61

5.1 PREFORMULATION STUDIES

5.1.1 PHYSICAL PARAMETERS
The drug samples were subjected to preformulation studies like pH, solubility,
partition coefficient, melting point and the values obtained were tabulated in table 5.1

TABLE 5.1 PREFORMULATION DATA FOR DRUG SAMPLES

Preformulation Tramadol Lornoxicam Aceclofenac* Paracetamol*

parameter HCl* HCl**
Melting point 181°C 227 °C 153°C 170°C
pH 4.85 3.82 6.8 6.5
Solubility in phosphate 50 µg/ml 42.98 µg/ml 4.0 mg/ml 5.6 mg/ml
buffer pH 6.8
Partition coefficient 9.4 1.8. 2.72 9.46
(pKa)
*1% aqueous solution ** 1% solution in dichloromethane: methanol (4:1)
The values of melting point are same as those of the literature citation.
There is a linear correlation between log flux and reciprocal of melting points indicating
that lower the melting point, the better is the penetration.
5.2 COMPATIBILITY STUDIES
5.2.1 FOR TRAMADOL HCL AND EXCIPIENTS
The drug-polymers interaction was studied by FTIR analysis. From the FTIR
studies, the characteristic IR absorption peaks for important functional groups were
identified and given in figure 5.1 and figure 5.2.
 62

FIG 5.1: FTIR SPECTRA OF TRAMADOL HCL (PURE DRUG)

FIG 5.2: FTIR SPECTRA OF TRAMADOL HCL AND HPMC (PHYSICAL

MIXTURE)
 63

Peak values obtained from the FTIR graphs were given in table 5.2.

TABLE 5.2: INTERPRETATIONS OF FTIR SPECTRA (TRAMADOL HCL)

Wave number (cm-1)

Tramadol Hydrochloride
Functional group Tramadol Hydrochloride + HPMC
pure drug physical mixture
O-H Stretching 3308.15 3308.10
C-H Stretching 2931.90 2930.97
C=C Asymmetric Stretching 1924.19 1923.13
C=C Aromatic Stretching 1608.70 1609.76

-CH3 bending 1480.75 1482.45

O-H bending 1411.45 1412.97

C-N Stretching 1289.42 1290.46

C-O Stretchig 1243.28 1244.20

-CH2 & C-H bending 983.16 985.76

O-H bending 701.98 702.11

5.2.2 FOR LORNOXICAM HCL AND EXCIPIENTS

Compatibility between lornoxicam hydrochloride and polymers was explained by
using FTIR studies. The absorption peaks obtained after subjecting to FTIR studies were
given in figure 5.3 and figure 5.4.
 64

FIG 5.3 FTIR SPECTRA OF LORNOXICAM HCL (PURE DRUG)

FIG 5.4: FTIR SPECTRA OF LORNOXICAM HCL WITH HPMC (PHYSICAL

MIXTURE)
 65

Values of peaks obtained from FTIR graphs were given in table 5.3

TABLE 5.3 INTERPRETATIONS OF FTIR SPECTRA (LORNOXICAM HCL)

Wave number (cm-1)

Lornoxicam Hydrochloride
Lornoxicam Hydrochloride
Functional group + HPMC
pure drug
physical mixture

N-H (aromatic) Stretching 3446.91 3360.11

C=O(Aromatic) Stretching 1647.26 1641.48

S=O 1099.46
1084.03
Stretching
C-H (aromatic) 3360.11
3566.50
Stretching
C=C (aromatic) 1545.03
1535.39
Stretching
C-N 1350.22
1327.07
Stretching
C-Cl 702.11
630.74
Stretching

5.2.3 FOR ACECLOFENAC AND EXCIPIENTS

Interactions between aceclofenac and excipients were studied by using FTIR. The
peaks obtained were given in figures 5.5 and figure 5.6 and interpretations from the peaks
were given in table 5.4
 66

FIG 5.5: FTIR SPECTRA OF ACECLOFENAC (PURE DRUG)

FIG 5.6: FTIR SPECTRA OF ACECLOFENAC WITH HPMC AND CARBOPOL

(PHYSICAL MIXTURE)
 67

TABLE 5.4: INTERPRETATIONS OF FTIR SPECTRA (ACECLOFENAC)

Wave number (cm-1)

Aceclofenac + HPMC &
Functional group Aceclofenac pure drug Carbopol (physical
mixture)
Secondary amine 3319.34 3322.55

Ester stretching 1770.97 1775.47

C-H aromatic stretching 3017.49 3018.75

C = C aromatic stretching 1404.72 1416.39

Carboxylic vibration 1716.63 1723.84

5.2.4 FOR PARACETAMOL WITH EXCIPIENTS

Compatibility between drugs and polymers has been studied by using FTIR.
Peaks obtained are given in figures 5.7 and figure 5.8.

FIG 5.7: FTIR SPECTRA OF PARACETAMOL (PURE DRUG)

 68

FIG 5.8: FTIR SPECTRA OF PARACETAMOL WITH HPMC (PHYSICAL

MIXTURE)
Values of the peaks obtained from FTIR graphs were given in table 5.5
TABLE 5.5: INTERPRETATIONS OF FTIR SPECTRA (PARACETAMOL)
Wave number (cm-1)

Functional group Paracetamol pure drug Paracetamol + HPMC

(physical mixture)
O-H stretching 3326.98 3348.55
N-H stretching 3413.77 3452.65
C=O (amide) stretching 1654.81 1685.34

Amide II band 1560.30 1575.87

C-N-H group 1259.43 1261.24

The FTIR studies of the pure drug and the polymers were studied. The peaks
obtained from pure drug were compared with those obtained from physical mixtures of
drug and polymer and given in tables 5.2 to 5.5. The results of FTIR studies did not show
any major changes in peaks which indicate there was no well-defined interaction between
 69

drug and excipients. This indicates that the drug was compatible with the formulation
components.
5.3 EVALUATION TESTS FOR BUCCAL PATCHES

5.3.1 PHYSICAL CHARACTERISTIC STUDIES:

The prepared patches were tested for weight variation, thickness, folding
endurance, density, percentage yield and drug content. The values obtained were given in
tables 5.6, 5.7 and 5.8 for tramadol hydrochloride, lornoxicam hydrochloride, aceclofenac
respectively in table 5.9 for the patch containing tramadol hydrochloride and paracetamol
respectively.
The rate of drug release from the patch majorly depends on swelling behavior and
bioadhesive strength of the patch depends on polymer composition in the patches. The
selection of patches was based on less breakage, sufficient thickness and promising
bioadhesive strength of the patches. From the data obtained, the patches with sufficient
strength (thickness and folding endurance) and better bioadhesive strength i.e.
formulations TF3, TF5, TF8 and TF10 from patches containing tramadol hydrochloride,
formulations LF3, LF8, LF9, LF13 and LF14 from patches containing lornoxicam
hydrochloride, formulations AF1, AF4, AF10, AF11 and AF14 from patches containing
aceclofenac and formulations TPF1, TPF9, TPF13 and TPF14 from patches with both
drugs (i.e. tramadol hydrochloride and paracetamol) were selected for further studies.
These patches also have better drug content than other formulations.
5.3.2 SURFACE pH STUDY:

The pH of the patches was determined by using pH paper. The patches were kept
in distilled water for sufficient time and pH was checked. It was found that the patches
were with nearly neutral pH. It indicates that patches of all drugs do not irritate buccal
mucosa.
 70

TABLE 5.6: PHYSICAL PARAMETERS OF BUCCAL PATCHES CONTAINING TRAMADOL HCL

FORMULATIONS Weight Thickness Folding Content Density* Yield* Bioadhesive

Variation* (mm) Endurance* Uniformity* (mg/CC) (%) Strength
(mg) (%) (mg)

TF1 165 ± 0.01 0.32 ± 0.01 472 ± 2 94.9 ± 0.12 0.46 ± 0.03 96 ± 1.2 11.77 ± 1.11
TF2 167 ± 0.01 0.31 ± 0.02 371 ± 4 94.2 ± 0.17 0.47 ± 0.02 98 ± 1.4 11.93 ± 1.16
TF3 166 ± 0.01 0.33 ± 0.01 410 ± 2 90.1 ± 0.13 0.49 ± 0.02 98 ± 1.2 12.32 ± 1.05
TF4 162 ± 0.02 0.34 ± 0.01 386 ± 2 93.2 ± 0.15 0.45 ± 0.01 94 ± 1.2 13.24 ± 1.03
TF5 164 ± 0.02 0.32 ± 0.02 392 ± 3 96.1 ± 0.18 0.42 ± 0.04 89 ± 1.1 12.46 ± 1.12
TF6 169 ± 0.03 0.36 ± 0.02 403 ± 4 88.9 ± 0.16 0.48 ± 0.01 92 ± 1.2 11.82 ± 1.14
TF7 160 ± 0.02 0.31 ± 0.03 452 ± 2 91.5 ± 0.17 0.46 ± 0.04 94 ± 1.2 12.12 ± 1.09
TF8 162 ± 0.01 0.32 ± 0.03 470 ± 5 91.2 ± 0.11 0.47 ± 0.02 93 ± 1.4 12.46 ± 1.06
TF9 167 ± 0.02 0.34 ± 0.03 447 ± 6 94.5 ± 0.16 0.42 ± 0.03 92 ± 1.2 12.36 ± 1.03
TF10 168 ± 0.03 0.36 ± 0.02 475 ± 2 86.5 ± 0.17 0.48 ± 0.04 93 ± 1.3 12.72 ± 1.12
*tests were performed on n=6 and the mean values are reported
 71

