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Results & Discussion
77
6. Characterization of Aceclofenac:
The sample of Aceclofenac was supplied by J. B. Chemicals Pvt Ltd. Mumbai, along with
certificate of analysis. Further tests were carried out as shown in the Table 23.
Batch No. : AF 5017
Expiry Date : June 2012.
6.1. Results of analysis:
Table 23 Results of analysis of Aceclofenac carried out in our laboratories
TEST SPECIFICATIONS OBSERVATION REMARKS
Description White long needle shaped
crystalline powder
White long needle shaped
crystalline powder
Complies
Solubility Practically insoluble in
water, Soluble in Methanol
and chloroform.
Practically insoluble in
water, Soluble in Methanol
and chloroform.
Complies
Identification To pass tests A & B Passes Complies
Melting point 153 – 158 0C 157.4
0C Complies
Water NMT 0.5% 0.34% Complies
Results & Discussion
78
6.1.1. Differential Scanning Calorimetry:
The thermogram of drug was characterized by single melting endotherm at 153.060C. The
DSC thermogram of the drug was found to be in agreement with the specifications.
Figure 8 DSC scans of Aceclofenac
Results & Discussion
79
6.1.2. Infra-Red Spectroscopy:
Results -
The IR spectrum has shown in Fig. 9
The results are tabulated in Table No. 24
Table 24 Wavelength of IR Spectrum of Aceclofenac
Wavelength Assignment
3319.01 cm-1 –N-H Stretching
2936.8 cm-1 Aromatic -C-H Stretching
1771.5 cm-1 -COO- Stretching
1716.8 cm-1 -C=O Stretching
1589.5 cm-1 -C=C cis/vinyl strong; trans weak bonds
750.0 cm-1 Aromatic-Cl
Figure 9 IR Spectra of Aceclofenac
75
0.0
177
3.1
678
1.1
1
10
56
.42
11
01
.64
11
50
.43
11
79
.05
12
56
.47
12
81
.51
13
44
.61
14
18
.30
14
38
.73
14
52
.44
14
80
.93
15
07
.54
15
77
.75
15
89
.52
17
16
.83
17
71
.55
23
59
.47
29
36
.81
33
19
.10
-10
0
10
20
30
40
50
60
70
80
%T
500 1000 1500 2000 2500 3000 3500 4000
cm-1
Results & Discussion
80
6.1.4. Determination λ max of Aceclofenac by UV:
The max was found to be 275 nm as shown in Fig. 10
Figure 10 UV Spectrum of Aceclofenac
Results & Discussion
81
6.2 Analytical method development by UV spectrophotometric method:
6.2.1. Preparation of standard plot in methanol:
The data for the standard plot of Aceclofenac in Methanol is shown in Table 25 the
standard plot is as shown in the Fig. 11 Beer Lambert law was obeyed over the range of 0-50
μg/ml, and the data was found to fit the equation:
y = 0.019x + 0.013 R² = 0.997
Table 25 Data for standard plot of Aceclofenac in Methanol
S. NO. Concentrations (μg/ml) Mean Absorbance ± S.D (n = 3)
1 0 0.000
2 10 0.218± 0.005
3 20 0.392± 0.005
4 30 0.595± 0.002
5 40 0.802± 0.002
6 50 0.950± 0.005
Figure 11 Standard plot of Aceclofenac in Methanol
Results & Discussion
82
6.2.2. Preparation of standard plot in pH 1.2:
The data for the standard plot of Aceclofenac in pH 1.2 is shown in Table 26. The
standard plot is as shown in the Fig. 12 Beer Lambert law was obeyed over the range of 0-50
μg/ml, and the data was found to fit the equations:
y = 0.001x - 0.000 R2 = 0.993
Table 26 Data for standard plot of Aceclofenac in pH 1.2
Figure 12 Standard plot of Aceclofenac in pH 1.2
Sr. No. Concentrations (μg/ml.) Mean Absorbance ± S.D (n = 3)
1 0 0.000
2 10 0.011 ± 0.004
3 20 0.018 ± 0.003
4 30 0.029 ± 0.003
5 40 0.041 ± 0.004
6 50 0.053± 0.003
Results & Discussion
83
6.2.3. Preparation of standard plot in buffer pH 6.4:
The data for the standard plot of Aceclofenac in pH 6.4 buffer is shown in Table 27 the
standard plot is as shown in the Fig. 13 Beer Lambert law was obeyed over the range of 0-50
μg/ml, and the data was found to fit the equations:
y = 0.016x -0.016 R2 = 0.995
Table 27 Data for standard plot of Aceclofenac in pH 6.4 buffer
Figure 13 Standard plot of Aceclofenac in pH 6.4 buffer
S. No. Concentrations (μg/ml.) Mean Absorbance ± S.D (n = 3)
1 0 0.000
2 10 0.129 ± 0.003
3 20 0.306 ± 0.004
4 30 0.498 ± 0.005
5 40 0.682 ± 0.003
6 50 0.806 ± 0.003
Results & Discussion
84
6.2.4. Preparation of standard plot in buffer pH 7.4:
The data for the standard plot of Aceclofenac in pH 7.4 buffer is shown in Table 28 the
standard plot is as shown in the Fig. 14 Beer Lambert law was obeyed over the range of 0-50
μg/ml, and the data was found to fit the equations:
y = 0.018x+0.005 R2 = 0.999
Table 28 Data for standard plot of Aceclofenac in pH 7.4 buffer
Figure 14 Standard plot of Aceclofenac in pH 7.4 buffer
S. No. Concentrations (μg/ml.) Mean Absorbance ± S.D (n = 3)
1 0 0.000
2 10 0.19 ± 0.003
3 20 0.365 ± 0.004
4 30 0.568 ± 0.003
5 40 0.726 ± 0.003
6 50 0.912± 0.003
Results & Discussion
85
6.3 PREFORMULATION STUDIES:-
6.3.1. Drug-Excipients compatibility studies:
The possible interaction between the drug and the excipients was studied by DSC and IR
spectroscopy. The results of DSC studies are given in Fig. 15. There was no considerable change
in the DSC endotherm values when aceclofenac was mixed with excipients compared to that of
pure aceclofenac. The IR spectra of pure aceclofenac and its physical mixtures with other
excipients are shown in fig. 16. Pure aceclofenac showed 2107.1, 1918.1, 1848.6, 1771.5 and
664.4 cm-1
wave numbers as major peaks. The results revealed no considerable changes in the IR
peaks of aceclofenac when mixed with excipients compared to pure aceclofenac.
Results & Discussion
86
Figure 15 DSC Thermograms. (1) 153.6=A. (2) 152.0=A+MCC. (3) 153.5= A+ MCC+ PVP
K30. (4) 152.8= A+ MCC+PVP K30+ Eudragit S100. A= Aceclofenac; MCC= Microcrystalline
Cellulose.
Results & Discussion
87
Figure 16 IR Spectra of aceclofenac and its physical mixtures with different excipients. a= A,
b==A+MCC, c= A+ MCC+ PVP K30, d= A+ MCC+PVP K30+ Eudragit S100. A=
Aceclofenac; MCC= Microcrystalline Cellulose.
