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FORMULATION AND EVALUATION OF ACECLOFENAC SODIUM
EFFERVESCENT TASTE MASKED GRANULES
Shet N*, Vaidya I, Banerjee N
Department of Quality Assurance, Dr. L. H. Hiranandani College of Pharmacy, Ulhasnagar-421003, India.
ABSTRACT
In the present study, effervescent taste masked granules of aceclofenac sodium were prepared by complexation
technique. Taste masking of drug was done by Eudragit E-100 (0.5:1w/w, drug: Eudragit E-100). Citric acid, tartaric acid,
sodium bicarbonate were used in 1:2:3 ratios for effervescent mixture. Prepared granules were evaluated for Angle of
repose, Flow rate, Bulk density, Tapped density, Compressibility index, Hausners ratio, Particle size, Effervescent time,
drug content, and in vitro dissolution studies. All the formulations showed disintegration time in range of 15 to 20 seconds.
The taste masked granules showed a drug release of 98% in 30 min. It was concluded that the prepared effervescent
granules enhanced the disintegration and dissolution rates, along with taste masking of the selected drug.
Key words: Aceclofenac sodium, Taste masking, Eudragit E-100, Effervescent Granules.
INTRODUCTION
Effervescent granules contain acid substances
and carbonates or bicarbonates which react rapidly in
presence of water by releasing carbon dioxide, they are
intended to dissolve or dispersed in water before use
(Connor Robert E et al., 2006). The aim of this study is
to develop and physicochemically evaluate the
effervescent taste masked granules of Aceclofenac
sodium.
Aceclofenac sodium is a nonsteroidal antiinflammatory drug (NSAID) which is used for various
painful indications. In comparison to other NSAIDs it
causes lesser adverse effects in gastrointestinal tract
(Harman Joel G, Limbard Lee E, 2001).
MATERIALS
Aceclofenac sodium was received as a gift
sample from Amoli Organics Pvt Ltd, India Eudragit ECorresponding Author
N. Shet
E-mail: [email protected]
100 was gifted from Evonik Pharma Degussa. Sucralose
gifted from J.K.Sucralose Inc.(India) Menthol gifted
from Reindeer Menthol, Sodium Bicarbonate, Citric
Acid, Tartaric Acid, were obtained from commercial
sources. All other reagents Polyvinyl Alcohol (PVA),
Isopropyl Alcohol (IPA), Acetone were of analytical
grade and there was no need for further purification.
METHODS
Preparation of Taste Masked Complex
Weighed amount of drug and polyacrylic cationic
polymer Eudragit E-100 (0.5: 1 drug: Polymer Ratio) was
complexed by using Acetone as a solvent. Complex was
obtained. Solvent was removed by evaporation and
complex was obtained (Anonymous 1).
Evaluation of ACE- EUDRAGIT E-100 complex
Molecular complex of drug resin complex
The IR spectra of ACE- EUDRAGIT E-100
complex were recorded using Fourier transform infra-red
spectrophotometer (IR Affinity -1 Fourier Transform
Infrared
Spectrophotometer
Shimadzu).
Sample
preparation involved, drying of Potassium Bromide
(KBr) in the oven to get rid of any moisture content then
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Shet N. et al. / International Journal of Biopharmaceutics. 2014; 5(1): 50-58.
mixing the sample with KBr by triturating in glass
mortar. Finally preparing of pellet and placing in the
sample holder. The spectrum was scanned over a
frequency range 4000– 400 cm-1.
DSC
The thermal analysis of the complex was carried
out on Exstars ІІ DSC 6220. The pan used was made up
of aluminium and the temperature range was from 30 0C
to 3000C under a continuous stream of inert gas nitrogen
at a rate of 100C/min. The sample taken was
approximately accurate weight of 10 mg.
Drug
entrapment
efficiency
by
UV
Spectrophotometer
5mg of the drug was dissolved in ethanol and
volume made up to 10ml water and absorbance was
measured (A) at wavelength of 273 nm. A specified
amount drug –polymer complex was weighed and
dissolved in ethanol , volume was made up to 10 ml with
water , absorbance was measured (B)at wavelength of
273 nm .% yield was calculated from the given formula :
% Drug Entrapment =B/A*100
Taste Evaluation
The taste of complex was checked by panel
method. The study protocol was explained and written
consent was obtained from volunteers. For this purpose 8
human volunteers were selected. Once placing the
complex in the mouth for 60 seconds, bitterness recorded
using a numerical scale. The numerical scale bears values
as 0 = Good, 1 = Tasteless, 2 = slightly bitter, 3 = bitter,
4 = very bitter, which was determined by formulator.
Preparation of taste masked granules
The weighed amount of drug complex was used.
Citric acid, tartaric acid , sodium bicarbonate were added
and mixed thoroughly. Then sufficient amount of
isopropyl alcohol containing PVP was added to this blend
and kneaded to form a dough mass. To this sucralose and
menthol were added. Solvent was removed by
evaporation at room temperature by air drying.
Subsequently, the obtained solid mass was passed
through sieve 8 # and was air dried for 15 to 20 minutes.
