Design and Evaluation of the Fast Dissolving Tablets
of Aceclofenac by Sublimation Technique
Sumanta Malakar, Ashok Kumar P.*, Suresh V. Kulkarni, Someshwara Rao B., Amit S. Yadav
Department
of Pharmaceutics, Sree Siddaganga
College of Pharmacy, B.H.Road, Tumkur-572102,
Karnataka, India.
ABSTRACT:
The purpose of this study was
to formulate and evaluate fast dissolving tablet of aceclofenac
by sublimation technology using camphor. Sodium starch
glycolate and crospovidone
were used as superdisintegrants. Tablets were
prepared by wet granulation technique. The granules were evaluated for angle of
repose, bulk density, tapped density and compressibility index. Tablets were
evaluated for weight variation, hardness, friability,
drug content, wetting time, in vitro dispersion and in vitro dissolution. In
vitro release studies were performed using USP
XXII dissolution apparatus type II (Electro lab, Mumbai, India) paddle method
in 900 ml of pH-7.4 at 75 rpm. Among all the formulation, F-6 shows 83.26%
release at the end of 22 min. Thus, F-6 was considered as the best among the
other formulations. The selected formulation F-6 was subjected to stability
studies for three months, which showed stability with respect to release
pattern.
KEYWORDS: Aceclofenac,
Sodium starch glycolate, Crospovidone,
Fast dissolving tablets.
INTRODUCTION
Of all the orally administered dosage forms, tablet is
most preferred because of ease of administration, compactness, and flexibility
in manufacturing. Many patients express difficulty in swallowing tablets and
hard gelatine capsules, resulting in non-compliance
and ineffective therapy.1 Recent advances in novel drug delivery
systems (NDDS) aim to enhance safety and efficacy of drug molecules by
formulating a convenient dosage form for administration and to achieve better
patient compliance. One such approach led to development of fast dissolving
tablets.2-4 Advantages of this drug delivery system include
administration without water, convenience of administration and accurate dosing
as compared to liquids, easy portability, ability to provide advantages of
liquid medication in the form of solid preparation, ideal for paediatric and geriatric patient and rapid dissolution or
absorption of the drug, which may produce rapid onset of action. Some drugs are
absorbed from mouth, pharynx and oesophagus as the
saliva passes down into the stomach and in such cases bioavailability of the
drug is increased, pre-gastric absorption can result in improved
bioavailability and as a result of reduced dosage, improved clinical
performance through a reduction of unwanted effects.
The basic approach used
in the development of fast disintegrating tablets in the use of various superdisintegrants like croscarmellose
sodium, sodium starch glycolate and crospovidone.
These agents bring
about fast disintegration due to increased water uptake which causes explosion
of tablet matrix.5 However, there are various techniques which are
used to prepare fast dissolving tablets, lyophillization6 and vacuum
drying7,8 involve maximization of the pore
structure of tablet matrix, thus leading to enhanced disintegration. But it
yield tablets that are fragile and hygroscopic. Sublimation gives less fragile
tablets by formation of a porus hydrophilic matrix
which picks up aqueous fluids and disintegrates quickly.9 In the present study, an attempt was made to develop fast
dissolving tablets of aceclofenac and to investigate
the effect of subliming agent on the release profile of the drug in the
tablets.
MATERIALS AND METHODS:
Materials:
Aceclofenac
and crospovidone were kindly obtained as a gift
samples, respectively, from Amoli Organics Pvt. Ltd.,
Mumbai and Tumkur Pharmaceuticals and Research Lab.
Pvt. Ltd., Tumkur, india. Sodium starch glycolate(SSG), Camphor,
sodium saccharin, mannitol, polyvinyl pyrollidone(PVP), isopropyl alcohol, talc and magnesium stearate were purchased from S.D. Fine Chemicals, Mumbai,
India. All the chemicals used were of analytical grade.