Results & Discussion
88
6.4 FORMULATION DEVELOPMENT:-
6.4.1. Design of complete multiple unit system:
Fig.17 shows the design of complete multiple unit system. The system consisted of drug
containing core pellets prepared by extrusion-spheronization process, coated with an inner pH-
dependent layer of Eudragit S100 and outer Effervescent layer of sodium bicarbonate and HPMC
K100M. Upon contact with the gastric fluid, carbon dioxide was liberated via neutralization
reaction with sodium bicarbonate and was entrapped in the hydrophilic polymeric membrane of
HPMC K100M. The system with a density less than 1 g/ml floated and maintained the buoyancy
till gas entrapped in the membrane is sufficient to maintain it. As the HPMC K100M dissolves
in medium, the gas entrapped releases and after a particular time the system settles down.
Eudragit S100 coating dissolves at pH ≥7 and complete release of drug occurred. Thus, outer
effervescent layer prolongs the gastric residence time of system and inner layer prevents the drug
release in stomach as well as in the proximal part of the small intestine.
Figure 17 Design of complete multiple unit system (Not to scale)
6.4.2. Preparation of core pellets:
The core pellets of aceclofenac were prepared using microcrystalline cellulose as diluent by
extrusion spheronization method. Different ratios of drug: MCC as shown in the table 13 were
taken for preparation of core pellets. Plane water was used as binder in the preparation of the
Drug containing core pellet
Enteric coating
(EudragitS100)
Effervescent layer
(Sodium bicarbonate and
HPMC K100M)
Results & Discussion
89
pellets. Batch F1 and F2 fails to produce extrudates as well as spherical pellets while F3, F4, F5
produced spherical pellets showing good physical properties.
i) Effect of moisture level on physical properties of pellets
The size and shape of pellets was found to depend on the amount of water added to form the
damp mass before extrusion. Increase in the amount of water increases the pellets diameter
where as low amount of moisture results in reduction of the yield of pellets due to feed loss
because of the improper wetting of the mass which fails to produce the extrudates. Thus the
amount of moisture (water) should be kept optimum i.e. 50 % so as to get desired size pellets
with maximum yield.
Table 29 Effect of moisture level on physical properties of pellets
Sr. No Material Moisture
(%)
Size distribution
(#) Shape
Yield
(%)
1 Drug-MCC 25 16- 20 Spherical < 60
2 Drug-MCC 50 16- 20 Spherical >90
3 Drug-MCC 75 10- 20 (wide) Dumble +Spherical >90
MCC: microcrystalline cellulose
ii) Effect of spheronization speed and time on physical properties of pellets
The speed and time of rotation affects the shape and size of the pellets. Any change in speed and
time results in the pellets of different shapes and sizes as shown in the table 30. Depending upon
the shape and size of pellets the speed of rotation and time should be optimized. At the speed of
1500 rpm for 10 minute, desired size of pellets (0.84-1.0 mm) were obtained hence 1500 rpm
and 10 minute was selected as optimised speed and time for the formulation of the core pellets.
Results & Discussion
90
Table 30 Effect of Spheronization speed and time on physical properties of pellets
Sr.
No.
Material Spheronization
speed (rpm)
Spheronization
Time(min)
Shape of pellets Size of
pellets
(mm)
1 Drug-MCC 500 10 Dumble Above 2.5
2 Drug-MCC 500 15 Dumble Above 2.5
3 Drug-MCC 750 10 Dumble Above 2
4 Drug-MCC 750 15 Dumble+Spherical Above 2
5 Drug-MCC 1000 10 Dumble+Spherical 1.0-2.0
6 Drug-MCC 1000 15 Spherical 0.84-1.0
7 Drug-MCC 1500 10 Spherical 0.84-1.0
8 Drug-MCC 1500 15 Spherical 0.84-1.0
6.4.3 Enteric coating of core aceclofenac pellets:
i) Effect of different coating levels on drug release
The aceclofenac pellets was coated upto 5, 10, 15 and 20% weight gain. The coated pellets were
then subjected to dissolution studies in pH 1.2 and 6.5 buffer. The result revealed that 5% weight
gain fails to give enteric effect where as, at 10% and 15% coating levels; the drug release in
acidic buffer was less than 7% and 2 % respectively while in pH 7.4, 15 % and 20 % coating
level showed 66 % and 40% drug release respectively.
Data from Table 31 revealed that 10, 15 and 20 % coating levels had released <10 % of
aceclofenac in acidic buffer, complying with the official requirement for enteric coated dosage
formulations. But, 15 % and 20 % coating fails to give immediate release in pH 7.4 buffer.
Hence 10 % weight gain was selected as optimum coating level which not only gave the enteric
effect but also gave immediate release in pH 7.4 buffer.
Results & Discussion
91
Table 31 % Drug Release at Different coating levels
Batch No. % Coating Responses
(% Drug Release)
Y1
( at 6th hour)
Y2
( at 7th hour)
F6 5 64 100
F7 10 7 98
F8 15 2 66
F9 20 0 40
6.4.4. Floating ability:
Buoyancy of pellets are directly related to its performance as a floating pulsatile drug delivery
system since lag time for pellets is equivalent to their floating time at the stomach and the
proximal small intestinal (jejunal) transit time (i.e. about 2 hrs.). The system should float in a
few minutes after contact with gastric fluid to prevent the dosage form transiting into the small
intestine together with food. [85] Floating property of pellets was studied by determining
buoyancy and time required for sinking all the pellets under study. Surfactant Tween-80 was
used in dissolution medium to simulate surface tension of human gastric juice (35-50 m N/m2)
[86]. The pellets layered with effervescent agent of 10% weight gain do not float because of
insufficient gas entrapment in the gellified hydrocolloid of HPMC K100M. In all the remaining
batches, pellets floated within 1 min after placing in 0.1N HCl as shown in the Fig. 18. The
floating ability of pellets were investigated with respected to the amount of effervescent agent
(NaHCO3: HPMC K100M ratio) and the layering level (% weight gain). The prolonged floating
time in pellets layered with lower amount of NaHCO3 was attributed to higher amount of HPMC
K100M which possessed higher entrapment capacity of the generated CO2. As the layering level
increases, floating time increases (Fig.18).
Results & Discussion
92
Figure 18 Floating behavior of layered pellets in 0.1 N HCl containing 0.02% w/v tween-80.
0
50
100
150
200
250
300
0 20 40 60 80 100
Sodium bicarbonate (%)
Flo
atin
g t
ime
(min
)
30% layering 50 % layering 70 % layering
Figure 19 Effect of % NaHCO3 layered onto the coated pellets and effect of % layering of
effervescent agent on floating time of the final pellets (complete multiple unit system.)
Results & Discussion
93
6.4.5. In-vitro drug release studies:
To simulate the pH variation in the GI tract, dissolution studies were performed first in 0.1 N
HCl (pH 1.2) for time equivalent to floating time (rounded to full hour instead of fraction) and
then 2 hours in phosphate buffer pH 6.4 (Jejunal transit time is about 2 hrs.) and finally at
phosphate buffer pH 7.4 till complete release of drug [87] out of Twelve batches, seven batches
namely, F11, F12, F13, F15, F16, F17 and F19 were selected for drug release studies. Less than
10 % release of aceclofenac was found at pH1.2 as well as at pH 6.4. After this lag, complete
drug was released within 1 hour in phosphate buffer pH 7.4 in which enteric coating of Eudragit
S100 got dissolved (Fig. 20). Finally, three batches i.e., F12, F13, F17 were selected for stability
studies.
Figure 20 Cumulative drug release profile.