This was further passed from 16 # to 20 #. Granules were
retained on 20# (Gupta AK, Bajaj SS, 2000).
Evaluation of Taste masked effervescent granules
Angle of Repose
The Angle of repose was determined by using
fixed funnel method. Accurately weighed 2 gm of
granules were taken in the funnel. The height of the
funnel was adjusted in such a way that the tip of the
funnel just touched the apex of the granules .The granules
were allowed to flow through the funnel freely on to the
surface .The diameter of the powder cone was measured
and the angle of repose was calculated using formula
(Nikam AD et al., 2007).
Tan θ= 2H/R
θ- angle of repose
Where H and R are the height and radius of the powder
cone respectively.
Flow Rate
Weight of Powder/ time required to flow.
Bulk Density (BD)
Weighed quantity of granules, which was
previously passed through #20 sieve and transferred in
100 ml graduated cylinder. Carefully level the powder
without compacting, and read the unsettled apparent
volume. Calculate the apparent bulk density in gm/ml by
the following formula
Bulk density (BD) = Weight of powder / Bulk volume
Tapped Density (TD)
Weighed quantity of granules, which was
previously passed through #20 sieve and transfer in 100
ml graduated cylinder. Then mechanically tap the
cylinder containing the sample by raising the cylinder
and allowing it to drop under its own weight using
mechanically tapped density tester that provides a fixed
drop of 14± 2 mm at a nominal rate of 300 drops per
minute. Tap the cylinder for 500 times initially and
measure the tapped volume (V1) to the nearest graduated
units, repeat the tapping an additional 750 times and
measure the tapped volume (V2) to the nearest graduated
units. If the difference between the two volumes is less
than 2% then final the volume (V2). Calculate the tapped
density in gm/ml by the following formula.
Tapped density (TD) = Weight of powder / Tapped
volume
Compressibility Index /Carr’s Index
The Compressibility Index of the powder blend
was determined by Carr’s compressibility index. It is a
simple test to evaluate the BD and TD of a powder and
the rate at which it packed down. The formula for Carr’s
Index is as below
Carr’s Index= [(TD-BD)*100]/ TD
Hausner’s Ratio
The Hausner’s ratio is a number that is
correlated to the flow ability of a powder or granular
material.
Hausner’s ratio = TD/BD
Particle Size
Optical microscopy was carried out to study the
size of granules. The mean particle size was calculated by
measuring the size of 200 particles with the help of
calibrated ocular micrometer.
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Effervescence time
Granules were allowed to disperse in water, time
required for complete dispersion was noted.
Drug entrapment efficiency
The percent drug entrapment efficiency was found to be
86% for 0.5:1 ratio.
In Vitro Drug Release Studies
The release rate of Taste Masked effervescent
granules of Aceclofenac was determined using USP
dissolution testing apparatus II (paddle method). The
dissolution test was performed using 900 ml of 0.1N
HCl, at 37 ±0.5°C and 50 rpm. A sample (5 ml) of the
solution was withdrawn from the dissolution apparatus at
0, 5, 10, 15, 20, 25, 30, 35, 40 and 45 min, filtered. The
samples were replaced with fresh dissolution medium of
same quantity. Absorbance of these solutions was
measured at 273 nm using UV-Spectrophotometer.
Cumulative percentage of drug release was calculated
using an equation obtained from a standard curve (Mark
G, 2008).
Taste Evaluation
The objective of this study is to conduct and
evaluate the palatability of complex of ACE- Eudragit E100.
When the batch of ACE- Eudragit E- 100 complex were
evaluated by human volunteers, the volunteers did not
feel any bitter taste after keeping the complex in the
mouth for 60 seconds, which confirmed that the bitter
taste of ACE was masked successfully. This is confirmed
by the scale marking of the volunteers.
Stability Studies
Formulation of Aceclofenac Taste Masked
effervescent granules, were packed individually in
laminated aluminum packs in such a manner that any
mechanical damage was minimal.
These were then stored at following conditions:
1)Long term storage (25°C ± 2°C/60% RH ± 5% RH
or30°C ± 2°C/65% RH ± 5% RH) for 3 months in glass
dessicator containing Sodium nitrite at or30°C ± 2°C
2 ) Accelerated 40°C ± 2°C/75% RH ± 5% RH for 3
months ( in humidity controlled oven )
Granules were examined for Effervescent time and Invitro dissolution study (Dr. Javed A et al., 2008).
RESULTS AND DISCUSSION
Evaluation of ACE- Eudragit E-100 complex
IR Spectroscopy
The FTIR spectrum of ACE- Eudragit E-100
complex with acetone prepared by kneading method
showed a shift in the peaks as compared to the pure
components and also new peaks appeared in the complex,
suggesting the formation of a complex.
DSC (Differential Scanning Calorimeter)
The DSC melting curve of ACE showed a
melting peak at 160.20C which corresponds to the
melting point ACE. The DSC thermogram of Eudragit E
100 shows a melting peak at 860C. The DSC thermogram
of ACE - Eudragit E-100 complex showed a single
melting peak at 1400C which does not correspond to the
melting of any of the components, suggesting there is a
formation of a complex between ACE and Eudragit E
100.
