatus
(model DT6R, Erweka, Heustenstamm,
Germany) fitted with a thermostat and a
variable speed synchronous motor. The
standard USP-paddles were removed from
the rods and replaced with stainless steel
clips to accommodate the tablet dies shown
in Figure 1.

The single tablet surface was exposed to
900 mL 0.1 M HCl at 37 1C and rotated at
50 rpm. At t = 0, the rods were pushed down
so that the bottom clearance was 5 cm. At t
= 1, 2, 4, 5, 6, 10, 20, 30, 45 and 60 minutes,
5 mL samples were withdrawn through
Millipore

pre-filters (Millipore, Milford, MA.,

USA) and transferred to 10 mL glass
containers. An equal volume of fresh,
preheated dissolution medium was added to
compensate the medium lost through
sampling. The samples were assayed at 274
nm against 0.1 M HCl as blank with a
Unicam spectrophotometer (model Helios ,
Unicam Ltd, Cambridge, UK). Dissolution
curves, the amount of drug dissolved
(mg/mL) versus time (min), were
constructed. Dissolution profiles presented
are the mean of at least four USP dissolution
test (6 flasks per test). For all tests sink
conditions were maintained.

Physical Properties and Disintegration Time
of Tablets

The physical properties (crushing strength,
thickness, and diameter) of 10 tablets of
each formulation at each compression force
were determined with a model PTB-311
Pharma Test tablet-test unit (Pharma Test,
Switzerland). The disintegration time of the
tablets was determined as the time
necessary for the tablets to be completely
released from the dies. The apparent density
of the tablets (mg/mm
3
) was calculated from
the powder weight (mg), the tablet radius
(mm) and the tablet thickness (mm).

Calculation of Dissolution Parameters

The initial dissolution rate (DR
i
, mg/mL/min)
represented the slope of the dissolution
curve between t
0
and t
6
. The slope was
determined through linear regression
analysis. The area under the dissolution
curve (AUC, mgmin/mL) between t
0
and t
60

was considered as an indication of drug
dissolution extent and was calculated using
the trapezoidal rule
28
.

Statistical Evaluation of Data

Statistical analysis was performed using the
statistical option available in Microsoft Excel
2000 for Windows (Microsoft

Corporation,
Seattle, Washington, USA). A 99%
confidence level (p < 0.01) was considered
satisfactory for indicating significant
differences. The mean values of the various
parameters determined, i.e., initial
dissolution rate (DRi), normalized area under
the dissolution curve (AUC), crushing
strength (CS) and disintegration time (DT),
were compared for significant differences
using one-way or two-way analysis of
variance (ANOVA) for single factor and two
factor comparisons respectively.

Results and Discussion

Table 1 summarizes the results for initial
dissolution rate (DR
i
), area under the
dissolution curve (AUC), disintegration time
(DT), and crushing strength (CS) of different
formulations at different compression forces.
Tables 2 and 3 list these results for tablets
stored under conditions simulating the
environmental conditions of the four climatic
zones defined by Grimm
26
.

Effect of Storage under Increased Relative
Humidity on the Physical Properties of the
Tablets

The crushing strength (CS) and density of all
formulations increased with an increase in
compression force, but levelled off above
154 MPa (Figure 2). The Ac-Di-Sol

concentration had little effect on crushing
strength and the disintegration time of the
tablets at different disintegrant
concentrations reflected the effect of
compression force (Figure 2). At each
Marais et al
Trop J Pharm Res, June 2003; 2 (1) 129
compression force, tablets containing 0% to
0.625% Ac-Di-Sol

did not disintegrate

during dissolution. However, when the
disintegrant concentration was increased to
above 1.25%, rapid disintegration occurred
at all applied forces. This meant that
disintegration times (DT) increased with an
increase of compression force at each
disintegrant concentration, but decreased as
the disintegrant concentration increased at a
specific compression pressure.