TABLE 5.7: PHYSICAL PARAMETERS OF BUCCAL PATCHES CONTAINING LORNOXICAM HCL

FORMULATIONS Weight Thickness Folding Content Density* Yield* Bioadhesive

Variation* (mm) Endurance* Uniformity* (mg/CC) (%) Strength
(mg) (%) (mg)
LF1 78.4 ± 0.02 0.23 ± 0.02 370 ± 3 98.72 ± 0.11 0.26 ± 0.02 92 ± 1.5 7.23 ± 1.13
LF2 84.6 ± 0.05 0.24 ± 0.02 370 ± 4 90.84 ± 0.10 0.26 ± 0.02 96 ± 1.3 7.92 ± 1.14
LF3 98.4 ± 0.07 0.26 ± 0.05 342 ± 2 95.32 ± 0.12 0.39 ± 0.03 89 ± 1.2 8.27 ± 1.02
LF4 52.6 ± 0.02 0.19 ± 0.01 312 ± 6 98.72 ± 0.17 0.34 ± 0.06 97 ± 1.8 6.34 ± 1.04
LF5 62.8 ± 0.04 0.25 ± 0.02 348 ± 8 98.75 ± 0.15 0.36 ± 0.04 98 ± 1.4 7.27 ± 1.06
LF6 71.8 ± 0.06 0.25 ± 0.04 332 ± 5 97.62 ± 0.11 0.48 ± 0.02 99 ± 1.6 7.98 ± 1.12
LF7 78.3 ± 0.01 0.24 ± 0.06 382 ± 3 96.34 ± 0.13 0.32 ± 0.02 95 ± 1.5 7.29 ± 1.03
LF8 86.2 ± 0.02 0.26 ± 0.03 388 ± 4 97.82 ± 0.12 0.46 ± 0.01 96 ± 1.4 8.13 ± 1.05
LF9 99.9 ± 0.01 0.28 ± 0.01 424 ± 2 91.32 ± 0.18 0.32 ± 0.03 88 ± 1.4 8.34 ± 1.08
LF10 51.2 ± 0.07 0.22 ± 0.08 324 ± 6 94.38 ± 0.17 0.38 ± 0.07 92 ± 1.3 6.48 ± 1.06
LF11 62.2 ± 0.04 0.28 ± 0.04 401 ± 4 98.52 ± 0.18 0.41 ± 0.02 101 ± 1.1 7.58 ± 1.12
LF12 63.4 ± 0.08 0.21 ± 0.02 422 ± 7 97.82 ± 0.19 0.46 ± 0.04 92 ± 1.4 7.82 ± 1.09
LF13 105.9 ± 0.01 0.29 ± 0.02 468 ± 2 90.85 ± 0.11 0.48 ± 0.02 94 ± 1.2 10.86 ± 1.05
LF14 176.8 ± 0.01 0.38 ± 0.05 489 ± 6 96.49 ± 0.16 0.49 ± 0.04 99 ± 1.2 12.24 ± 1.17
*tests were performed on n=6 and the mean are reported
 72

TABLE 5.8: PHYSICAL PARAMETERS OF BUCCAL PATCHES CONTAINING ACECLOFENAC

Weight Content Bioadhesive

Thickness Folding Density* Yield*
FORMULATIONS Variation* Uniformity* Strength
(mm) Endurance* (mg/CC) (%)
(mg) (%) (mg)
AF1 274.41 ± 0.01 0.424 ± 0.04 415 ± 3 97.6 ± 0.11 0.461 ± 0.02 93 ± 1.4 8.37 ± 1.14
AF2 272.33 ± 0.02 0.415 ± 0.04 417 ± 5 96.8 ± 0.14 0.367 ± 0.04 95 ± 1.7 8.22 ± 1.07
AF3 271.35 ± 0.02 0.417 ± 0.02 411 ± 2 96.9 ± 0.16 0.363 ± 0.02 92 ± 1.6 8.12 ± 1.04
AF4 270.92 ± 0.01 0.421 ± 0.01 412 ± 3 98.4 ± 0.17 0.378 ± 0.02 96 ± 1.2 7.36 ± 1.08
AF5 272.87 ± 0.03 0.410 ± 0.03 410 ± 2 96.1 ± 0.12 0.338 ± 0.05 89 ± 1.4 7.38 ± 1.14
AF6 274.72 ± 0.01 0.412 ± 0.03 414 ± 3 96.4 ± 0.15 0.442 ± 0.06 94 ± 1.8 6.89 ± 1.05
AF7 269.24 ± 0.01 0.424 ± 0.02 417 ± 4 101.6 ± 0.18 0.499 ± 0.02 96 ± 1.4 11.82 ± 1.14
AF8 267.52 ± 0.02 0.427 ± 0.02 413 ± 3 98.5 ± 0.16 0.492 ± 0.02 98 ± 1.2 8.28 ± 1.12
AF9 270.37 ± 0.01 0.417 ± 0.02 426 ± 2 98.4 ± 0.16 0.436 ± 0.05 94 ± 1.4 8.26 ± 1.03
AF10 270.25 ± 0.02 0.423 ± 0.03 417 ± 6 96.8 ± 0.11 0.468 ± 0.03 97 ± 1.2 8.09 ± 1.05
AF11 271.26±0.02 0.412±0.02 426±5 95.2±0.12 0.472±0.06 98±1.3 7.92±1.08
AF12 270.28±0.03 0.424±0.02 413±6 93.0±0.14 0.465±0.04 97±1.5 7.54±1.10
AF13 270.37±0.02 0.422±0.03 432±3 90.0±0.13 0.462±0.02 96±1.6 7.24±1.05
AF14 269.42±0.04 0.428±0.03 440±4 97.6±0.16 0.464±0.05 96±1.5 11.77±1.12
 73

* tests were performed on n=6 and the mean values are reported

TABLE 5.9: PHYSICAL PARAMETERS OF BUCCAL PATCHES CONTAINING TRAMADOL HCL AND

PARACETAMOL

FORMU Weight Folding Content uniformity (%) Bioadhesive

Thickness Density* Yield
LATION Variation* Endurance Strength
* (mm) TRM PAR (mg/cc) (%)
S (mg) * (mg)
TPF1 438.28 ± 0.02 0.78 ± 0.03 508 ± 3 95.2 ± 0.13 101.1 ± 0.12 0.520 ± 0.02 96 ± 1.3 20.82 ± 1.14
TPF2 402.26 ± 0.01 0.8 ± 0.02 498 ± 2 85.2 ± 0.12 98.3 ± 0.12 0.476 ± 0.04 92 ± 1.5 19.32 ± 1.10
TPF3 387.38 ± 0.03 0.78 ± 0.04 479 ± 3 89.2 ± 0.15 95.7 ± 0.14 0.574 ± 0.02 93 ± 1.3 19.24 ± 1.05
TPF4 433.82 ± 0.01 0.73 ± 0.01 476 ± 2 85.6 ± 0.14 94.6 ± 0.16 0.489 ± 0.06 92 ± 1.4 20.33 ± 1.08
TPF5 432.23 ± 0.01 0.76 ± 0.04 489 ± 6 92.4 ± 0.12 102.7 ± 0.13 0.430 ± 0.04 89 ± 1.6 16.28 ± 1.06
TPF6 473.42 ± 0.03 0.78 ± 0.06 385 ± 5 87.8 ± 0.16 97.3 ± 0.12 0.590 ± 0.03 97 ± 1.7 17.34 ± 1.05
TPF7 432.84 ± 0.01 0.72 ± 0.08 427 ± 3 88.6 ± 0.12 97.9 ± 0.12 0.610 ± 0.05 92 ± 1.6 19.86 ± 1.05
TPF8 422.34 ± 0.01 0.72 ± 0.02 419 ± 2 93.7 ± 0.13 100.2 ± 0.14 0.600 ± 0.04 89 ± 1.3 19.27 ± 1.10
TPF9 434.32 ± 0.01 0.76 ± 0.03 515 ± 2 96.6 ± 0.12 98.8 ± 0.13 0.590 ± 0.05 88 ± 1.4 20.78 ± 1.14
TPF10 434.82 ± 0.02 0.79 ± 0.02 415 ± 4 89.2 ± 0.16 97.3 ± 0.14 0.620 ± 0.04 98 ± 1.2 19.73 ± 1.05
TPF11 433.82 ± 0.03 0.60 ± 0.03 457 ± 2 92.6 ± 0.15 101.8 ± 0.12 0.570 ± 0.03 92 ± 1.2 19.28 ± 1.02
TPF12 434.76 ± 0.02 0.61 ± 0.02 446 ± 3 88.2 ± 0.13 97.3 ± 0.11 0.612 ± 0.04 91 ± 1.4 19.26 ± 1.07
TPF13 445.82 ± 0.02 0.76 ± 0.04 507 ± 2 90.0 ± 0.12 88.8 ± 0.12 0.592 ± 0.02 93 ± 1.5 21.49 ± 1.04
 74

TPF14 435.32 ± 0.01 0.79 ± 0.02 510 ± 4 93.3 ± 0.16 98.8 ± 0.14 0.570 ± 0.02 96 ± 1.2 21.34 ± 1.14
*tests were performed on n=6 and the mean values are reported
 75

5.3.3 Swelling index:

Even though several formulations with various combinations are prepared, only
those with reproducible and satisfactory results were selected for further studies. The
swelling behavior of selected patches for tramadol hydrochloride, lornoxicam
hydrochloride, aceclofenac and patch with combination drugs were given in the figures
5.9, 5.10, 5.11 and 5.12 respectively.