Method:
Formulation
of mouth dissolving tablets:
The fast disintegrating
tablets of aceclofenac were prepared using the subliming
agent camphor, SSG and crospovidone as superdisintegrants, mannitol as a
diluent, sodium saccharin as sweetening agent, alcoholic solution of PVP
(10%w/v) as binder and magnesium stearate with talc
as a flow promoter (see Table 1). The drug and other ingredients were mixed
together, and a sufficient quantity of alcoholic solution of PVP (10%w/v) was
added and mixed to form a coherent mass. The wet mass was granulated using
sieve no. 12 and regranulated after drying through
sieve no. 16.
Table 1: Composition
of different batches of fast dissolving aceclofenac
tablets.
|
Ingredient |
F-1 (mg) |
F-2 (mg) |
F-3 (mg) |
F-4 (mg) |
F-5 (mg) |
F-6 (mg) |
|
Aceclofenac |
100 |
100 |
100 |
100 |
100 |
100 |
|
Sodium
starch glycolate |
20 |
- |
20 |
- |
20 |
- |
|
Crospovidone |
- |
20 |
- |
20 |
- |
20 |
|
Camphor |
- |
- |
20 |
20 |
40 |
40 |
|
Sodium
saccharin |
2 |
2 |
2 |
2 |
2 |
2 |
|
Mannitol |
72 |
72 |
52 |
52 |
32 |
32 |
|
Magnesium
stearate |
2 |
2 |
2 |
2 |
2 |
2 |
|
Talc |
4 |
4 |
4 |
4 |
4 |
4 |
Granules of the formulations
containing either of the superdisintegrants but
without camphor (F1 or F2) were dried in a tray dryer (Tempo instruments and
equipments, Mumbai) at 60°C for 30 min. resulting in localized drying. Since
the melting point of aceclofenac is 149- 153 °C,
drying the granules at 60°C does not affect the stability of aceclofenac. Other granular formulations (F3 to F6)
contained a subliming agent and were dried at room temperature, 20-22 °C for
8hrs. The dried granules were then blended with talc, magnesium stearate and compressed into tablets using a 9.5mm punch
rotary tablet machine (Labindia Pharmatech,
Ahmedabad, India).
Evaluation of granules:
The
angle of repose was measured by using funnel method10, which indicates the flowability
of the granules. Loose bulk density (LBD) and tapped bulk density (TBD) 11 were measured using the
formula: LBD= weight of the powder / volume
of the packing. TBD= weight of the powder / tapped volume of the packing.
Compressibility index12
of the granules was determined by using the formula: CI (%) = [(TBD-LBD/TBD)] ×100.The physical properties of
granules were shown in Table 2.
Evaluation
of the tablets:
All
prepared matrix tablets were evaluated for its uniformity of weight, hardness,
friability and thickness according to official methods13 shown in Table 3.
Hardness:
The crushing strength of the
tablets was measured using a Monsanto hardness tester. Three tablets from each
formulation batch were tested randomly and the average reading noted.
Friability:14
Ten tablets were weighed and
placed in a Roche friabilator and the equipment was rotated
at 25 rpm for 4 min. The tablets were taken out, dedusted
and reweighed. The percentage friability of the tablets was measured as per the
following formula,
Percentage friability = Initial
weight – Final weight x 100
Initial weight
Weight
Variation:
Randomly, twenty tablets
were selected after compression and the mean weight was determined. None of the
tablets deviated from the average weight by more than ±7.5% (USP XX).
Drug
content:
Twenty tablets were weighed
and powdered. An amount of the powder equivalent to 20mg of aceclofenac
was dissolved in 100ml of pH 7.4 phosphate buffer, filtered, diluted suitably and
analyzed for drug content at 273nm using UV-Visible spectrophotometer (UV 160
Shimadzu, Japan).