6.4.6. Evaluation of core and complete multiple unit system
i. Drug content:
For Batches F12, F13 and F17, Drug containing core pellets were shown drug content as
96.25%, 98.21% and 95.72% respectively. These results were within the official specification
limits. Hence these batches were preceded for further processing. In final layered pellets of the
same batches, drug content was found to be 99.78%, 100.26 and 99.58 respectively which is
also within the official specification limits.
0
20
40
60
80
100
120
0 100 200 300 400 500
TIme (Minutes)
Cumulative
release (%)
F11
F12
F13
F15
F16
F17
F19
Results & Discussion
94
ii. Size Distribution:
The distribution of size fractions of pellets are shown in Fig. 21. The dominant size (maximum
size) fraction of drug containing core pellets were 0.84-1mm and that of the layered pellets were
1.41-2.00 mm for batch F13.
Figure 21 The size distribution of the pellets (determined by sieve analysis).
iii. Shape analysis:
Spherical shape is an important pellet characterization parameter as the shape of the pellets can
affect other properties such as flowability and coating performance. The prerequisite for
successful processing is that shape of the pellets is of high quality. The two shape factors are
calculated, roundness and aspect ratio, are sensitive parameters for evaluating pellet shape. Drug
containing core pellets have shown circularity factor of 0.912±0.032 and the aspect ratio of
1.121±0.092. This shows that pellets were of ideal shape for further processing. Final layered
pellets have shown circularity factor of 0.902±0.059 and the aspect ratio of 1.168±0.095.This
indicates that pellets were having good flowability.
iv. Friability:
The friability of the drug containing core pellets was 0.08±0.002%. This indicates that the core
pellets were quite hard and able to withstand the mechanical stresses of the subsequent process.
0
10
20
30
40
50
60
70
80
90
<0.84 0.84-1.00 1.00-1.41 1.41-2.00 >2.00
Size fraction (mm)
Core pellets
Batch F13
Weight
Retained (%)
Results & Discussion
95
The friability of the final layered pellets was 0.09±0.005% which indicates that they can
withstand handling, shipping, storage and operation like filling.
v. Scanning electron microscopy (SEM):
Fig. 22A shows the appearance of external morphology of the core pellet under SEM. The core
pellets were spherical agglomerates with a slightly rough surface. The surface of the coated
pellets was smoother than the core pellet (Fig. 22B). Fig. 22C is the cut section of a coated pellet
which shows the uniformity of the coating. Fig. 22D shows surface morphology of layered pellet
having uniform rough surface. Fig. 22E is the cut section of layered pellet in which uniform layer
of effervescent agent is deposited during the layering process.
Results & Discussion
96
A) B)
C) D)
E)
Figure 22 SEM pictures of pellets.
Results & Discussion
97
vi . Physical properties:-
The final layered pellets were evaluated for its physical properties for the following parameters
shown in Table 32. The pellets possess good physical properties as per specifications.
Table 32 Evaluation of Physical properties of final layered pellets
Sr.No. Physical properties
Values(n=3 ± SD)
1 Angle of repose 27.66 ± 1.52
2 Bulk density 0.7034 ± 0.012
3 Tapped density 0.7597 ± 0.004
4 Hausner’s ratio 0.9255 ± 0.0108
5 Carr’s index 7.39 ± 1.105
6.5. Stability testing of Aceclofenac pellets:-
6.5.1. Formulation-1 (F12):
Table 33 Evaluation of parameter on accelerated stability study at 40C + 2
C & 75% RH + 5
%
PARAMETER TIME PERIOD (MONTHS)
0 1 2 3 4
5 6
Physical appearance White colored spherical pellets
Drug assay (%) 99.78 99.54 98.24 96.00 95.87
95.50 94.88
Drug release after 6th Hrs (Y1) 5 5 5 6 6
7
7
Drug release after 7th Hrs (Y2) 96 96 97 95 96
96
95
Results & Discussion
98
Table 34 Evaluation of parameter on real time stability study at 25C + 2
C & 60 % RH + 5%
6.5.2. Formulation-2 (F 13):
Table 35 Evaluation of parameter on accelerated stability study at 40C + 2
C & 75 % RH + 5 %
Parameter Time period (months)
0 1 2 3 4 5 6
Physical appearance White colored spherical pellets
Drug assay (%) 100.26 99.92 99.46 98.24 98.01 97.75 97.21
Drug release after 6th Hrs
(Y1) 3 4 3 3 4
4 3
Drug release after 7th Hrs
(Y2) 96 99 97 96 96
96 95
Parameter Time period (months)
0 6
Physical appearance White colored spherical pellets
Drug assay (%) 99.78 98.66
Drug release after 6th Hrs (Y1) 6 7
Drug release after 7th Hrs (Y2) 97 98
Results & Discussion
99
Table 36 Evaluation of parameter on real time stability study at 25C + 2
C & 60% RH + 5%
6.5.3. Formulation-3 (F17):
Table 37 Evaluation of parameter on accelerated stability study at 40C + 2
C / 75 % RH + 5 %
Parameter Time period (months)
0 1 2 3 4 5 6
Physical appearance White coloured spherical pellets
Drug assay (%) 99.58 99.12 98.68 98.62 98.47 98.23 98.03
Drug release after 6th Hrs
(Y1) 2 3 5 3
5 4 4
Drug release after 7th Hrs
(Y2) 98 99 101 97
96 96 95
Parameter Time period (months)
0 6
Physical appearance White colored spherical pellets
Drug assay (%) 100.26 98.46
Drug release after 6th Hrs (Y1) 6 4
Drug release after 7th Hrs (Y2) 98 94
Results & Discussion
100
Table 38 Evaluation of parameter on real time stability study at 25C+ 2
C / 60% RH + 5%
From the above stability study it was found that all three formulations were stable at 40C + 2
C
/ 75% RH + 5% and 25C + 2
C /60% RH + 5% for six months. Assay of the formulation was
found to be within specified range. There was no degradation of Aceclofenac in all three
formulations. All three formulations were found satisfactory with respect to physical appearance
and drug release. All the three developed pellets showed no drug precipitation till 24 hr at room
temperature and at 40C + 2
C / 75% RH + 5%.
Optimized pellets remain spherical and stable for 6 months at ambient temperature and at 40C +
2C / 75% RH + 5 %.
Parameter Time period (months)
0 6
Physical appearance White coloured spherical pellets
Drug assay (%) 99.58 98.62
Drug release after 6th Hrs (Y1) 7 8
Drug release after 7th Hrs (Y2) 100 98
Results & Discussion
101
6.6. Preformulation study
6.6.1. Excipient Compatibility study
The possible interaction between the drug and the polymers were studied by Differential
Scanning Calorimeter (DSC) and IR spectroscopy.
6.6.2. Differential Scanning Calorimeter
The possible interaction between the aceclofenac and the HPMC K4M, HPMC K15M, HPMC
K100M were studied by DSC. The results of DSC studies are shown in fig 23 to 27. There was
no considerable change in the DSC endotherm values, when aceclofenac was mixed with HPMC
K4M, HPMC K15M, and HPMC K100M, compared to that of pure aceclofenac.
Figure 23 DSC thermogram of plain Aceclofenac.
Results & Discussion
102
Figure 24 DSC thermogram of plain HPMC K4M.
Figure 25 DSC thermogram of plain HPMC K15M
Results & Discussion
103
.
Figure 26 DSC thermogram of plain HPMC K100M.