0.25
Weight gained (%)

0.2

0.15 TF3

0.1 TF5
TF8
0.05
TF10
0
3 6 9 12 15
Time (min)

FIG 5.9: SWELLING CHARACTERS OF SELECTED PATCHES CONTAINING

TRAMADOL HCL

0.3

0.25
Weight gained (%)

0.2 LF3

0.15 LF8
LF9
0.1
LF13
0.05
LF14
0
3 6 9 12 15
Time (min)

FIG 5.10: SWELLING CHARACTERS OF SELECTED PATCHES

CONTAINING LORNOXICAM HCL
 76

0.25

0.2
Weight gained (%)

0.15 AF1
AF4
0.1 AF10
AF11
0.05 AF12

0
3 6 9 12 15
Time (min)

FIG 5.11: SWELLING CHARACTERS OF SELECTED PATCHES

CONTAINING ACECLOFENAC

0.12

0.1
Weight gained (%)

0.08
TPF1
0.06
TPF9

0.04 TPF13
TPF14
0.02

0
3 6 9 12 15
Time (min)

FIG 5.12: SWELLING CHARACTERS OF SELECTED PATCHES

CONTAINING TRAMADOL HCL AND PARACETAMOL
 77

From the graphs it is clear that the swelling behavior of buccal patches is
encouraging for drugs to release from patches. Constant raise in the weight of patch
shows that there could be no hindering for the drugs to release from the prepared buccal
patches.

5.4 INVITRO PERMEATION STUDIES

The drug permeation profiles from formulations of selected patches across sheep
buccal mucosa over a period of 12 hrs is shown in figures 5.13, 5.14, 5.15, 5.16 and 5.17
of patches containing tramadol hydrochloride, lornoxicam hydrochloride, and
aceclofenac and patch containing two drugs i.e. tramadol hydrochloride and paracetamol
respectively.
 78

TABLE 5.10: INVITRO PERMEATION PROFILES OF TRAMADOL HCL

FROM SELECTED PATCHES

Time
S. No TF3 (%) TF5 (%) TF8 (%) TF10 (%)
(hrs)
1 0 0 0 0 0
2 2 5.54 ± 0.02 6.5 ± 0.01 7.32 ± 0.02 8.81 ± 0.01
3 4 20.4 ± 0.03 24.3 ± 0.02 22.8 ± 0.02 23.9 ± 0.02
4 6 38.4 ± 0.02 40.9 ± 0.02 44.9 ± 0.02 43.2 ± 0.02
5 8 59.2 ± 0.02 68.9 ± 0.02 64.4 ± 0.04 68.6 ± 0.02
6 10 75.9 ± 0.03 87.7 ± 0.02 82.2 ± 0.02 85.8 ± 0.01
7 12 96.8 ± 0.03 100.3 ± 0.02 100.0 ± 0.01 101 ± 0.01
Mean ± SD, n = 3

120
Cumulative % drug permeated

100

80
TF3
60
TF5
TF8
40
TF10
20

0
0 2 4 6 8 10 12 14
Time (hrs)

FIG 5.13: INVITRO PERMEATION PROFILES OF SELECTED BUCCAL

PATCHES (TRAMADOL HCL)
 79

TABLE 5.11: INVITRO PERMEATION PROFILES OF LORNOXICAM HCL

FROM SELECTED PATCHES

Time
S. No LF3 (%) LF8 (%) LF9 (%) LF13 (%) LF14 (%)
(hrs)
1 0 0 0 0 0 0
2 2 3.23 ± 0.02 5.82 ± 0.03 8.35 ± 0.02 7.81 ± 0.01 8.37 ± 0.02
3 4 21.4 ± 0.03 22.3 ± 0.02 20.8 ± 0.02 21.9 ± 0.02 24.4 ± 0.01
4 6 36.4 ± 0.02 42.9 ± 0.02 45.9 ± 0.03 42.8 ± 0.03 42.8 ± 0.02
5 8 56.2 ± 0.01 68.7 ± 0.01 62.4 ± 0.02 68.8 ± 0.02 71.6 ± 0.02
6 10 80.4 ± 0.01 86.8 ± 0.01 88.9 ± 0.01 87.8 ± 0.02 85.9 ± 0.01
7 12 98.5 ± 0.02 101.4 ± 0.02 101.1 ± 0.02 102.4 ± 0.01 101.2 ± 0.03
Mean ± SD, n = 3

120
Cumulative % drug permeated

100

80 LF3
LF8
60
LF9
40 LF13
LF14
20

0
0 2 4 6 8 10 12 14
Time (hrs)

FIG 5.14: INVITRO PERMEATION PROFILES OF LORNOXICAM HCL

BUCCAL PATCHES
 80

TABLE 5.12: INVITRO PERMEATION PROFILES OF ACECLOFENAC FROM

SELECTED PATCHES

Time
S. No AF1 (%) AF4 (%) AF10 (%) AF11 (%) AF12 (%)
(hrs)
1 0 0 0 0 0 0
2 2 5.34 ± 0.01 3.82 ± 0.02 6.28 ± 0.02 6.86 ± 0.02 5.98 ± 0.03
3 4 18.5 ± 0.02 16.5 ± 0.02 20.3 ± 0.03 23.2 ± 0.02 25.6 ± 0.03
4 6 40.9 ± 0.02 34.7 ± 0.01 45.8 ± 0.02 44.4 ± 0.03 45.8 ± 0.02
5 8 55.8 ± 0.01 50.5 ± 0.02 64.4 ± 0.02 65.9 ± 0.05 70.9 ± 0.05
6 10 77.8 ± 0.05 73.9 ± 0.01 84.7 ± 0.03 88.9 ± 0.03 93.3 ± 0.03
7 12 102.2 ± 0.07 97.4 ± 0.02 100.3 ± 0.02 101.2 ± 0.02 102.2 ± 0.05
Mean ± SD, n = 3

120
Cumulative % drug permeated

100

80 AF1
AF4
60
AF10
40 AF11
AF12
20

0
0 2 4 6 8 10 12 14
Time (hrs)

FIG 5.15: INVITRO PERMEATION PROFILES OF ACECLOFENAC BUCCAL

PATCHES
 81

TABLE 5.13: INVITRO PERMEATION PROFILES OF PARACETAMOL FROM

SELECTED PATCHES CONTAINING BOTH DRUGS

Time
S. No TPF1 (%) TPF9 (%) TPF13 (%) TPF14 (%)
(hrs)
1 0 0 0 0 0
2 2 5.34 ± 0.01 6.82 ± 0.02 6.28 ± 0.02 5.36 ± 0.02
3 4 17.5 ± 0.02 17.8 ± 0.05 18.9 ± 0.03 18.2 ± 0.05
4 6 35.8 ± 0.04 35.2 ± 0.02 36.3 ± 0.06 30.8 ± 0.02
5 8 67.8 ± 0.02 64.5 ± 0.03 66.4 ± 0.02 56.2 ± 0.03
6 10 92.8 ± 0.03 86.3 ± 0.02 90.9 ± 0.01 78.6 ± 0.02
7 12 100.2 ± 0.04 102.2 ± 0.03 101.0 ± 0.02 94.4 ± 0.02
Mean ± SD, n = 3

120
Cumulative % drug permeated

100

80
TPF1
60
TPF9
40
TPF13

20 TPF14

0
0 2 4 6 8 10 12 14
Time (hrs)

FIG 5.16: INVITRO PERMEATION PROFILES OF PARACETAMOL FROM

BUCCAL PATCHES CONTAINING BOTH DRUGS
 82

TABLE 5.14: INVITRO PERMEATION PROFILES OF TRAMADOL HCL

FROM SELECTED PATCHES CONTAINING BOTH DRUGS

Time
S. No TPF1 (%) TPF9 (%) TPF13 (%) TPF14 (%)
(hrs)
1 0 0 0 0 0
2 2 6.02 ± 0.02 6.23 ± 0.04 7.86 ± 0.02 6.65 ± 0.03
3 4 17.53 ± 0.03 16.92 ± 0.03 20.58 ± 0.03 17.98 ± 0.02
4 6 32.67 ± 0.02 36.24 ± 0.02 34.32 ± 0.02 28.82 ± 0.04
5 8 64.34 ± 0.03 63.57 ± 0.03 67.73 ± 0.04 55.32 ± 0.02
6 10 83.26 ± 0.02 81.87 ± 0.05 83.04 ± 0.02 76.52 ± 0.03
7 12 100.3 ± 0.02 101.7 ± 0.03 100.9 ± 0.02 97.82 ± 0.01
Mean ± SD, n = 3

120
Cumulative % drug permeated

100

80
TPF1
60
TPF9
40
TPF13

20 TPF14

0
0 2 4 6 8 10 12 14
Time (hrs)

FIG 5.17: INVITRO PERMEATION PROFILES OF TRAMADOL HCL FROM

BUCCAL PATCHES CONTAINING BOTH DRUGS
The results of drug permeation from tramadol hydrochloride buccal patches
(figure 5.13), lornoxicam hydrochloride buccal patches (figure 5.14), aceclofenac buccal
 83

patches (figure 5.15) and buccal patches containing both drugs (figure 5.16 & figure
5.17) through sheep buccal mucosa reveals that drug permeation through buccal mucosa
in 12 hrs were ranging from 94% to 100%. This publishes that drugs were permeated
through sheep mucosa thus they can possibly permeate through human buccal mucosa.