Table 2:Granule
properties of the different formulations of fast dissolving aceclofenac
tablets.
|
Parameters |
F-1 |
F-2 |
F-3 |
F-4 |
F-5 |
F-6 |
|
Angle
of repose (θ) |
25.13±0.20 |
25.45±0.25 |
24.87±0.065 |
25±0.195 |
24.87±0.06 |
24.75±0.06 |
|
Loose
bulk density (LBD) (g/ml) |
0.56
± 0.20 |
0.52
± 0.10 |
0.54
± 0.075 |
0.50
± 0.12 |
0.43
± 0.19 |
0.47
± 0.15 |
|
Tapped
bulk density (TBD) (g/ml) |
0.64
± 0.175 |
0.59
± 0.12 |
0.63
± 0.025 |
0.57
± 0.097 |
0.49
± 0.05 |
0.55
± 0.21 |
|
Compressibility
index (%) |
12.50
± 0.015 |
11.86
± 0.93 |
14.28
± 0.425 |
12.28
± 0.14 |
12.24
± 0.37 |
14.54
± 0.19 |
Table 3:Tablet
properties of the different formulations of fast dissolving aceclofenac
tablets.
|
Formulation |
Weight variation (mg)** |
CPR (%) |
Hardness* (kg/cm2) |
Friability (%)** |
In vitro dispersion time (sec)* |
Wetting time* (sec) |
Drug content (%)* |
Thickness* (mm) |
|
F-1 |
203±3 |
72.70 |
3.5±1.20 |
0.557 |
120±0.55 |
135±2.30 |
97.9±0.12 |
2.49±0.05 |
|
F-2 |
204±2 |
79.05 |
3.2±1.60 |
0.521 |
98±0.84 |
110±2.10 |
98.2±0.27 |
2.76±0.00 |
|
F-3 |
198±6 |
72.21 |
3.7±2.10 |
0.483 |
67±1.14 |
81±1.90 |
97.7±0.31 |
2.76±0.05 |
|
F-4 |
195±8 |
77.84 |
3.3±1.40 |
0.441 |
42±1.30 |
56±1.60 |
98.5±0.17 |
2.26±0.17 |
|
F-5 |
200±2 |
80.71 |
3.5±1.60 |
0.636 |
39±1.67 |
48±1.80 |
98.9±0.28 |
2.56±0.05 |
|
F-6 |
205±4 |
83.26 |
3.6±1.10 |
0.713 |
32±1.79 |
41±1.20 |
99.2±0.10 |
2.42±0.17 |
*(n=5), **(n=20), All the readings are expressed in average
of three determinations.
Wetting
time:15
A piece of tissue paper
(12cmx10.75cm) folded twice was placed in a Petri dish (Internal Diameter=9cm)
containing 9ml of buffer solution simulating saliva pH 7.4, which had the
following composition, NaCl (0.126g), KCl (0.964g), KSCN (0.189g), KH2PO4 (0.655g) and urea
(0.200g) in 1Litre of distilled water14. A tablet was placed on the paper and
the time taken for complete wetting was noted. Three tablets from each
formulation were randomly selected and the average wetting time was noted. The
results are tabulated in Table 2.
In-vitro
dispersion time:16
In-vitro dispersion time was measured by dropping a tablet in a
10ml measuring cylinder containing 6ml of buffer solution (pH 7.4).
Figure 1. In-vitro
dissolution profile of F-1 to F-6 formulations.
In-vitro drug release studies:
In-vitro drug release studies of all the formulations were
carried out using tablet dissolution test apparatus (USP XXII type II Electro
lab, Mumbai, India) at 75 rpm. Phosphate buffer pH7.4 was used as the
dissolution media with temperature maintained at 37±1ºC. Samples were withdrawn
at different intervals, diluted suitably and analyzed at 273nm for cumulative
drug release using Shimadzu UV-Visible spectrophotometer.
Stability studies:
Short term stability studies
on the optimum formulation (F-6) were carried out by storing the tablets (in
amber colored rubber stoppered vials) at 40°/75% RH
for 3 weeks. At every 1 week intervals, the tablets were examined for physical
changes, properties, drug content and in vitro release studies17.