Evaluation of Taste Masked Effervescent Granules
Angle of repose
Values of angle of repose: 25- 300 show
excellent flow properties, 31-350 show good flow
properties, 36-400 show fair flow properties and 41-450
showing passable flow properties.
The angle of repose observed was 33.120 which indicates
good flow properties.
Carr’s index
The Compressibility index (Carr’s index) is a
measure of the propensity of a powder to be compressed.
It is determined from the bulk and tapped densities. In
theory, the less compressible a material the more
flowable it is. As such, it is measures of the relative
importance of interparticulate interactions. In a free
flowing powder, such interactions are generally less
significant, and the bulk and tapped densities will be
closer in value. For poorer flowing materials, there are
frequently greater inter-particle interactions, and a greater
difference between the bulk and tapped densities will be
observed. The Carr’s index observed is 7.13% which
indicates excellent compressibility of the granules.
Hausner’s ratio
Lower Hausner’s ratio (<1.25) indicates better
flow properties than higher ones, between 1.25 to 1.5
showing moderate flow properties and more than 1.5
poor flow.
The observed Hausner’s ratio was 1.36, indicating
moderate flow properties.
In Vitro Drug Release Studies
The release of Aceclofenac from Taste Masked
effervescent granules of Aceclofenac is 99.1% within 45
minutes.
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Table 1. Formula for the preparation of Taste masked effervescent Granules
Ingredients
Drug : Polymer complex (05:1 )
Citric acid
Tartaric Acid
Sodium bicarbonate
Sucralose
Menthol
PVA in IPA
Table 2. Drug entrapment efficiency of ACE in complex
Drug Polymer
0.25:1
0.5:1
1:1
Table 3. Taste evaluation score by volunteers
Batch
No.
1
2
3
1(0.25:1)
1
0
1
2(0.5:1)
0
0
0
3(1:1)
2
1
1
4
1
1
1
Quantity
125 mg
72:72
109.08
218.16
1%
0.02
qs.
Drug Entrapment Efficiency
79%
86 %
82%
Volunteers
5
1
0
1
6
2
0
2
7
1
0
2
Scale: 0 = Good, 1 = Tasteless, 2 = slightly bitter, 3 = bitter, 4 = very bitter
Table 4. Compressibility index values
Compressibility index
≤10
11-15
16-20
21-25
26-31
32-37
>38
Table 5. Drug release profile of ACE
Time (mins.)
0
5
10
15
20
25
30
35
40
45
Table 6. Evaluation of taste masked effervescent granules
Angle of repose
Flow rate
Bulk density
Tapped density
Compressibility/ Carr’s index
Hausners ratio
Particle Size (μm)
Effervescence time
Dissolution % drug release
Properties
Excellent
Good
Fair
Passable
Poor
Very Poor
Very Very Poor
Formulation (batch no. 2) % release
24.7
43.2
58.4
67.6
74.1
80.3
84.5
89.8
92.9
99.1
33.120
61.5mg/sec
0.08786gm/cm3
0.09461gm/cm3
7.13%
1.36
149
15sec
99.1%
8
2
0
1
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Shet N. et al. / International Journal of Biopharmaceutics. 2014; 5(1): 50-58.
Table 7. Result of stability Study for batch 2 of Aceclofenac sodium effervescent granules at 30°C ± 2°C/75% RH ± 5% RH
Parameter
Effervescent time
Dissolution study
Initial
15sec
99.0%
1 month
14.9sec
98.6%
2 month
14.9
97.0%
3 month
14.7
96.5%
Table 8. Result of stability Study for batch 2 of Aceclofenac sodium effervescent granules at 40°C ± 2°C/75% RH ± 5% RH
Parameter
Effervescent time
Dissolution study
Initial
15.1sec
98.9%
Fig 1. FTIR spectrum of Aceclofenac sodium
Fig 2. FTIR spectrum of Eudragit E-100
1 month
15sec
97.4%
2 month
14.9sec
96.2%
3 month
14.8sec
95.0%
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Shet N. et al. / International Journal of Biopharmaceutics. 2014; 5(1): 50-58.
Fig 3. FTIR spectrum of ACE- Eudragit E-100 (0.5:1)
Fig 4. FTIR spectrum of ACE- Eudragit E-100 (0.25:1)
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Fig 5. FTIR spectrum of ACE- Eudragit E-100 (1:1)
Fig 6. DSC thermogram of Aceclofenac sodium
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Fig 7. DSC thermogram of Eudragit E-100
Fig 8. DSC thermogram of ACE - Eudragit E-100 (0.5) complex
Fig 9. Release profile of Aceclofenac in effervescent granules
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CONCLUSION
From the above studies, it can be concluded that
the prepared Effervescent Taste Masked Granules
enhance the disintegration and dissolution rates, along
with taste masking of the selected drug and hence have
good potential for use with paediatric and geriatric
patients.
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