6. characterization of aceclofenac -...

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


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


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


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


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


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


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


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



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


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



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


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.


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.


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.


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)


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.


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



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.


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).


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.)


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


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 (%)


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.


96

A) B)

C) D)

E)

Figure 22 SEM pictures of pellets.


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


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):


C & 75 % RH + 5 %

Parameter Time period (months)

0 1 2 3 4 5 6


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


(Y2) 96 99 97 96 96

96 95


0 6


Drug assay (%) 99.78 98.66

Drug release after 6th Hrs (Y1) 6 7



99

Table 36 Evaluation of parameter on real time stability study at 25C + 2

C & 60% RH + 5%

6.5.3. Formulation-3 (F17):


C / 75 % RH + 5 %


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


(Y1) 2 3 5 3

5 4 4


(Y2) 98 99 101 97

96 96 95


0 6


Drug assay (%) 100.26 98.46




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 %.


0 6

Physical appearance White coloured spherical pellets

Drug assay (%) 99.58 98.62




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.


102

Figure 24 DSC thermogram of plain HPMC K4M.

Figure 25 DSC thermogram of plain HPMC K15M


103

.

Figure 26 DSC thermogram of plain HPMC K100M.


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



Sample Name: ACL+HPMC K4


Annotation:

[Temp Program]

Start Temp 100.0


[C/min ] [ C ] [ min ]

15.00 200.0 0 Nitrogen


[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


Detector: DSC-60





Annotation:

[Temp Program]

Start Temp 100.0


[C/min ] [ C ] [ min ]

15.00 200.0 0 Nitrogen


[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


Detector: DSC-60





Annotation:

[Temp Program]

Start Temp 100.0


[C/min ] [ C ] [ min ]

15.00 200.0 0 Nitrogen


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)


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.


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.


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.


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


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.


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.


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


111

Figure 33 Standard curve of aceclofenac in 0.1 N HCl

Figure 34 Standard curve of aceclofenac in phosphate buffer pH 6.8


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



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.


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.


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,


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.


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.


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.


117



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.



118


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.


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


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.


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




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)


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)


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


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.


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


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


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.


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.


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.


127

Figure 51 In vitro release profile of Aceclofenac from tablet F25, F26, Formulation in 0.1 N HCl



F30 formulation follows the principle of pulsatile release, i.e. initial lag phase followed by

instant release as shown in Figure 53.


128



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


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


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


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.


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


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.

6. characterization of aceclofenac -...

Documents