5.5 DRUG ANALYSIS IN THE PREPARED PATCHES

5.5.1 RELEASE OF TRAMADOL HYDROCHLORIDE FROM BUCCAL

PATCHES
a) Standard graph of tramadol hydrochloride:
The standard graph of tramadol hydrochloride in phosphate buffer pH 6.8 was
prepared by using Shimadzu 1800 UV-VIS spectrophotometer at 273 nm and the
standard values were tabulated in table 5.15. The linearity range was observed between 0
– 80 µg/ml for tramadol hydrochloride (figure 5.18).
TABLE 5.15: VALUES OF STANDARD GRAPH OF TRAMADOL
HYDROCHLORIDE
Concentration
S. No Absorbance
(µg/ml)
1 0 0
2 10 0.116
3 20 0.228
4 40 0.459
5 60 0.697
6 80 0.908
 84

1
0.9 y = 0.0114x + 0.0015
R² = 0.9997
0.8
0.7
Absorbance

0.6
0.5
0.4
0.3
0.2
0.1
0
0 10 20 30 40 50 60 70 80 90
Concentration (µg/ml)

FIG 5.18: STANDARD GRAPH OF TRAMADOL HCL

b) Drug release studies

Drug release profiles of tramadol hydrochloride from selected patches i.e. TF3,
TF5, TF8 and TF10 is given in figure 5.19.

TABLE NO 5.16: CUMULATIVE PERCENTAGE DRUG RELEASE FROM

SELECTED BUCCAL PATCHES (TRAMADOL HCL)
Time
S. No TF3 (%) TF5 (%) TF8 (%) TF10 (%)
(hrs)
1 0 0 0 0 0
2 2 6.54 ± 0.02 7.5 ± 0.01 9.32 ± 0.02 10.81 ± 0.01
3 4 23.42 ± 0.04 26.34 ± 0.01 24.77 ± 0.03 25.92 ± 0.02
4 6 41.38 ± 0.02 44.87 ± 0.02 48.88 ± 0.03 47.8 ± 0.01
5 8 60.23 ± 0.01 70.65 ± 0.02 68.37 ± 0.02 70.82 ± 0.01
6 10 78.85 ± 0.01 89.28 ± 0.06 90.27 ± 0.01 85.82 ± 0.01
7 12 99.95 ± 0.01 100.03 ± 0.01 101.05 ± 0.01 100.26 ± 0.02
Mean ± SD, n = 3
 85

120

100
% Drug release

80
TF3
60
TF5
40 TF8
TF10
20

0
0 2 4 6 8 10 12 14
Time (hrs)

FIG 5.19: DRUG RELEASE PROFILES OF TRAMADOL HCL FROM

SELECTED PATCHES
From the data obtained it is evident that formulation TF3 was releasing drug in
slower manner than other formulations. From graph it was evident that time taken for
total drug release from TF3 was about 12 hrs (99.95%) where as from other formulations
it was between 10 to 12 hrs (90% released by 10th hr) of administration.
So, this patch (TF3) was further subjected to kinetic studies to understand drug
release pattern from the patch. The data obtained was substituted in Zero order, First
order, Higuchi and Korsmeyer-peppas models and the graphs obtained were given in
figures 5.20- 5.23.
 86

120

y = 9.317x - 13.491
100 R² = 0.9988
Cumulative % drug release

80

60

40

20

0
0 2 4 6 8 10 12 14
Time (Hrs)

FIG 5.20: ZERO ORDER KINETICS FOR FORMULATION TF3

2.5
Log cumulative % drug remaining

y = -0.0788x + 2.1817
2 R² = 0.9476

1.5

0.5

0
0 2 4 6 8 10 12
Time (Hrs)

FIG 5.21: FIRST ORDER KINETICS FOR FORMULATION TF3

 87

120

100 y = 51.952x - 83.453

Cumulative % drug release

R² = 0.9897
80

60

40

20

0
0 0.5 1 1.5 2 2.5 3 3.5 4

Square root of time (hrs)

FIG 5.22: HIGUCHI MODEL KINETICS FOR FORMULATION TF3

2.5

2 y = 1.5032x + 0.4094
Log cumulative % drug release

R² = 0.9917

1.5

0.5

0
0 0.2 0.4 0.6 0.8 1 1.2
Log time (hrs)

FIG 5.23: KORSMEYER-PEPPAS MODEL KINETICS FOR FORMULATION

TF3

The data of drug release kinetics of formulation TF3 is given in the table 5.17
 88

TABLE 5.17: CORRELATION COEFFICIENT VALUES FOR FORMULATION

TF3 OF TRAMADOL HCL
Model Zero order First order Higuchi Korsmeyer-peppas
Correlation coefficient 0.998 0.947 0.989 0.991 n = 0.409
values

The drug release from formulation TF3 was explained by zero order kinetics as
the plot showed highest linearity (r²= 0.998), as the drug release was best fitted in zero
order kinetics, it indicates that the rate of drug release is independent of its concentration.
The ‘r²’ value of Higuchi plot was found to be 0.989 indicating that the drug release
included diffusion as one of the release mechanisms. From the Korsmeyer-peppas
equation the ‘n’ value describes drug release mechanism. The ‘n’ value of formulation
TF3 was found to be 0.409, which shows that drug release from formulation TF3 buccal
patch follows fickian diffusion.
5.5.2 RELEASE OF LORNOXICAM HCL FROM BUCCAL PATCHES

a) Standard graph of Lornoxicam hydrochloride:

The standard graph of Lornoxicam hydrochloride in phosphate buffer pH 6.8 was

prepared by using Shimadzu 1800 UV-VIS spectrophotometer at 375 nm and the
standard values were tabulated in table 5.18. The linearity range was observed between 0
– 30 µg/ml for lornoxicam hydrochloride (figure 5.24).
 89

TABLE 5.18: VALUES OF STANDARD GRAPH OF LORNOXICAM HCL

Concentration Absorbance
S. No
(µg/ml)
1 0 0
2 5 0.173
3 10 0.317
4 15 0.485
5 20 0.623
6 25 0.794
7 30 0.972

1.2

1 y = 0.0319x + 0.0023
R² = 0.9991
0.8
Absorbance

0.6

0.4

0.2

0
0 5 10 15 20 25 30 35
Concentration (µg/ml)

FIG 5.24: STANDARD GRAPH OF LORNOXICAM HCL

b) Drug release studies

Drug release from selected buccal patches of lornoxicam hydrochloride viz., LF3,
LF8, LF9, LF13 and LF14 was given in figure 5.25
 90

TABLE NO 5.19: CUMULATIVE PERCENTAGE DRUG RELEASE FROM

SELECTED BUCCAL PATCHES (LORNOXICAM HCL)
S. Time
LF3 (%) LF8 (%) LF9 (%) LF13 (%) LF14 (%)
No (hrs)
1 0 0 0 0 0 0
2 2 5.23 ± 0.01 7.82 ± 0.02 10.35 ± 0.02 10.81 ± 0.02 10.37 ± 0.01
3 4 23.42 ± 0.01 26.34 ± 0.02 24.77 ± 0.01 25.92 ± 0.03 27.36 ± 0.01
4 6 41.38 ± 0.06 44.87 ± 0.02 48.88 ± 0.01 47.8 ± 0.01 45.76 ± 0.02
5 8 60.23 ± 0.03 70.65 ± 0.01 68.37 ± 0.02 70.82 ± 0.01 75.98 ± 0.02
6 10 84.35 ± 0.02 92.79 ± 0.01 90.87 ± 0.02 93.8 ± 0.01 97.87 ± 0.02
7 12 99.92 ± 0.02 102.43 ± 0.01 100.42 ± 0.03 100.26 ± 0.02 101.72 ± 0.01
Mean ± SD, n = 3

120

100
% Drug release

80
LF3
60 LF8
LF9
40
LF13
20 LF14

0
0 2 4 6 8 10 12 14
Time (hrs)

FIG 5.25: DRUG RELEASE PROFILE OF LORNOXICAM HCL FROM

SELECTED PATCHES
From the above graph it is evident that time taken for total drug release from LF3
was more than 12 hrs where as from other formulations it has reached more than 90% by
 91

10 hrs of administration. Thus formulation LF3 was further subjected to kinetic studies to
understand drug release pattern. The data obtained was substituted in Zero order, First
order, Higuchi and Korsmeyer-peppas models and the graphs obtained were given in
figures 5.26- 5.29.