RESULTS AND
DISCUSSION:
Fast
dissolving tablets of Aceclofenac were prepared by
wet granulation process using camphor as subliming agent. Sodium starch glycolate and crospovidone were
used as super disintegrants. Water insoluble diluents
such as microcrystalline cellulose and dicalcium
phosphate were omitted from the study as they are expected to cause an
unacceptable feeling of grittiness in the mouth. Among the soluble diluents, mannitol was selected as a diluent considering its
advantages in terms of easy availability and negative heat of dissolution.
Granulation
is the key process in the production of many dosage forms. A granule is an
aggregation of component particles held together by bonds of finite strength.
To ensure good content uniformity and to avoid flow related intertablet
weight variation problems, wet granulation is preferred in routine commercial
production. Wet granulation was thus used in the present study. The granules of
the different formulations were evaluated for angle of repose, loose bulk
density, tapped bulk density, and compressibility index.
The
results of angle of repose and compressibility index (%) ranged from (24.750
+ 0.06 to 25.450 + 0.25) and (11.76 + 0.19 to
14.85+ 0.96), respectively. The results of loose bulk
density and tapped bulk density ranged from (9.2 + 0.10 to 9.4 +
0.20) and (7.95 + 0.05 to 8.275 + 0.175), respectively.
The results of angle of repose (<30) indicate good flow properties of
granules18,19. This was further supported by lower
compressibility index values16.
The lowest compressibility index is 5-15% which indicates excellent flow
properties (Table 2). The physical properties of different batches of fast
dissolving tablets are given in (Table 3). Tablet mean thickness was almost
uniform in all the formulations. The thickness varies between 2.26±0.17 to
2.76±0.05 mm. The prepared tablets in all the formulations possessed good
mechanical strength with sufficient hardness in the range of 3.2±1.60 to
3.7±2.10 kg/sq cm. Friability values below 1% were an indication of good
mechanical resistance of the tablets. Formulations prepared by sublimation
method were found to be more friable. All the tablets from each formulation
passed weight variation test, as the % weight variation was within the pharmacopoeial limits of ±7.5% of the weight. The weight
variation in all the six formulations was found to be 195 to 205 mg, which was
in pharmacopoeial limits of ±7.5% of the average
weight. The percentage drug content of all the tablets was found to be between
97.7 to 99.2% of aceclofenac which was within the
acceptable limits. The wetting time for all the six formulations was performed
in triplicate. The values lie between 41±1.2 to 135±2.3 sec. In vitro
dispersion is a special parameter in which the time taken by the tablet to
produce complete dispersion is measured. The time for all the six formulations
varied between 32 to 120 sec. Tablets were prepared using superdisintegrants
alone (F-1 & F-2) and in combination of a superdisintegrants
and a subliming agent, camphor (F-3 to F-6). The wetting time, in vitro
dispersion time of the tablets were also considerably reduced in tablets
containing camphor which may be attributed due to the porous structure formed
thus facilitating the disintegrants to bring about
faster disintegration.
The
in vitro dissolution profile
indicated faster and maximum drug release from formulation F-6. Stability studies shown that there was no significant change when
compared with zero day of formulation (F-6).
CONCLUSION:
The
release of drug from the F6 formulation was quick when compared to other
formulations. The tablets containing a combination of mannitol,
crospovidone and camphor showed faster
disintegration. When camphor is used, more porous tablets are produced. The
water uptake and subsequent disintegration is thus facilitated. It is obvious
that in the presence of crospovidone, wicking is
facilitated. Sublimation technique would be an effective alternative approach
compared with the use of more expensive adjuvant in the formulation of fast
dissolving tablets with improved drug dissolution.
ACKNOWLEDGEMENT:
The
authors are thankful to the management, Sree Siddaganga College of Pharmacy, for providing necessary
facilities to carry out this work.
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Received
on 11.03.2010
Accepted on 17.05.2010
© A&V Publication all right reserved
Research Journal of Pharmaceutical
Dosage Forms and Technology.
2(3): May-June 2010, 233-236