Results & Discussion
104
[A]
0.00 2.00 4.00 6.00
Time [min]
-20.00
-10.00
0.00
mW
DSC
100.00
150.00
200.00
C
Temp
File Name: ACECLOFENAC 2008-05-06.tad
Detector: DSC-60
Acquisition Date 08/05/06
Acquisition Time 11:20:32(+0530)
Sample Name: ACECLOFENAC
Sample Weight: 2.850[mg]
Annotation:
[Temp Program]
Start Temp 100.0
Temp Rate Hold Temp Hold Time Gas
[C/min ] [ C ] [ min ]
15.00 200.0 0 Nitrogen
Thermal Analysis Result
[B]
0.00 2.00 4.00 6.00
Time [min]
-6.00
-4.00
-2.00
mW
DSC
100.00
150.00
200.00
C
Temp
File Name: ACL+HPMC K4 2008-05-06.tad
Detector: DSC-60
Acquisition Date 08/05/06
Acquisition Time 12:11:47(+0530)
Sample Name: ACL+HPMC K4
Sample Weight: 3.030[mg]
Annotation:
[Temp Program]
Start Temp 100.0
Temp Rate Hold Temp Hold Time Gas
[C/min ] [ C ] [ min ]
15.00 200.0 0 Nitrogen
Thermal Analysis Result
[C]
0.00 2.00 4.00 6.00
Time [min]
-5.00
-4.00
-3.00
-2.00
-1.00
0.00
mW
DSC
100.00
150.00
200.00
C
Temp
File Name: ACL+HPMC K15 2008-05-06.tad
Detector: DSC-60
Acquisition Date 08/05/06
Acquisition Time 12:24:33(+0530)
Sample Name: ACL+HPMC K15
Sample Weight: 3.320[mg]
Annotation:
[Temp Program]
Start Temp 100.0
Temp Rate Hold Temp Hold Time Gas
[C/min ] [ C ] [ min ]
15.00 200.0 0 Nitrogen
Thermal Analysis Result
[D]
0.00 2.00 4.00 6.00
Time [min]
-5.00
-4.00
-3.00
-2.00
-1.00
0.00
mW
DSC
100.00
150.00
200.00
C
Temp
File Name: ACL+HPMC K100 2008-05-06.tad
Detector: DSC-60
Acquisition Date 08/05/06
Acquisition Time 12:36:54(+0530)
Sample Name: ACL+HPMC K100
Sample Weight: 2.910[mg]
Annotation:
[Temp Program]
Start Temp 100.0
Temp Rate Hold Temp Hold Time Gas
[C/min ] [ C ] [ min ]
15.00 200.0 0 Nitrogen
Thermal Analysis Result
Figure 27 [A] DSC thermogram of Aceclofenac, [B] DSC thermogram of
Aceclofenac+HPMCK4M(1:1), [C] DSC thermogram of Aceclofenac+HPMCK15M(1:1), [D]
DSC thermogram of Aceclofenac + HPMC K100M (1:1)
Results & Discussion
105
6.6.3. Infrared spectroscopy
The possible interaction between the drug and the polymers were studied by IR spectroscopy.
The IR spectra’s of pure aceclofenac, HPMC K4M, HPMC K15M, HPMC K100M and physical
mixture of aceclofenac with HPMC K4M, HPMC K15M, and HPMC K100M are shown in
Figure 28 to 32. Pure aceclofenac showed 3319.10, 2936.81, 2359.47, 1771.56, 1716.83 and
750.01 cm-1
wave number as major peaks. The results revealed no considerable changes in the IR
peaks of aceclofenac when mixed with polymers compared to pure aceclofenac, Shown in,
Table 39.
Table 39 Comparison of major IR peaks of drug polymer mixture with pure Aceclofenac
Aceclofenac Aceclofenac : HPMC
K4M (1:1)
Aceclofenac : HPMC
K15M (1:1)
Aceclofenac : HPMC
100M (1:1)
3319.10 3318.66 3318.68 3318.92
2936.81 2936.72 2936.59 2936.61
1771.56 1771.39 1771.24 1771.43
1716.83 1716.49 1716.48 1716.69
750.01 749.70 749.70 749.81
HPMC K4M= Hydroxypropyl methylcellulose K4M, HPMC K15M= Hydroxypropyl
methylcellulose K15M, HPMC K100M= Hydroxypropyl methylcellulose K100M.
Results & Discussion
106
75
0.0
177
3.1
678
1.1
1
10
56
.42
11
01
.64
11
50
.43
11
79
.05
12
56
.47
12
81
.51
13
44
.61
14
18
.30
14
38
.73
14
52
.44
14
80
.93
15
07
.54
15
77
.75
15
89
.52
17
16
.83
17
71
.55
23
59
.47
29
36
.81
33
19
.10
-10
0
10
20
30
40
50
60
70
80%
T
500 1000 1500 2000 2500 3000 3500 4000
cm-1
Figure 28 IR spectra of plain Aceclofenac
569.
18
945.
65
1065
.02
1375
.06
1457
.31
1652
.95
2360
.36
2933
.26
3459
.75
0
5
10
15
20
25
30
35
40
45
%T
500 1000 1500 2000 2500 3000 3500 4000
cm-1
Figure 29 IR spectra of plain HPMC K4M.
Results & Discussion
107
668.
29
1056
.33
1457
.09
1506
.81
1539
.91
1558
.81
1653
.04
1717
.28
2359
.55
2925
.43
3446
.53
36
38
40
42
44
46
48
50
52
54
56
58
60
62
64
66
68
70
72
74
%T
500 1000 1500 2000 2500 3000 3500 4000
cm-1
Figure 30 IR spectra of plain HPMC K15M
569.
59
945.
62
1063
.04
1375
.23
1457
.67
1653
.34
2360
.52
2931
.40
3466
.10
0
5
10
15
20
25
30
35
40
45
50
%T
500 1000 1500 2000 2500 3000 3500 4000
cm-1
Figure 31 IR spectra of plain HPMC K00M.
Results & Discussion
108
569.59
945.62
1063.0
4
1375.2
3
1457.6
7
1653.3
4
2360.5
2
2931.4
0
3466.1
0
0
5
10
15
20
25
30
35
40
45
50
%T
500 1000 1500 2000 2500 3000 3500 4000
cm-1 [A]
450.97
479.05
511.38
537.84
610.12
667.92
717.30
749.70
772.99
780.94
850.99
899.27
964.85
1056.0
9
1150.0
01256.2
5128
1.30
1344.2
7
1417.9
4145
2.26
1507.3
9157
7.65
1589.3
2
1716.4
8
1771.2
42936.5
9
3318.6
8
-10
-5
0
5
10
15
20
25
30
35
%T
500 1000 1500 2000 2500 3000 3500 4000
cm-1 [B]
[C]
451.08
479.09
511.56
537.93
610.13
668.10
717.38
749.81
772.98
780.99
851.17
899.34
964.91
1056.1
8
1150.0
91256.3
1128
1.31
1344.3
3
1418.1
0145
2.30
1507.4
6157
7.61
1589.3
6
1716.6
9
1771.4
3
2936.6
1
3318.9
2
-10
-5
0
5
10
15
20
25
30
35
40
45
%T
500 1000 1500 2000 2500 3000 3500 4000
cm-1
[D]
Figure 32 [A] IR spectra of plain Aceclofenac [B] IR spectra of Aceclofenac + HPMC K4M
(1:1). [C] IR spectra of Aceclofenac + HPMC K15M (1:1), [D]. IR spectra of Aceclofenac +
HPMC K100M (1:1)
450.98
479.06
511.45
537.75
610.18
668.03
717.25
749.70
773.00
851.17
899.28
964.88
1149.6
4
1256.3
51344.3
4
1452.2
5
1507.5
21577.7
1158
9.39
1716.4
9
1771.3
9
1921.2
9
2936.7
2
3318.6
6
-10
-5
0
5
10
15
20
25
30
35
%T
500 1000 1500 2000 2500 3000 3500 4000
cm-1
Results & Discussion
109
6.6.4. Drug Solubility Study
The available literature on solubility profile of aceclofenac indicated that the drug is freely
soluble in acetone, methanol and practically insoluble in water. The results of aceclofenac
solubility in various media and effect of different excipients are shown in Table 40 and Table 41.