120
y = 9.5506x - 14.214
Cumulative % drug release

100 R² = 0.997

80

60

40

20

0
0 2 4 6 8 10 12 14
Time (hrs)

FIG 5.26: ZERO ORDER KINETICS FOR FORMULATION LF3

2.5
Log cumulative % drug remaining

y = -0.092x + 2.232
2 R² = 0.898

1.5

0.5

0
0 2 4 6 8 10 12
Time (hrs)

FIG 5.27: FIRST ORDER KINETICS FOR FORMULATION LF3

 92

120
y = 46.508x - 65.877
100 R² = 0.9751
Cumulative % drug release
80

60

40

20

0
0 0.5 1 1.5 2 2.5 3 3.5 4
-20
Time (hrs)

FIG 5.28: HIGUCHI MODEL KINETICS FOR FORMULATION LF3

2.5
Log cumulative % drug release

y = 1.5148x + 0.4052
2 R² = 0.9912

1.5

0.5

0
0 0.2 0.4 0.6 0.8 1 1.2
Log time (hrs)

FIG 5.29: KORSMEYER-PEPPAS MODEL KINETICS FOR FORMULATION

LF3
 93

The data of drug release kinetics of formulation LF3 is given in the table 5.20

TABLE 5.20: CORRELATION COEFFICIENT VALUES FOR FORMULATION

LF3 OF LORNOXICAM HCL

Model Zero order First order Higuchi Korsmeyer- peppas

Correlation coefficient 0.997 0.898 0.975 0.991 n = 0.405
values

The drug release of formulation LF3 was explained by zero order kinetics as the
plot showed highest linearity (r²= 0.997), as the drug release was best fit into zero order
kinetics, it indicates that the rate of drug release from buccal patch is independent of its
concentration. The ‘r²’ value of Higuchi plot was found to be 0.975 indicating that the
drug release included diffusion as one of the release mechanisms. The ‘n’ value from the
korsmeyer-peppas equation explains the mechanism of drug release from buccal patch.
The ‘n’ value of formulation LF3 was found to be 0.405, which refers to fickian
diffusion.
5.5.3 RELEASE OF ACECLOFENAC FROM BUCCAL PATCHES
a) Standard graph of Aceclofenac:
The standard graph of aceclofenac in phosphate buffer pH6.8 was prepared by
using Shimadzu 1800 UV-VIS spectrophotometer at 278 nm and the standard values
were tabulated in table 5.21. The linearity range was observed between 0 – 5 µg/ml for
aceclofenac (figure 5.30).
 94

TABLE 5.21: VALUES OF STANDARD GRAPH OF ACECLOFENAC

Concentration
S. No Absorbance
(µg/ml)
1 0 0
2 1 0.184
3 2 0.365
4 3 0.562
5 4 0.751
6 5 0.920

1
0.9
0.8
0.7
y = 0.1855x
Absorbance

0.6 R² = 0.9997
0.5
0.4
0.3
0.2
0.1
0
0 1 2 3 4 5 6
Concentration (µg/ml)

FIG 5.30: STANDARD GRAPH OF ACECLOFENAC

b) Drug Release studies

Drug release profiles of aceclofenac buccal patches of selected formulations viz.,

AF1, AF4, AF10, AF11 and AF12 were given in table 5.22 and figure 5.31.
 95

TABLE NO 5.22: CUMULATIVE PERCENTAGE DRUG RELEASE FROM

SELECTED BUCCAL PATCHES (ACECLOFENAC)

S. No
Time AF1 (%) AF4 (%) AF10 (%) AF11 (%) AF12 (%)
(hrs)
1 0 0 0 0 0 0

2 2 7.34 ± 0.02 4.82 ± 0.02 8.28 ± 0.04 8.86 ± 0.02 7.98 ± 0.02

3 4 20.47 ± 0.01 18.46 ± 0.04 22.27 ± 0.05 24.98 ± 0.03 27.64 ± 0.04

4 6 42.87 ± 0.01 38.72 ± 0.02 47.83 ± 0.02 46.36 ± 0.04 47.82 ± 0.03

5 8 58.82 ± 0.01 52.47 ± 0.01 68.37 ± 0.02 69.87 ± 0.05 72.86 ± 0.02

6 10 78.82 ± 0.02 74.85 ± 0.04 87.72 ± 0.05 90.86 ± 0.02 95.27 ± 0.04

7 12 104.82 ± 0.02 99.5 ± 0.04 102.5 ± 0.03 100 ± 0.03 100 ± 0.02

Mean ± SD, n = 3

120

100
% Drug release

80
AF1

60 AF4
AF10
40
AF11

20 AF12

0
0 2 4 6 8 10 12 14
Time (hrs)

FIG 5.31: DRUG RELEASE PROFILES OF ACECLOFENAC FROM SELECTED

PATCHES
 96

From the graph it is evident that time taken for total drug release from AF4 was
about 12 hrs (99.5% at 12 hrs) whereas other formulations has reached 100% drug release
between 10 to 12 hrs. Thus formulation AF4 was further subjected to kinetic studies to
understand drug release pattern from the patch. The data obtained was substituted in Zero
order, First order, Higuchi and Korsmeyer-peppas models and the graphs obtained were
given in figures 5.32 - 5.35.

120

100 y = 9.376x - 17.495

Cumulative % drug release

R² = 0.9899

80

60

40

20

0
0 2 4 6 8 10 12 14
Time (hrs)

FIG 5.32: ZERO ORDER KINETICS FOR FORMULATION AF4

 97

2.5

Log cumulative % drug remaining 2

y = -0.0696x + 2.1653
R² = 0.9371

1.5

0.5

0
0 2 4 6 8 10 12
Time (hrs)

FIG 5.33: FIRST ORDER KINETICS FOR FORMULATION AF4

120

y = 53.45x - 91.244
100
Cumulative % drug release

R² = 0.9744

80

60

40

20

0
0 0.5 1 1.5 2 2.5 3 3.5 4
Square root of time (hrs)

FIG 5.34: HIGUCHI MODEL KINETICS FOR FORMULATION AF4

 98

Log cumulative % drug release 2.5

y = 1.6691x + 0.227
2 R² = 0.9902

1.5

0.5

0
0 0.2 0.4 0.6 0.8 1 1.2
Log time (hrs)

FIG 5.35: KORSMEYER-PEPPAS MODEL KINETICS FOR

FORMULATION AF4

The data of drug release kinetics of formulation AF4 is given in the table 5.23

TABLE 5.23: CORRELATION COEFFICIENT VALUES FOR FORMULATION

AF4 OF ACECLOFENAC
Model Zero order First order Higuchi Korsmeyer -peppas
Correlation coefficient
0.989 0.937 0.974 0.990 n = 0.227
values

The drug release from formulation AF4 exhibited zero order kinetics as seen in
the plot with highest linearity (r²= 0.989), as the drug release was best fitted in zero order
kinetics, it indicates that the rate of drug release is independent of its concentration. The
‘r²’ value of Higuchi plot was found to be 0.974 indicating that the drug release included
diffusion as one of the release mechanisms. Based on the ‘n’ value from the Korsmeyer-
peppas equation the mechanism for drug release was determined. The ‘n’ value of
 99

formulation AF4 was found to be 0.227, which explains that drug release from
aceclofenac formulation AF4 follows fickian diffusion mechanism.
5.5.4 RELEASE OF DRUGS (TRAMADOL HCL & PARACETAMOL) FROM
BUCCAL PATCHES

a) Standard Graph of Paracetamol:

The standard graph of paracetamol in phosphate buffer pH 6.8 was prepared by

using Shimadzu 1800 UV-VIS spectrophotometer at 248 nm and the standard values
were tabulated in table 5.24. The linearity range was observed between 0 – 10 µg/ml for
paracetamol (figure 5.36).
TABLE 5.24: STANDARD VALUES OF PARACETAMOL

Concentration
S. No Absorbance
(µg/ml)
1 0 0
2 2 0.183
3 4 0.362
4 6 0.520
5 8 0.695
6 10 0.825
 100

0.9
0.8
0.7
y = 0.0852x
0.6 R² = 0.9967
Absorbance

0.5
0.4
0.3
0.2
0.1
0
0 2 4 6 8 10 12
Concentration (µg/ml)

FIG 5.36: STANDARD GRAPH OF PARACETAMOL

b) Drug Release studies

Drug release profiles from selected buccal patches i.e. TPF1, TPF9, TPF13 and
TPF14 were given in tables 5.25 and 5.26 and in figures 5.37 and 5.38.
TABLE NO 5.25: CUMULATIVE PERCENTAGE DRUG RELEASE FROM
SELECTED BUCCAL PATCHES CONTAINING BOTH DRUGS
(PARACETAMOL)
Time
S. No TPF1 (%) TPF9 (%) TPF13 (%) TPF14 (%)
(hrs)
1 0 0 0 0 0