The increase in DT with an increase of
compression force could be attributed to the
reduced liquid penetration into the tablet
structure and hence the increased tablet
strength and density as shown in Figure 3.
This increase in tablet density hampered
liquid penetration and access to disintegrant
particle and the development of an effective
disintegrating force inside the tablets. When
tablets were stored under relatively high
relative humidities of 60 and 70 % (results
for climatic zones II and IV listed in Table 2
and 3) disintegration times decreased with
time because moisture from the environment
penetrated the tablets and softened them.
Results for CS and DT listed in Tables 2 and
3 showed that storage at low relative
humidities at 21C and 30C (Zone I and II)
did not significantly change the disintegration
time and hardness of the tablets. In contrast
when exposed to humidities of 60 % and 70
% the tablets became softer and after 3
months those tablets containing 2.5 % and
10.0 % Ac-Di-Sol

disintegrated in the Petri-

dishes in which it was stored.

Table 1: The initial dissolution rate (DR
i
), area under the dissolution curve (AUC), disintegration
time (DT) and crushing strength (CS) of furosemide tablets containing increasing concentrations of
Ac-Di-Sol

and compressed at 77-308 MPa. The values in parenthesis are the percentage relative
standard deviation (% RSD)

Parameters
Ac-Di-Sol
(% w/w)

Compression
Force (MPa) DR
i
x10
-5

(mg/mL/min)
AUC
i
x10
-2

(mg.min/mL)
DT
(min:sec)
CS
(N)
0 77 4.8 (5.9) 8.8 (13.2) n/d 97.1 (5.1)
154 3.8 (15.1) 5.9 (32.2) n/d 189.5 (4.3)
231 3.4 (36.1) 4.8 (18.6) n/d 231.4 (3.7)
308 2.0 (7.2) 2.4 (17.2) n/d 239.5 (3.5)
0.625 77 9.4 (23.7) 13.5 (17.9) n/d 106.7 (7.0)
154 8.1 (37.9) 13.0 (23.9) n/d 196.0 (6.6)
231 6.9 (15.8) 11.8 (17.9) n/d 236.2 (5.4)
308 1.7 (19.0) 3.1 (33.2) n/d 249.8 (2.5)
1.25 77 32.4 (4.0) 38.4 (5.1) 0:27 (7.7) 113.2 (6.2)
154 24.6 (12.0) 30.7 (5.9) 1:42 (3.2) 198.3 (7.3)
231 16.0 (15.3) 23.1 (11.4) 3:24 (3.4) 237.9 (4.5)
308 10.0 (10.6) 16.6 (9.5) 4:06 (3.5) 239.7 (3.3)
2.5 77 37.8 (2.6) 40.6 (2.3) 0:22 (6.7) 102.2 (2.9)
154 26.4 (8.4) 32.3 (6.7) 1:34 (3.3) 190.7 (6.9)
231 18.1 (5.2) 24.7 (5.0) 2:49 (3.0) 219.7 (4.4)
308 13.3 (12.5) 20.9 (17.5) 3:34 (1.4) 230.5 (5.3)
10 77 60.4 (4.8) 52.7 (4.2) 0:14 (4.2) 105.1 (3.4)
154 40.5 (17.0) 42.2 (10.6) 0:35 (13.6) 197.8 (1.4)
231 26.5 (6.2) 24.9 (2.5) 0:55 (5.2) 236.0 (2.6)
308 26.1 (3.9) 36.9 (3.5) 1:06 (2.5) no data
n/d, no disintegration
Marais et al
Trop J Pharm Res, June 2003; 2 (1) 130
Effect of Disintegrant Concentration,
Compression Force and Storage on DR
i
and
AUC