The solubility of aceclofenac in water was very less. Aceclofenac showed pH dependent
solubility. At lower pH, the solubility was less and as the pH was raised from acidic to 6.8 the
solubility drastically improved. Further increasing pH from 6.8 to 7.4 the solubility again
decreased. Effect of excipients like DCP, MCC, MS does not affect the solubility of
Aceclofenac, but further addition of HPMC, Sodium bicarbonate, and citric acid slightly
increased the solubility, but no considerable change was found.
Table 40 Solubility of Aceclofenac in different solution media.
Medium Solubility (mg/ml)
Distilled Water 0.085±0.001
0.1 N HCl 0.007±0.001
Phosphate buffer pH 6.8 13.183±0.554
Phosphate buffer pH 7.4 7.531±0.400
All values are expressed as mean ± SD, n=3
Table 41 Solubility of Aceclofenac mixture with different excipients in 0.1 N HCl.
Aceclofenac + Excipients Solubility (mg/ml)
ACL+ MCC+DCP+MS 0.007±0.000
ACL+HPMC K4M+MCC+DCP+SBC+CA+MS 0.013±0.001
All values are expressed as mean ± SD, n=3, ACL= Aceclofenac, MCC= Microcrystalline
cellulose, DCP= Dicalcium phosphate, MS= Magnesium stearate, HPMC K4M= Hydroxypropyl
methylcellulose K4M, SBC= Sodium bicarbonate, CA= Citric acid.
Results & Discussion
110
6.6.5. Micromeritic properties
The results of micromeritic properties are presented in Table 42. Plain aceclofenac exhibited
angle of repose value of 51.75o indicating extremely poor flow property. It was further supported
by high Carr’s index value of 28.51 % and Hausner’s ratio of 1.40. Flow property improving
directly compressible vehicles like MCC slightly improve flow property, indicated by decrease
in angle of repose value, supported by Carr’s index and Hausner ratio value.
Further incorporation of DCP considerably improved flow properties as indicated by reduction in
the values of angle of repose, Carr’s index and Hausner ratio.
Table 42 Micromeritic properties of Aceclofenac and mixtures of Aceclofenac with excipients.
All values are expressed as mean ± SD, n=3, ACL= Aceclofenac, MCC= Microcrystalline
cellulose, DCP= Dicalcium phosphate, MS= Magnesium stearate.
6.6.6. Melting point
Observed melting point of aceclofenac was found in the range of 150 - 152oC, which comply
with given literature value.
6.6.7. Loss on drying
Calculated LOD of aceclofenac was 0.502 %, which comply with given literature value.
6.6.8. Analytical method
Spectrum of aceclofenac was obtained in 0.1 N HCl and phosphate buffer pH 6.8 solutions,
observed wavelength maxima was 273.2 nm and 274.2 nm respectively. At this particular
wavelength absorbance of aceclofenac in 0.1 N HCl and phosphate buffer pH 6.8 solution was
taken, a linear curve was obtained with co-relation regression value was 0.99968 and 0.99965
respectively, shown in Figure 33 and Figure 34.
Excipients Angle of Repose Carr’s Index (%) Hausner Ratio Flow pattern
Pure Aceclofenac 51.750±0.541 28.51±0.212 1.40±0.095 Poor
ACL+MCC 40.920±0.292 22.±0.291 1.34±0.067 Poor
ACL+MCC+DCP 22.220±0.225 13.10±0.099 1.25±0.002 Very good
Results & Discussion
111
Figure 33 Standard curve of aceclofenac in 0.1 N HCl
Figure 34 Standard curve of aceclofenac in phosphate buffer pH 6.8
Results & Discussion
112
6.7. Formulation Development
Floating tablets, containing drug and polymer, are one of the simplest approaches for controlled
release and pulsatile release of a drug. Among the different types of hydrophilic polymers
reported, HPMC was used because of its associated advantages, In addition, HPMC is a pH
independent material and the drug release rates from HPMC matrix formulations are generally
independent of processing variables, such as compaction pressure, drug particle size and
incorporation of lubricant.
6.7.1. Direct compression
Oral solid dosage forms which are commonly used today because of various advantages to
patients. Under the heading of oral solid dosage form, tablet is one of the dosage forms which
have a global market. Today direct compression preferred over wet granulation and dry
granulation because of its well known advantages. [118]
6.7.2. Triple layer tablet formulation
For the development of floating pulsatile release triple layer tablet was prepared. Formulated
triple layer tablet was composed of three layers, top layer containing hydrophobic polymer (ethyl
cellulose) dispersed with various percentage of gas generating agents, middle layer contains
active ingredient (Aceclofenac) with other additives and bottom layer composed of hydrophilic
polymer (HPMC K4M).
Initially tablet was characterized for floating ability and result of floating ability are shown in
Table 43.
Table 43 Floating ability of various triple layer tablet formulation
F Floating onset time
(min)
Floating duration
(min) Integrity
F1 not float not float Broken
F2 not float not float Broken
F3 not float not float Broken
F4 18 30 Separate into layers
F5 6 -8 45 Separate into layers
F6 <3 45 Separate into layers
F7 <3 90 Separate into layers
F8 <1 470 Intact
F= Formulation code.
Results & Discussion
113
Formulations from F1 to F3 get dispersed immediately in the medium without floating; this was
due to the lower percentage of gas generating agent and polymer. Then formulation from F5 to
F7 was formulated with higher percentage of gas generating agents and polymer. Then tablets
float, but floating lag time was higher with short period of floating and tablet gets separated into
layers.
During the process of layer separation it was observed that hydrophobic layer get separate
initially and hydrophilic layer attached as such to middle layer. Hence it can be concluded that
hydrophobic layer unable to make bonding with the middle layer. From this it is decided that top
and bottom layer should be of hydrophilic polymer to avoid the problem of layer separation.
Then F8 formulation was prepared by replacing Ethyl Cellulose with HPMC K4M. F8
formulation shows optimum floating lag time and duration. But during initial 8 h study in 0.1N
HCl shows that open surface of middle layer get exposed to dissolution medium. Due to this
medium exposure middle layer get erode slowly and this fails to show pulsatile release.
From this study it is concluded that, polymer coating to the surrounding surface of middle layer
was necessary to avoid the contact of dissolution media.
6.7.3. Dry coated floating-pulsatile release formulation
To coat middle layer with polymer it is necessary to coat either by spray coating or by
compression coating. Here compression coating was selected because of work feasibility and
simplicity. For compression coating first of all core tablet having diameter and thickness less
than final intact tablet was compressed.
6.7.4. Core tablet formulation
Core tablet (CT1, CT2) were formulated having diameter 8 mm, average weight 200.01 mg and
average thickness 2.07 mm. CT1 was formulated without sodium starch glycolate (SSG) and
CT2 was compressed by adding 8 % Sodium Starch Glycolate (SSG) to show pulsatile release
after the complete erosion of polymer coating.