2 2 8.02 ± 0.01 8.28 ± 0.03 8.76 ± 0.02 7.85 ± 0.02

3 4 19.73 ± 0.01 18.82 ± 0.04 21.58 ± 0.02 19.98 ± 0.01

4 6 34.77 ± 0.02 38.24 ± 0.03 36.32 ± 0.03 30.82 ± 0.02

5 8 66.34 ± 0.01 64.57 ± 0.06 69.73 ± 0.04 58.32 ± 0.01

6 10 85.26 ± 0.02 83.87 ± 0.01 87.04 ± 0.04 77.52 ± 0.01

7 12 101.27 ± 0.02 100 .04± 0.02 100 ± 0.01 99.89 ± 0.01

Mean ± SD, n = 3
 101

120

100
% Drug release

80

TPF1
60
TPF9
40 TPF13
TPF14
20

0
0 2 4 6 8 10 12 14
Time (hrs)

FIG 5.37: DRUG RELEASE PROFILES OF PARACETAMOL FROM

SELECTED PATCHES CONTAINING BOTH DRUGS

TABLE NO 5.26: CUMULATIVE PERCENTAGE DRUG RELEASE FROM

SELECTED BUCCAL PATCHES CONTAINING BOTH DRUGS
(TRAMADOL HCL)

S. No
Time TPF1 (%) TPF9 (%) TPF13 (%) TPF14 (%)
(hrs)
1 0 0 0 0 0

2 2 7.34 ± 0.02 8.82 ± 0.01 8.28 ± 0.02 6.36 ± 0.02

3 4 19.47 ± 0.02 19.82 ± 0.01 20.87 ± 0.02 18.98 ± 0.02

4 6 36.77 ± 0.03 37.24 ± 0.04 38.32 ± 0.01 32.82 ± 0.04

5 8 68.82 ± 0.02 65.47 ± 0.02 68.37 ± 0.01 59.23 ± 0.05

6 10 90.82 ± 0.03 88.27 ± 0.03 91.87 ± 0.02 79.55 ± 0.02

7 12 101.45 ± 0.02 100.05 ± 0.02 104.32 ± 0.02 99.52 ± 0.01

Mean ± SD, n = 3
 102

120

100
% Drug release

80

TPF1
60
TPF9
40 TPF13
TPF14
20

0
0 2 4 6 8 10 12 14
Time (hrs)

FIG 5.38: DRUG RELEASE PROFILES OF TRAMADOL HCL FROM

SELECTED PATCHES CONTAINING BOTH DRUGS

From the above graphs it was evident that time taken for total drug release from
TPF14 was about 12 hrs. But the drugs from other patches were released totally between
10 to 12 hrs. Thus formulation TPF14 was chosen for kinetic studies to understand drug
release pattern from the patch. The data obtained was substituted in Zero order, First
order, Higuchi and Korsmeyer - peppas models and the graphs obtained were given in
figures 5.39 - 5.46.
 103

d) DRUG RELEASE KINETICS FOR PARACETAMOL

120

y = 9.4323x - 16.966
Cumulative % Drug release
100
R² = 0.98
80

60

40

20

0
0 2 4 6 8 10 12 14
Time (hrs)

FIG 5.39: ZERO ORDER KINETICS FOR FORMULATION TPF14

(PARACETAMOL)

2.5
Log cumulative % drug remaining

y = -0.0754x + 2.1878
2 R² = 0.9038

1.5

0.5

0
0 2 4 6 8 10 12
Time (hrs)

FIG 5.40: FIRST ORDER KINETICS FOR FORMULATION TPF14

(PARACETAMOL)
 104

120

100
Cumulative % drug release y = 56.136x - 98.531
R² = 0.9725
80

60

40

20

0
0 0.5 1 1.5 2 2.5 3 3.5 4
Square root of time (hrs)

FIG 5.41: HIGUCHI MODEL KINETICS FOR FORMULATION TPF14

(PARACETAMOL)

2.5
Log cumulative % drug release

y = 1.436x + 0.44
2
R² = 0.9926

1.5

0.5

0
0 0.2 0.4 0.6 0.8 1 1.2
Log Time (hrs)

FIG 5.42: KORSMEYER-PEPPAS MODEL KINETICS FOR FORMULATION

TPF14 (PARACETAMOL)
 105

a) DRUG RELEASE KINETICS FOR TRAMADOL HCL

120

100 y = 9.626x - 17.975

Cumulative % drug release

R² = 0.9875

80

60

40

20

0
0 2 4 6 8 10 12 14
Time (hrs)

FIG 5.43: ZERO ORDER KINETICS FOR FORMULATION TPF14

(TRAMADOL HCL)

2.5
Log cumulative % drug remaining

y = -0.081x + 2.2112
2 R² = 0.9054

1.5

0.5

0
0 2 4 6 8 10 12
Time (hrs)

FIG 5.44: FIRST ORDER KINETICS FOR FORMULATION TPF14

(TRAMADOL HCL)
 106

120

100 y = 56.635x - 99.201

R² = 0.9836

80
% drug release

60

40

20

0
0 0.5 1 1.5 2 2.5 3 3.5 4
Square root time (hrs)

FIG 5.45: HIGUCHI MODEL KINETICS FOR FORMULATION TPF14

(TRAMADOL HCL)

2.5

y = 1.5559x + 0.3351
Log cumulative % drug release

2 R² = 0.9977

1.5

0.5

0
0 0.2 0.4 0.6 0.8 1 1.2
Log time (hrs)

FIG 5.46: KORSMEYER-PEPPAS MODEL KINETICS FOR FORMULATION

TPF14 (TRAMADOL HCL)
 107

The data of drug release kinetics of formulation TPF14 for both tramadol
hydrochloride and paracetamol from the buccal patches is given in the table 5.27

TABLE 5.27: CORRELATION COEFFICIENT VALUES FOR FORMULATION

TPF14 CONTAINING BOTH DRUGS

Zero First
Model Higuchi Korsmeyer-peppas
order order
Correlation coefficient r² r² r² r² n
values
Tramadol hydrochloride 0.987 0.905 0.983 0.997 0.335
Paracetamol 0.980 0.903 0.972 0.992 0.440

Release of both drugs i.e. tramadol hydrochloride and paracetamol from

formulation TPF14 was explained by zero order kinetics as the plot showed highest
linearity (r² = 0.987 and r² = 0.980 respectively) as the drug release was best fitted in zero
order kinetics. This indicates that the rate at which drugs release from patch is
independent of concentration. The ‘r²’ value of Higuchi plot was found to be 0.983 and
0.972 indicating that the drug release includes diffusion as one of the release
mechanisms. Based on the ‘n’ values from the Korsmeyer-peppas equation the
mechanism for drug release was determined. The ‘n’ values of formulation TPF14 was
found to be 0.335 and 0.440 for tramadol hydrochloride and paracetamol respectively
which refers to fickian diffusion.
5.6. MORPHOLOGY OF THE PATCH
Scanning electron microscopy images of the optimized patches were given in
following figures. Figure 5.47 are SEM images of buccal patch containing tramadol
hydrochloride, figure 5.48 are SEM images of buccal patch containing lornoxicam
hydrochloride, figure 5.49 are SEM images of buccal patch containing aceclofenac and
figure 5.50 are SEM images of buccal patch containing both tramadol hydrochloride and
paracetamol. The SEM images of patches revealed that the surface of the patch was
uniform, smooth and without the evidence of pores. Cross section view of the patch
 108

shows porous and layered like structure which indicates mucus secretion may enter into
patch, swell and facilitate drug release.

(a) Cross sectional view (b) Top view

FIG 5.47: SEM IMAGES OF PATCH TF3 OF TRAMADOL HCL

(a) Top view (b) Cross sectional view

FIG 5.48: SEM IMAGES OF PATCH LF3 OF LORNOXICAM HCL
 109

(a) Top view (b) Cross sectional view

FIG 5.49: SEM IMAGES OF PATCH AF4 OF ACECLOFENAC

(a) Cross sectional view (b) Top view

FIG 5.50: SEM IMAGES OF PATCH TPF14 OF PATCH CONTAINING

BOTH DRUGS (TRAMADOL HCL & PARACETAMOL)
 110

5.7 PHARMACOKINETIC STUDIES:

5.7.1 FOR TRAMADOL HCL BUCCAL PATCHES

Standard chromatogram of tramadol hydrochloride in rabbit plasma is given in

figure 5.51. The values for calibration curve of tramadol hydrochloride in rabbit plasma
are given in table 5.28 where as calibration curve is given in figure 5.52.