Figures 4 - 6 show the influence of storage
conditions on the release of furosemide from
the tablets. At all compression forces
increasing Ac-Di-Sol

concentration resulted
in increased furosemide dissolution (Figure
4). At each disintegrant concentration,
however, dissolution decreased with an
increase in compression force (Figure 5).
Since compression force and disintegrant
concentration influenced the DT of the
tablets as well as the dissolution of
furosemide, it was expected that changes in
DT would be reflected in the dissolution
profiles of furosemide. The results in Figure
6 confirmed the relationship between DT and
the dissolution parameters. A decreased DT
with increased disintegrant concentrations
resulted in an increase in the DR
i
and AUC
at all compression forces. This result
indicates that the dissolution of furosemide
from tablets containing Ac-Di-Sol

mainly
depended on the DT of the formulations.
Hence, for furosemide/Ac-Di-Sol

formula-
tions, DT was an indication of the initial
dissolution rate of the drug. Because higher
Ac-Di-Sol

concentrations improved the rate

and extent of liquid uptake and penetration
into the tablets, tablets broke up quicker and
thus exposed the drug particles to the
dissolution medium very quickly, improving
the contact between drug particles and
solvent molecules. Rapid tablet
disintegration thus optimized the drug
surface area available to the medium,
Table 2: The initial dissolution rate (DR
i
), area under the dissolution curve (AUC), disintegration
time (DT) and crushing strength (CS) of furosemide tablets containing increasing concentrations
of Ac-Di-Sol

, compressed at 154 MPa and stored for 1 month under conditions simulating the
four climatic zones. The values in parenthesis are the percentage relative standard deviation (%
RSD)

Parameters Ac-Di-Sol
(% w/w)
Climatic
Zone
DR
i
x10
-5

(mg/mL/min)
AUC
i
x10
-2

(mg.min/mL)
DT
(min:sec)
CS
(N)
0 I 5.2 (3.8) 9.1 (12.1) n/d

181.2 (3.6)
II 8.6 (5.2) 15.2 (11.2) n/d 125.3 (5.3)
III 4.3 (16.1) 7.8 (8.6) n/d 178.3 (4.2)
IV 9.2 (6.8) 13.4 (16.2) n/d 118.6 (4.7)
1.25 I 8.2 (15.1) 15.4 (11.8) 1:51 (5.4) 201.3 (4.1)
II 16.1 (9.3) 18.3 (9.2) 6:28 (7.2) 128.6 (4.2)
III 9.3 (11.2) 12.9 (8.6) 2:11 (4.6) 194.2 (3.8)
IV 17.8 (6.8) 20.6 (6.2) 5:06 (6.2) 119.8 (5.1)
2.50 I 27.6 (5.9) 39.4 (6.8) 2:16 (6.2) 201.6 (7.6)
II 28.4 (11.2) 36.8 (8.9) 1:09 (7.1) 127.8 (8.6)
III 25.4 (8.1) 40.1 (6.2) 1:49 (3.8) 211.2 (9.2)
IV 30.6 (7.9) 36.3 (12.2) 1:11 (4.8) 136.3 (4.2)
10.0 I 40.2 (11.1) 48.3 (9.2) 1:19 (3.6) 189.5 (2.7)
II 58.6 (7.7) 53.6 (10.1) 0:51 (4.2) 114.4 (3.2)
III 49.6 (12.7) 50.8 (12.3) 1:21 (5.1) 188.4 (5.2)
IV 52.4 (9.8) 51.4 (8.9) 0.56 (6.2) 118.6 (4.6)
Zone I (21C/45% relative humidity, RH), temperate - includes the United Kingdom, Northern Europe, Canada
and Russia. Zone II (25C/60% RH), mediterranean or subtropical - includes the United States, Japan and
Southern Europe. Zone III (30C/35% RH), hot and dry - includes Australia, Argentina and Egypt. Zone IV
(30C/70% RH), hot and humid - includes Brazil, Ghana, Indonesia, Nicaragua and the Philippines; n/d, no
disintegration.
Marais et al
Trop J Pharm Res, June 2003; 2 (1) 131
resulting in increased DR
i
and AUC of
furosemide. For tablets stored at relatively
high relative humidities it was evident that
the decrease in hardness and disintegration
time, results listed in Table 2 and 3,
increased the dissolution rate of furosemide
from tablets and that this effect was more
pronounced for tablets containing more than
1 % of Ac-Di-Sol

.