6.7.5. Dry coating of core tablet
By using CT1 and CT2 as a core tablet floating-pulsatile release tablets was formulated in
different batches F9 to F30.
Results & Discussion
114
6.7.6. Characterization of coating level
To characterize the effect of coating level on floating ability, using HPMC K4M as a coating
polymer F9 to F12 batches were prepared, obtained results are shown in Figure 35.
Initially F9 and F10 batches were formulated by taking 16 % and 25 % HPMC K4M and
compressed using 10 mm flat faced punch tooling. Here core tablet having mean diameter of 8
mm and final dry coated tablet having diameter of 10 mm (coating of 2 mm thickness). Then
buoyancy test was carried out, tablet get float with floating lag time 12 second and all tablets get
dispersed within 5 – 10 minutes. Hence F9 and F10 formulations unable to float for required
period. It may be due to lower % of polymer that unable to form swollen gel.
Then F11 batch was formulated by increasing the amount of HPMC K4M from 25 % to 33 %
using 10 mm flat faced punch tooling. In buoyancy test tablet get separated into layers after 77
min. It means that, the amount of MCC and DCP in coating mixture was responsible for early
separation of layers.
Then F12 was formulated by replacing the concentration of MCC and DCP by HPMC K4M, i.e.
75 % HPMC K4M. Buoyancy test was performed, again tablet float for 94 min and separated
into layer.
Figure 35 Effect of polymer concentration and coating level on floating duration.
From Buoyancy study of F9 to F12 batches, it is concluded that core tablet of 8 mm and intact
tablet of 10 mm diameter unable to float up to 480 min. It indicates that coating thickness of 2
mm get erodes earlier and core tablet get dropped early, hence it need to increase the coating
thickness.
Then F13, F14, F15 was formulated by increasing the coating thickness from 2 mm to 4 mm,
Results & Discussion
115
observed results are shown in Figure 36. Final dry coated tablet was compressed on 12 mm flat
faced punch tooling, by using polymer concentration 33%, 50%, 75 % respectively. Buoyancy
test was performed on F13, F14, and F15, tablet float without separating into layers, but tablet of
F13 float for 720 min, F14 for 1080 min and F15 remains float till 1440 min.
4 mm coating level keeps the tablet intact, but floating duration was increased beyond limit. Our
aim was that the tablet should be float for 480 min only, so further study was done by adjusting
polymer percentage.
Figure 36 Effect of polymer concentration and coating level on floating duration.
6.7.7. Adjustment of floating duration with HPMC K4M
The main objective was tablet should have 480 min gastro retention without drug release
followed by pulsatile release.
To achieve this objective CT2 (containing super disintegrate SSG) was taken as a core, and F16,
F17, and F18 was formulated with 33 %, 50 % and 75 % polymer concentration respectively.
Observed results shown in Figure 37. Buoyancy test was carried out for all three formulations,
F16 tablet get burst after 120 min, F17 tablet burst at 210 min and F18 tablet remain float till 372
min. This bursting effect was observed because of super disintegrate added to core. Hence
further study was done by excluding SSG from core tablet to avoid bursting effect.
Results & Discussion
116
Figure 37 Effect of polymer concentration and coating level on floating duration
Then F19, F20, F21, F22 batches were formulated, by using CT1 as a core tablet, with 15 %,
20%, 25%, 30% HPMC K4M as a coating polymer respectively. Observed effect of polymer
concentration on floating duration shown in Figure 38.
Buoyancy test was performed on F19 to F22 batches, tablet of F19 batch was dispersed within 8
min in dissolution medium. It indicates that the HPMC K4M concentration to be increased.
Then F20 batch was formulated by adding 20 % HPMC K4M. Buoyancy test indicates that tablet
float for 30 min after that it gets disintegrate. Hence it again requires to increase the
concentration of HPMC K4M.
Further F21 was formulated by using 25 % of HPMC K4M, tablet get float till 240 min after that
core tablet get dropped. Then F22 was formulated by adding 30 % of HPMC K4M, tablet get
float till 540 min, after that core tablet get dropped in dissolution media. From this buoyancy
pattern of F21 and F22, it is concluded that, required HPMC K4M concentration should be in
between 25 % to 30 %.
Hence F23 was formulated using 27.5 % HPMC K4M, this formulation float till 473 min and
maintains its shape without dropping the inner core tablet. At 473 min all coating get erode and
inner core tablet get dropped, this formulation shows required pulsatile release pattern which is
required for the treatment of rheumatoid arthritis and osteoarthritis. Hence F23 formulation
considered optimized formulation for HPMC K4M polymer.
Results & Discussion
117
Figure 38 Effect of polymer concentration and coating level on floating duration
6.7.8. Adjustment of floating duration with HPMC K15M
The batches F24, F25, and F26 were prepared by using HPMC K15M as a coating polymer with
15%, 20%, and 25% respectively. Obtained results are in Figure 39.
Tablet of F24 formulation get dispersed within 10 min. Then concentration of coating polymer
was increased up to 20 % and F25 was formulated, even though the tablet gets dispersed after
180 min. Further F26 was formulated with 25% of HPMC K15M, this formulation float till 472
min satisfactorily, after that tablet coating get burst and inner core tablet get dropped. Hence F26
formulation follows the objective of pulsatile fashion and considered optimized formulation for
HPMC K15M polymer.
Figure 39 Effect of polymer concentration and coating level on floating duration
Results & Discussion
118
6.7.9. Adjustment of floating duration with HPMC K100M
Floating duration of formulation was adjusted by using HPMC K100M as a coating polymer.
Formulation F27, F28, and F29 was prepared with 10%, 15%, and 20% HPMC K100M
respectively. Obtained results are shown in Figure 40.
Tablets of F27 to F29 formulations were dispersed within 2 to 20 min because of lower % of
polymer. F30 was formulated with 25% HPMC K100M, this formulation float till 476 min
satisfactorily, thereafter tablet coating get burst and inner core tablet get dropped. Hence F30
formulation follows the objective of pulsatile fashion and considered optimized formulation for
HPMC K100M polymer.
Figure 40 Effect of polymer concentration and coating level on floating duration.
The dry coated tablet was designed for floating pulsatile release fashion, by using three different
grades of HPMC polymer from batch no. F9 - F30. Among this F23, F26 and F30 considered
optimized formulation for HPMC K4M, HPMC K15M, and HPMC K100M respectively.
6.8. Evaluation of dry mixed powder characteristics
The results of micromeritic properties are presented in Table 43. The method employed for
tabletting in this work was direct compression for which the drug, mixture of drug and
excipients, polymers should possess good flow and compacting properties. Plain aceclofenac
exhibited angle of repose value of 51.75o indicating extremely poor flow property. It was further
supported by high Carr’s index value of 28.51 % and Hausner’s ratio of 1.40.
Hence it was necessary to use flow property improving directly compressible vehicles like
dicalcium phosphate (DCP) and microcrystalline cellulose (MCC). The incorporation of these
Results & Discussion
119
diluents into aceclofenac considerably improved flow properties as indicated by reduction in the
values of angle of repose, Carr’s index and Hausner’s ratio. Although both vehicles selected
exhibit good flow properties.
Result of micromeritic properties of dry coated material presented in Table 44 shows excellent
flow properties.