Diclofenac
Tramadol

FIG 5.51: STANDARD CHROMATOGRAM OF TRAMADOL HCL IN RABBIT

PLASMA
 111

TABLE 5.28: VALUES FOR CALIBRATION CURVE OF TRAMADOL HCL

Concentration
S. No Area
(ng/ml)
1 0 0
2 100 4643.85
3 200 9687.7
4 300 13831.6
5 400 18465.4
6 500 23219.3
7 600 27893.3

30000

25000
y = 46.465x
20000 R² = 0.9997

15000
Area

10000

5000

0
0 100 200 300 400 500 600 700
Concentration (ng/ml)

FIG 5.52: CALIBRATION CURVE OF TRAMADOL HCL IN RABBIT PLASMA

 112

Plasma concentration values of tramadol hydrochloride from both buccal patch

and tablet (marketed product) i.e. Contramal are provided in table 5.29 and the graphs of
the same are given in figure 5.53.

TABLE 5.29: PLASMA CONCENTRATIONS OF TRAMADOL HCL BUCCAL

PATCH (TF3) AND CONTRAMAL

Tramadol
Time Hydrochloride buccal Contramal
S. No
(h) patch (Marketed product)
(TF3) (ng/ml)
1 0 0 0
2 0.5 312.42 ± 0.02 213.11 ± 0.04
3 1 445.12 ± 0.04 374.13±0.01
4 1.5 724.31 ± 0.01 456.12±0.05
5 2 325.34 ± 0.03 514.33±0.04
6 2.5 278.14 ± 0.04 345.12±0.04
7 3 150.26 ± 0.06 257.13±0.03
8 3.5 98.22 ± 0.06 212.12±0.05
9 4 55.23 ± 0.01 135.11±0.05
10 4.5 34.12 ± 0.04 77.12±0.07
11 6 0 63.11±0
12 8 0 41±0
13 12 0 0
14 16 0 0
15 20 0 0
16 24 0 0
Mean ± SD, n = 6
 113

800

700
Plasma drug concentration (ng/ml)

Tramadol Optimized
600 Formulation (TF3)
Contramal (Tablet, marketed
500
Product)
400

300

200

100

0
0 5 10 15 20 25 30
-100
Time (hrs)

FIG 5.53: PLASMA CONCENTRATIONS OF TRAMADOL HCL BUCCAL

PATCH (TF3) AND CONTRAMAL

TABLE 5.30: COMPARISON OF PHARMACOKINETIC PARAMETERS OF

TRAMADOL HCL BUCCAL PATCH (TF3) AND CONTRAMAL

Tramadol Hydrochloride
S. No Parameters buccal patch Contramal
(Marketed product)
(TF3)
1 Cmax (ng/ml) 724.31 ± 0.01 514.33 ± 0.04
2 AUC 0-t (ng h/ml) 8215.35 ± 0.12 6723.15 ± 0.02
3 AUC0-∞ (ng h/ml) 11167.75 ± 0.14 8945.14 ± 0.02
4 Tmax (h) 1.52 ± 0.12 2.00 ± 0.14
5 t 1/2 (h) 2.0 ± 0.014 3.55 ± 0.05

Bioavailability Parameters

Mean plasma concentrations profiles of prepared tramadol hydrochloride buccal

patch formulation TF3 and marketed conventional product are presented in figure 5.53.
Tramadol hydrochloride buccal patch TF3, released maximum concentration of drug
 114

within 90 minutes when compared to 120 minutes in case of marketed product

(Contramal). All the pharmacokinetic parameters were presented in table 5.30. In this
study the immediate drug absorption was achieved with the TF3 formulation. The
average peak concentration obtained from marketed product (Contramal) was lower than
that of the buccal patch (514.33 ± 0.04ng/ml versus 724.31 ± 0.01ng/ml). AUC represents
the total integrated area under the blood concentration-time profile. It indicates the total
amount of drug that reaches the systemic circulation after administration. Thus, it is
crucial parameter in identifying the bioavailability of drug from any dosage form. AUC0-
inf for formulation TF3 was higher (11167.75 ± 0.14ng h/ml) than that of marketed
product (8945.14 ± 0.02ng h/ml). Statistically, AUC0-t of the formulation TF3 was
significantly higher (p<0.05) as compared to that of marketed product. The result
indicates that the formulation TF3 could increase the bioavailability of tramadol
hydrochloride in vivo effectively. In this study, the tramadol hydrochloride buccal patch
produced higher bioavailability and immediate release than that of the marketed product.
5.7.2 FOR LORNOXICAM HCL BUCCAL PATCHES

Standard chromatogram of lornoxicam hydrochloride in rabbit plasma is given in

figure 5.54. The values for calibration curve of lornoxicam hydrochloride in rabbit
plasma are given in table 5.31 where as calibration curve is given in figure 5.55.
Thiocolchicoside

Lornoxicam

FIG 5.54: STANDARD CHROMATOGRAM OF LORNOXICAM HCL IN

RABBIT PLASMA
 115

TABLE 5.31: VALUES FOR CALIBRATION CURVE OF LORNOXICAM HCL

Concentration
S. No Area
(ng/ml)
1 0 0
2 100 3403.85
3 200 6806.72
4 300 10209.36
5 400 13615.42
6 500 17019.38
7 600 20418.32

25000

y = 34.034x
20000 R² = 1

15000
Area

10000

5000

0
0 100 200 300 400 500 600 700

Concentration (ng/ml)

FIG 5.55: CALIBRATION CURVE OF LORNOXICAM HCL IN RABBIT

PLASMA
 116

Plasma concentration values of lornoxicam hydrochloride from both buccal patch

and tablet (marketed product) i.e. Lefocam are provided in table 5.32 and the graphs of
the same are given in figure 5.56.

TABLE 5.32: PLASMA CONCENTRATIONS OF LORNOXICAM HCL BUCCAL

PATCH (LF3) AND LEFOCAM

Time Lornoxicam Hydrochloride Lefocam

S. No (Marketed
(h) buccal patch (LF3) (ng/ml) product)
1 0 0 0
2 0.5 194.31 ± 0.01 121.11 ± 0.01
3 1 267.21 ± 0.02 183.12 ± 0.01
4 1.5 384.12 ± 0.04 268.17 ± 0.03
5 2 231.13 ± 0.01 323.31 ± 0.02
6 2.5 141.14 ± 0.02 232.11 ± 0.02
7 3 110.15 ± 0.05 141.15 ± 0.01
8 3.5 78.11 ± 0.03 102.11 ± 0.03
9 4 45.11 ± 0.06 88.11 ± 0.01
10 4.5 24.12 ± 0.01 63.13 ± 0.03
11 6 0 42 ± 0.02
12 8 0 32 ± 0.01
13 12 0 0
14 16 0 0
15 20 0 0
16 24 0 0
Mean ± SD, n = 6
 117

450
400
Plasma drug concentration (ng/ml)

Lornoxicam buccal patch

350
(LF3)
300
Lefocam (Tablet,marketed
250 product)
200
150
100
50
0
0 5 10 15 20 25 30
-50
Time (hrs)

FIG 5.56: PLASMA CONCENTRATIONS OF LORNOXICAM HCL BUCCAL

PATCH (LF3) AND LEFOCAM

TABLE 5.33: COMPARISON OF PHARMACOKINETIC PARAMETERS OF

LORNOXICAM HCL BUCCAL PATCH (LF3) AND LEFOCAM.

Lornoxicam Hydrochloride Lefocam

S. No Parameters
buccal patch (LF3) (Marketed product)
1 Cmax (ng/ml) 384.12 ± 0.04 323.31 ± 0.02
2 AUC 0-t (ng h/ml) 3122.15 ± 0.22 2713.21 ± 0.02
3 AUC0-∞ (ng h/ml) 5133.15 ± 0.24 3912.11 ± 0.01
4 Tmax (h) 1.52 ± 0.12 2.02 ± 0.12
5 t 1/2 (h) 2.0 ± 0.014 3.08 ± 0.02

Bioavailability Parameters
Plasma concentration profiles of formulation LF3 of lornoxicam hydrochloride
buccal patch and marketed conventional product are given in figure 5.56. Formulation
LF3 of lornoxicam hydrochloride buccal patch showed its maximum concentration within
90 minutes where drug from marketed product (Lefocam) has taken 120 minutes to reach
 118

its maximum concentration. All the pharmacokinetic parameters are given in table 5.33.
In this study the immediate drug absorption was achieved with the test formulation. The
average peak concentration of the marketed product (Lefocam) was lower than that of
buccal patch LF3 (323.31 ± 0.02ng/ml versus 384.12 ± 0.04ng/ml). AUC0-inf for
formulation LF3 was higher (5133.15 ± 0.24 ng h/ml) than the marketed product
(3912.11 ± 0.01 ng h/ml). Statistically, AUC0-t of the formulation LF3 was significantly
higher (p<0.05) as compared to marketed product. The results indicated that the
formulation LF3 could increase the bioavailability of Lornoxicam hydrochloride in vivo
effectively. In this study, the lornoxicam hydrochloride patches produced higher
bioavailability and immediate release than that of the marketed product.
5.7.3 FOR ACECLOFENAC BUCCAL PATCHES

Standard chromatogram of aceclofenac in rabbit plasma is given in figure 5.57.

The values for calibration curve of aceclofenac in rabbit plasma are given in table 5.34
where as calibration curve is given in figure 5.58.