These results indicate that the good water
uptake and effective swelling by Ac-Di-Sol

were dominant in ensuring fast drug
dissolution. In disintegrating systems
(1.25% Ac-Di-Sol

), a maximum contact
area of the drug was quickly exposed to the
dissolution medium resulting in more rapid
dissolution of furosemide. For example, at 77
MPa and 10% Ac-Di-Sol

, the DR
i
was
approximately 12.5 times higher compared
to the rate at 0% disintegrant. The problem
with higher concentrations of disintegrant is
that when tablets were exposed to
environments where the relative humidity is
quite high, Zone II and IV, it lead to softening
and eventual disintegration of the tablets.
Therefore, tablets containing high
concentrations of super disintegrants should
be probably packaged and labelled to protect
them from atmospheric moisture.

Correlation between DR
i
and AUC

For disintegrating systems, Ac-Di-Sol

concentrations above 1.25%, the DR
i
and
AUC

increased linearly with disintegrant
concentration. In this study this quantitative
Table 3: The initial dissolution rate (DR
i
), area under the dissolution curve (AUC), disintegration
time (DT) and crushing strength (CS) of furosemide tablets containing increasing concentrations of
Ac-Di-Sol

, compressed at 154 MPa and stored for 3 months under conditions simulating the four
climatic zones. The values in parenthesis are the percentage relative standard deviation (% RSD)

Parameters Ac-Di-Sol
(% w/w)
Climatic
Zone
DR
i
x10
-5

(mg/mL/min)
AUC
i
x10
-2

(mg.min/mL)
DT
(min:sec)
CS
(N)
0 I 6.5 (5.4) 14.5 (11.2) n/d 209.8 (5.7)
II 27.8 (8.3) 39.8 (4.5) 1:12 (5.5) 117.8 (9.5)
III 7.4 (10.7) 12.6 (4.3) n/d

221.3 (3.1)
IV 23.9 (11.2) 41.4 (7.5) 1:06 (6.7) 107.9 (12.3)
1.25 I 7.9 (11.9) 13.5 (7.6) 1:20 (4.4)

197.2 (4.1)
II 22.1 (5.4) 24.5 (12.3) 0:52 (6.2) 106.7 (5.1)
III 11.2 (8.7) 12.1 (11.2) 1:32 (4.3)

201.9 (3.2)
IV 19.4 (5.6) 26.7 (6.5) 0:41 (3.4) 103.6 (4.0)
2.50 I 32.1 (12.3) 41.3 (6.5) 2:54 (4.8) 189.5 (3.5)
II 50.4 (8.7) 55.6 (9.2) 0:32 (2.1) 56.2 (10.9)
III 37.1 (8.7) 48.9 (8.7) 2:01 (5.1) 192.5 (6.1)
IV dis

dis

dis

dis

10.0 I 42.3 (12.3) 46.5 (15.2) 1:11 (2.8) 179.8 (2.1)
II dis

dis

dis

dis

III 47.6 (11.3) 54.3 (9.8) 0.57 (4.3) 187.5 (5.0)
IV dis

dis

dis

dis

Zone I (21C/45% relative humidity, RH), temperate - includes the United Kingdom, Northern Europe, Canada
and Russia. Zone II (25C/60% RH), mediterranean or subtropical - includes the United States, Japan and
Southern Europe. Zone III (30C/35% RH), hot and dry - includes Australia, Argentina and Egypt. Zone IV
(30C/70% RH), hot and humid - includes Brazil, Ghana, Indonesia, Nicaragua and the Philippines; n/d, no
disintegration; dis, tablets disintegrated during storage.
Marais et al
Trop J Pharm Res, June 2003; 2 (1) 132
0
50
100
150
200
250
300
50 150 250 350
Compression force (MPa)
C
r
u
s
h
i
n
g

s
t
r
e
n
g
t
h

(
N
)
1.0
1.1
1.2
1.3
1.4
1.5
D
e
n
s
i
t
y

(
m
g
/
m
m
3
)
Figure 2: The effect of compression force on the crushing
strength (solid lines) and density (dashed lines) of the
tablets at different concentrations of Ac-Di-Sol