Degree of homogeneity of blend was studied to characterize the dry mixing process. The
observations shown in table 45 indicates uniform mixing of blend.
Table 44 Micromeritic properties of Aceclofenac with different excipients.
All values are expressed as mean ± SD, n=3, ACL= Aceclofenac, MCC= Microcrystalline
cellulose, DCP= Dicalcium phosphate, MS= Magnesium stearate, HPMC K4M= Hydroxypropyl
methylcellulose K4M, SBC= Sodium bicarbonate, CA= Citric acid, HPMC K15M=
Hydroxypropyl methylcellulose K15M, HPMC K100M= Hydroxypropyl methylcellulose
K100M.
6.9. Evaluation of Tablet characteristics
Physicochemical properties of tablet
The results of physicochemical evaluation of tablets are given in Table 46. The tablets of
formulation F8 was found uniform with respect to thickness (3.50 - 3.56 mm), diameter (12 mm)
and hardness (5.4 - 7.2 kg/cm2). The friability (0.40 – 0.73%) and weight variation test complies
as per Indian Phamacopoeia (I.P.) limits. Good and uniform drug content (>98%) was observed
within the batches.
Excipients Angle of
Repose
Carr’s
Index (%)
Hausner’s
Ratio
Flow
property
Degree of
Blend
Homogeniety
(% w/w)
Pure Aceclofenac 51.750±0.541 28.51±0.212 1.40±0.095 Poor
ACL+MCC 40.920±0.292 22.23±0.291 1.37±0.038 Poor
ACL+MCC+DCP 22.220±0.225 13.10±0.099 1.34±0.067 Very good
ACL+MCC+DCP+MS 21.650±0.138 10.28±0.025 1.25±0.002 Very good 98.32±0.325
HPMCK4M+MCC+DCP+SBC+CA+MS 11.280±0.292 13.42±0.162 1.13±0.015 Excellent
HPMCK15M+MCC+DCP+SBC+CA+MS 11.130±0.165 13.40±0.165 1.15±0.005 Excellent
HPMCK100M+MCC+DCP+SBC+CA+MS 11.360±0.425 13.43±0.360 1.15±0.001 Excellent
Results & Discussion
120
The core tablet (CT1, CT2) formulation was found uniform with respect to thickness (2.04 – 2.17
mm), diameter (8 mm), and hardness (5.1 - 6.2 kg/cm2). Friability (0.72 to 0.86%) and weight
variation test complies as per I. P. limits. Good and uniform drug content (>98%) was observed
within the batches. Hence, the tablets containing drug, DCP, MCC, and magnesium stearate
could be prepared satisfactorily by direct compression method.
The final dry coated tablets (FPRT) of F23 were found uniform with respect to thickness (3.20 -
3.35 mm), diameter (12 mm) and hardness (5.7 - 6.9 kg/cm2). The friability (0.72 – 0.84%) and
weight variation test complies as per I. P. limits. Good and uniform drug content (>98%) was
observed within the batches.
Tablets of F26 were found uniform with respect to thickness (3.20 - 3.36 mm), diameter (12 mm)
and hardness (5.6 - 7.0 kg/cm2). The friability (0.58 – 0.86%) and weight variation test complies
as per I. P. limits. Good and uniform drug content (>98%) was observed within the batches.
Tablets F30 were found uniform with respect to thickness (3.18 - 3.34 mm), diameter (12 mm)
and hardness (5.6 - 6.8 kg/cm2). The friability (0.55 – 0.78%) and weight variation test complies
as per I. P. limits. Good and uniform drug content (>98%) was observed within the batches.
All physicochemical properties of F23, F26, and F30 batches were found within limit. Hence, the
tablets containing drug, HPMC, DCP, MCC, SBC, CA and magnesium stearate could be
prepared satisfactorily by direct compression method.
Table 45 Physicochemical properties of F8, CT1, F23, F26, F30 formulations.
F Weight
Variation n=20
Thickness
(mm) n=20
Hardness
(kg/cm2)
n=20
Friability
(%) n=20
Drug Content
(%) n=3
F8 650.10±0.641 3.52±0.014 6.28±0.566 0.64±0.085 98.38±0.202
CT1 200.01±1.041 2.07±0.040 5.64±0.412 0.78±0.041 98.39±0.187
F23 600.96±1.912 3.26±0.042 6.17±0.383 0.77±0.039 98.34±0.198
F26 601.07±1.584 3.26±0.056 6.24±0.441 0.71±0.075 98.36±0.204
F30 600.34±1.379 3.25±0.048 6.19±0.477 0.66±0.066 98.45±0.203
All values are expressed as mean ± SD. F= Formulation code, CT1= Core tablet 1
Results & Discussion
121
Buoyancy determination
Initially floating lag time and duration of tablet was determined simply by placing tablet in 500
ml beaker containing 0.1 N HCl. Observed floating lag time for F8, F23, F26, and F30 was 42,
12, 21, 32 second and floating duration was >1320 min. Then buoyancy study for the same batch
was done in 900 ml dissolution test apparatus at 37.5˚C at 100 rpm. Observed floating lag time
for F8, F23, F26, and F30 was 42, 12, 21, and 32 second and floating duration was 470, 473,
472, and 476 min respectively. From the results it is observed that paddle rotation speed reduces
the floating duration. Floating character of tablet of all three formulations are shown in Figure 41
to Figure 43 while floating lag time and duration shown graphically in Figure 44 and Figure 45
respectively.
Results & Discussion
122
Figure 41 In vitro buoyancy of a) F23 at 0 second, b) F23 at 12 second
Figure 42 In vitro buoyancy studies of a) F26 at 0 second, b) F26 at 13 second, c) F26 at 21
second
Figure 43 In vitro buoyancy of a) F30 at 0 second, b) F30 at 32 second
Results & Discussion
123
Figure 44 Upper view of in vitro buoyancy a) F23, b) F26, c) F30 formulations
.
Figure 45 Floating duration of various formulations
Figure 46 Floating lag time of various formulations
Results & Discussion
124
In vitro Dissolution Study
In vitro dissolution test was carried out in 0.1 N HCl for initial 480 min followed by in phosphate
buffer pH 6.8 for further 120 min. Results of in vitro dissolution test is presented in Table 46.
Table 46 % Cumulative release of aceclofenac for initial 480 min in 0.1 N HCl followed by
120min in phosphate buffer pH6.8 of different formulations.
Time
(min) % Cumulative Drug Release
F8 F13 F14 F15 F21 F22 F23 F25 F26 F30
60 4.28 3.84 4.64 0.20 3.92 4.28 4.56 0.37 4.39 4.48
120 6.28 4.03 4.74 0.60 4.89 5.29 5.14 0.68 5.28 4.50
180 6.58 4.11 5.51 0.86 5.51 5.73 5.33 1.01 5.45 4.77
240 6.62 4.75 6.29 1.27 6.08 5.96 5.85 5.68 5.09
300 6.63 4.94 6.67 2.22 6.56 5.95 5.74 5.25
360 7.42 5.69 6.69 2.29 6.62 6.31 6.14 5.43
420 8.21 5.73 7.01 2.85 6.65 6.96 6.71 5.81
480 10.66 6.70 7.09 3.88 7.96 6.98 6.72 5.88
495 26.21 65.08 70.76 62.87
510 45.07 77.86 77.94 71.91
540 53.02 7.96 82.76 85.78 88.49
570 56.59 93.18 92.05 92.93
600 60.77 97.87 98.18 97.49
630 67.41
660 71.34
1440 9.81 7.97 4.06
Initially dissolution test was performed on F8 formulation in 0.1 N HCl for initial 480 min then
followed by phosphate buffer pH 6.8 for 180 min. % cumulative drug release of F8 formulation
at the end of 660 min was 71.34% only as shown in Figure 47.
Results & Discussion
125
In vitro dissolution test was carried for F13, 14, 15 formulations. The tablets float until 1440 min
and at the end of 1440 min 9.81%, 7.97%, 4.06% drug release was observed respectively (shown
in Figure 48). Hence this formulation did not follow the principle of pulsatile release.
Figure 48 in vitro release profile of Aceclofenac from F13, F14, and F15 Formulation in 0.1 N
HCl
Drug release profile of F21, F22 and F23 shown in Figure 49. In this F21 shows 6.08 % drug
release at the end of 240 min while F22 floats for 540 min and at the end of 540 min 6.96 % drug
release was observed. Both formulations did not follow the principle of pulsatile release.
F23 shows 6.98 % drug release at the end of 480 min, drug release profile of F23 represented in
Figure 49 Which shows optimum drug release profile i.e. initial lag phase of 480 min with 6.98
Figure 47 In vitro release profile of Aceclofenac from triple layer floating tablet F8
Formulation for initial 480 min in 0.1 N HCl followed by 120min in phosphate
buffer pH6.8.
Results & Discussion
126
% drug release followed by 97.87 % release within 120 min.
Figure 49 in vitro release profile of Aceclofenac from F21, F22, and F23 Formulation in 0.1 N
HCl
Figure 50 In vitro release profile of Aceclofenac from F23 Formulation for initial 480 min in 0.1
N HCl followed by 120min in phosphate buffer pH6.8.
Further F25 formulation shows 1.01 % drug release at the end of 180 min after that tablet gets
burst. F25 does not follow the principle of pulsatile release, shown in Figure 51. But F26
formulation shows 6.97 % drug release at the end of 480 min followed by 98.18 % drug release
in phosphate buffer pH 6.8 within 120 min. hence this formulation follows the principle of
pulsatile release Figure 52.
Results & Discussion
127
Figure 51 In vitro release profile of Aceclofenac from tablet F25, F26, Formulation in 0.1 N HCl
Figure 52 In vitro release profile of Aceclofenac from F26 Formulation for initial 480 min in 0.1
N HCl followed by 120min in phosphate buffer pH6.8.
F30 formulation follows the principle of pulsatile release, i.e. initial lag phase followed by
instant release as shown in Figure 53.
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128
Figure 53 In vitro release profile of Aceclofenac from F30 Formulation for initial 480 min in 0.1
N HCl followed by 120min in phosphate buffer pH6.8.
Here Figure 54 shows the drug release profile of F23, F26, and F30 formulation, which follows
the pulsatile release pattern.
Figure 54 In vitro release profile of Aceclofenac from F23, F26, F30 Formulation for initial 480
min in 0.1 N HCl followed by 120min in phosphate buffer pH6.8.
Swelling Characteristics
Result of swelling characteristics are shown in Table 47 and Table 48. Figure 55 shows initial
tablet without swelling, Figure 56 shows swelled tablet after 180 min. Figure 57 shows swelling
after 360 min. Figure 58 shows the increase thickness of tablet after 360 min.
Tablet of F30 formulation composed of HPMC K100M polymer was shows more swelling than
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129
HPMC K4M (F23) and HPMC K15M (F26). HPMC K4M was shown less water uptake capacity
than HPMC K15M and HPMC K100M.
HPMC K100M polymer was shows more swelling, because HPMC K100M having more
viscosity than HPMC K4M and HPMC K15M
Table 47 Data collection of change in surface area of F23, F26, F30 formulations
Time (min)
Surface area of F23 Surface area of F26 Surface area of F30
0 272.40 272.40 272.40
30 323.70 326.28 344.59
60 347.76 328.70 350.03
120 350.03 341.41 350.94
180 351.40 351.85 364.56
240 352.08 371.37 372.28
300 352.53 372.28 375.00
360 352.99 374.10 375.23
Table 48 Data collection of Change in diameter of F23, F26, and F30 Formulations.
Time (min)
Change in diameter of Change in thickness of
F23 F26 F30 F23 F26 F30
0 12 12 12 3.24 3.24 3.26
30 14.26 14.40 15.18 5.18 5.22 6.02
60 15.32 14.48 15.42 6.10 6.24 7.12
120 15.42 15.04 15.46 6.22 6.38 7.16
180 15.48 15.50 16.06 6.42 6.48 7.32
240 15.52 16.36 16.40 6.46 6.52 7.38
300 15.54 16.40 16.52 6.48 6.56 7.40
360 15.56 16.48 16.56 6.52 6.56 7.42
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130
Figure 55 Initial tablet before adding to water a) F23 b) F26 c) F30
Figure 56 Swelled tablet after 3 h a) F23, b) F26 c) F30
Figure 57 Swelled tablet after 6 h a) F23, b) F26 c) F30
Figure 58 Side view of swelled tablet after 6 h a) F23 b) F26 c) F30 formulations
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131
Stability Study:
Subjected formulations for stability study of six months were evaluated for buoyancy (floating
lag time, floating duration), drug content, and in vitro drug release, obtained results of buoyancy
and drug content shown in Table 49.
Table 49 Results of buoyancy, drug content of stability sample
F Floating lag time (Sec) Floating duration
(min)
Drug content (%), n=2
370C 50
0C 37
0C 50
0C 37
0C 50
0C
F23 15 17 475 471 98.33±0.275 98.27±0.353
F26 22 25 473 472 98.02±0.155 97.95±0.148
F30 36 32 477 473 98.06±0.205 98.05±0.056
Results of % cumulative release provided in Table 50, and in vitro drug release pattern shown in
Figure 59 and Figure 60.
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132
Table 50 % Cumulative release aceclofenac for initial 480 min in 0.1 N HCl followed by 120
min in phosphate buffer pH 6.8 of different formulations.
% Cumulative release
Time
(Min) F23 F26 F30
37°C 50°C 37°C 50°C 37°C 50°C
60 4.28 2.62
3.84 4.40
0.20 3.58
12 6.28 4.51
4.03 4.61
0.60 3.72
180 6.58 5.66
4.11 4.87
0.86 4.43
240 6.62 5.87
4.75 5.09
1.27 4.74
300 6.63 6.08
4.94 5.25
2.22 5.14
360 7.42 6.47
5.69 5.45
2.29 5.54
420 8.21 7.13
5.73 5.82
2.85 5.76
480 10.66 7.32
6.70 5.88
3.88 5.91
495 65.08 62.87
70.76 62.87
62.80 62.87
510 77.86 70.38
77.94 71.01
71.91 71.15
540 82.76 88.76
85.78 89.39
88.49 88.76
570 93.18 94.17
92.05 93.83
92.93 93.32
600 97.01 97.60
97.52 97.67
95.98 97.74
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133
Figure 59 In vitro dissolution study of F23, F26, and F30 formulations for initial 480 min in 0.1
N HCl followed by 120min in phosphate buffer pH6.8 at 37°C
Figure 60 In vitro dissolution study of F23, F26, and F30 formulations for initial 480 min in 0.1
N HCl followed by 120min in phosphate buffer pH6.8 at 50°C
From above observations it was conclude that there was no significant change in the buoyancy,
drug content, and in vitro drug release pattern of the tablets.