. , 0%;
, 0.625%; , 1.25%; , 2.5%; , 10%.
relationships between Ac-Di-Sol

concentration and the DR
i
and AUC provided
a means to estimate these parameters at
any concentration within the concentration
range. Figure 7 shows the effect of the initial
dissolution rate of furosemide on the extent
of dissolution (AUC). The AUC increased
linearly with the initial dissolution rate of the
drug. This indicated that faster initial
dissolution rates lead to more
furosemide going into solution but
the slopes of the lines decreased
with an increase in disintegrant
concentration, indicating that at the
lowest disintegrant concentration,
0.625%, compression force had the
most pronounced effect on the
dissolution of furosemide. At this
disintegrant concentration, the DR
i

and AUC of furosemide decreased
by 81% and 77%, respectively, with
an increase in force from 77 to 308
MPa, compared to a decrease of
only 56 and 30% at 10% Ac-Di-
Sol

. These results suggested that

at lower Ac-Di-Sol

concentrations,
an increase in compression force
opposed and suppressed the
swelling mechanism of the
disintegrant. At the highest
concentration (10%), the
disintegration mechanism was the
dominating force in determining
both the rate and extent of
dissolution. Between the lowest and
highest concentrations, the
dissolution of furosemide depended
on both disintegrant concentration
and compression force.

The DR
i
versus AUC relationship
held true for tablets stored up to 6
months under conditions simulating
climatic Zone I and III. At higher
relative humidities, Zone II and IV,
the softening of tablets with time led
to unpredictable changes in tablet
disintegration and the quantitative
relationship between Ac-Di-Sol

concentration and the DR
i
and AUC
no longer applied.

Conclusion

The results confirmed that fast disintegration
of tablets is a prerequisite for improving the
dissolution of furosemide because drug
dissolution improved significantly when
tablets rapidly disintegrated within 1-2
minutes. This could be attributed to an
00:00
00:43
01:26
02:10
02:53
03:36
04:19
D
i
s
i
n
t
e
g
r
a
t
i
o
n

t
i
m
e

(
m
i
n
:
s
e
c
)
0* 0.625* 1.25 2.5 10
Ac-Di-Sol
(R)
concentration (% w/w)
Figure 3: The effect of compression force on the
disintegration times of formulations containing various
concentrations of Ac-Di-Sol

. *, no disintegration occurred.
, 77 MPa; , 154 MPa; , 231 MPa; , 308 Mpa.
Marais et al
Trop J Pharm Res, June 2003; 2 (1) 133
increase in the speed at which the maximum
surface-area of the sparingly water-soluble
drug is exposed to the dissolution medium.

Using two novel indicators, the initial
dissolution rate (DR
i
) and extent of
dissolution (AUC) it was shown that for
directly compressed furosemide tablets
disintegration times correlated well with
these two parameters and could be used to
predict the overall dissolution behaviour of
the drug. The linear relationship between the
DR
i
and AUC confirmed that the extent of
dissolution was almost entirely dependent on
the initial dissolution rate of the drug. This
relationship was used to determine the rate
and extent of drug dissolution at any
concentration within a range of 1.25 to 10%
Ac-Di-Sol.

Although an increase in compression force
increased the disintegration times of tablets
Ac-Di-Sol

proved to be an efficient
disintegrant at relatively low concentrations
of 2.5-10 % because it has the ability to
rapidly release hydrophobic drug particles
from tablets. However, tablets containing
high concentrations of this disintegrant must
be protected from atmospheric moisture
because storage at high relative humidities
lead to the softening of tablets. This effect
must be taken into account by formulators in
countries where tablets will be exposed to
high relative humidities, climatic zones II and
IV. Tablets manufactured and distributed in
these regions must be adequately protected
against moisture.

Acknowledgments

The authors would like to acknowledge
financial assistance from the National
Research Foundation of South Africa. FMC
International, Wallingstown, Ireland, is also
thanked for generous supplies of Avicel
PH200 and Ac-di-Sol.

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