FIG 5.57: STANDARD CHROMATOGRAM OF ACECLOFENAC IN RABBIT

PLASMA
 119

TABLE 5.34: VALUES FOR CALIBRATION CURVE OF ACECLOFENAC

Concentration
S. No Area
(ng/ml)
1 0 0
2 100 4142.85
3 200 8284.70
4 300 12427.60
5 400 16568.40
6 500 20710.30
7 600 24852.30

25000

y = 41.422x
20000 R² = 1

15000
Area

10000

5000

0
0 100 200 300 400 500 600

Concentration (ng/ml)

FIG 5.58: CALIBRATION CURVE OF ACECLOFENAC IN RABBIT PLASMA

 120

Plasma concentration values of aceclofenac from both buccal patch and tablet
(marketed product) i.e. Zerodol are provided in table 5.35 and the graphs of the same are
given in figure 5.59.
TABLE 5.35: PLASMA CONCENTRATIONS OF ACECLOFENAC BUCCAL
PATCH (AF4) AND ZERODOL

Aceclofenac buccal patch Zerodol

S. No Time (h) (Marketed
(AF4) (ng/ml) product)
1 0 0±0 0±0
2 0.5 224.12 ± 0.02 143.11 ± 0.04
3 1 215.12 ± 0.04 234.12 ± 0.01
4 1.5 416.31 ± 0.01 273.12 ± 0.05
5 2 305.34 ± 0.03 314.13 ± 0.02
6 2.5 241.14 ± 0.04 375.11 ± 0.01
7 3 130.21 ± 0.06 217.12 ± 0.03
8 3.5 71.21 ± 0.06 182.11 ± 0.05
9 4 31.21 ± 0.01 115.11 ± 0.05
10 4.5 14.11 ± 0.02 71.11 ± 0.07
11 6 0±0 62.15 ± 0
12 8 0±0 41 ± 0
13 12 0±0 0±0
14 16 0±0 0±0
15 20 0±0 0±0
16 24 0±0 0±0
Mean ± SD, n = 6
 121

500
450
Aceclofenac buccal patch
(AF4)
Plasma drug concentration (ng/ml)

400
350 Zerodol (Tablet, marketed
product)
300
250
200
150
100
50
0
0 5 10 15 20 25 30
-50
Time (hrs)

FIG 5.59: PLASMA CONCENTRATIONS OF ACECLOFENAC BUCCAL

PATCH (AF4) AND ZERODOL

TABLE 5.36: COMPARISON OF PHARMACOKINETIC PARAMETERS OF

ACECLOFENAC BUCCAL PATCH (AF4) AND ZERODOL

Aceclofenac buccal patch Zerodol

S. No Parameters (Marketed
(F4) product)
1 Cmax (ng/ml) 416.31 ± 0.01 375.11 ± 0.01
2 AUC 0-t (ng h/ml) 6225.31 ± 0.42 4923.12 ± 0.02
3 AUC0-∞ (ng h/ml) 9167.75 ± 0.14 7145.12 ± 0.02
4 Tmax (h) 1.56 ± 0.12 2.50 ± 0.14
5 t 1/2 (h) 2.2 ± 0.014 4.05 ± 0.05
 122

Bioavailability Parameters

Mean blood concentration profiles of aceclofenac buccal patch formulation AF4

and marketed conventional product are shown in figure 5.59. Aceclofenac buccal patch
formulation AF4 reaches it Cmax within 90 minutes of administration where as that of
marketed product (Zerodol) was 150 minutes. All the pharmacokinetic parameters are
presented in table 5.36. In this study the immediate drug absorption was achieved with
the test formulation. The average peak concentration of the marketed product was lower
than that of the buccal patch AF4 (375.11 ± 0.01 ng/ml versus 416.31 ± 0.01ng/ml).
AUC0-inf for formulation AF4 was higher (9167.75 ± 0.14 ng h/ml) than the marketed
product (7145.12 ± 0.02 ng h/ml). Statistically, AUC0-t of the formulation AF4 was
significantly higher (p<0.05) as compared to that of marketed product. The result
indicates that the formulation F4 could increase the bioavailability of aceclofenac in vivo
effectively. In this study, the aceclofenac patches produced higher bioavailability and
immediate release than that of the marketed product.
5.7.4 FOR BUCCAL PATCH CONTAINING BOTH DRUGS (TRAMADOL HCL
& PARACETAMOL

Standard chromatogram of tramadol hydrochloride and paracetamol in rabbit

plasma are given in figure 5.60. The values for calibration curves of tramadol
hydrochloride and paracetamol in rabbit plasma are given in tables 5.37 and 5.38 where
as calibration curves are given in figures 5.61 and 5.62.
 123

FIG 5.60: STANDARD CHROMATOGRAM OF PARACETAMOL &

TRAMADOL HCL IN RABBIT PLASMA

TABLE 5.37: VALUES FOR CALIBRATION CURVE OF PARACETAMOL

Concentration
S. No Area
(ng/ml)
1 0 0
2 100 3903.85
3 200 7807.70
4 300 11711.60
5 400 15615.40
6 500 19519.30

7 600 21293.30
 124

25000

20000 y = 37.634x
R² = 0.9928

15000
Area

10000

5000

0
0 100 200 300 400 500 600 700
Concentration (ng/ml)

FIG 5.61: CALIBRATION CURVE OF PARACETAMOL IN RABBIT PLASMA

TABLE 5.38: VALUES FOR CALIBRATION CURVE OF TRAMADOL HCL

Concentration
S. No Area
(ng/ml)
1 0 0

2 100 4643.85

3 200 9687.70

4 300 13831.6

5 400 18465.4

6 500 23219.3

7 600 27893.3
 125

30000

25000

20000
y = 46.465x
R² = 0.9997
15000
Area

10000

5000

0
0 100 200 300 400 500 600 700
Concentration (ng/ml)

FIG 5.62: CALIBRATION CURVE OF TRAMADOL HCL IN RABBIT PLASMA

 126

Plasma concentration values of paracetamol from both buccal patch (containing

tramadol hydrochloride and paracetamol) and tablet (marketed product containing
tramadol hydrochloride and paracetamol) i.e. Acuvin are provided in table 5.39 and 5.40.
the plasma concentration curves of the same are given in figure 5.63 and 5.64..

TABLE 5.39: PLASMA CONCENTRATIONS OF BUCCAL PATCH (TPF14)

AND ACUVIN (FOR PARACETAMOL)

Time Paracetamol buccal patch Acuvin

S. No
(h) F14 (ng/ml) (Marketed product)
1 0 0±0 0±0
2 0.5 212.41 ± 0.02 103.12 ± 0.04
3 1 424.11 ± 0.01 174.11 ± 0.01
4 1.5 345.11 ± 0.04 256.16 ± 0.05
5 2 225.14 ± 0.03 314.32 ± 0.04
6 2.5 178.15 ± 0.04 245.11 ± 0.04
7 3 100.16 ± 0.06 157.15 ± 0.03
8 3.5 78.21 ± 0.06 112.11 ± 0.05
9 4 45.13 ± 0.01 85.12 ± 0.05
10 4.5 24.11 ± 0.04 67.13 ± 0.07
11 6 0±0 43 ± 0
12 8 0±0 31 ± 0
13 12 0±0 0±0
14 16 0±0 0±0
15 20 0±0 0±0
16 24 0±0 0±0
Mean ± SD, n = 6
 127

450

400 Paracetamol release from

Plasma drug concentration (ng/ml)

buccal patch (TPF14)

350
Acuvin (Tablet, marketed
300
product)
250

200

150

100

50

0
0 5 10 15 20 25 30
-50
Time (hrs)

FIG 5.63: PLASMA CONCENTRATIONS OF PARACETAMOL FROM

BUCCAL PATCH (TPF14) AND ACUVIN

700
Tramadol release from
600
Plasma drug concentration (ng/ml)

buccal patch (TPF14)

500 Acuvin (Tablet, marketed
product)
400

300

200

100

0
0 5 10 15 20 25 30
-100 Time (hrs)

FIG 5.64: PLASMA CONCENTRATIONS OF TRAMADOL HCL FROM

BUCCAL PATCH (TPF14) AND ACUVIN

 128

TABLE 5.40: PLASMA CONCENTRATIONS OF BUCCAL PATCH (TPF14)

AND ACUVIN (FOR TRAMADOL HCL)

Tramadol Hydrochloride
Time Acuvin
S. No buccal patch
(h) (Marketed product)
TPF14 (ng/ml)
1 0 0±0 0±0
2 0.5 277.12±0.02 213.11±0.04
3 1 315.22±0.04 374.13±0.01
4 1.5 624.31±0.01 456.12±0.05
5 2 315.34±0.03 514.33±0.04
6 2.5 238.74±0.02 345.12±0.04
7 3 120.36±0.04 257.13±0.03
8 3.5 78.22±0.03 212.12±0.05
9 4 35.23±0.02 135.11±0.05
10 4.5 24.12±0.02 77.12±0.07
11 6 0±0 63.11±0
12 8 0±0 41±0
13 12 0±0 0±0
14 16 0±0 0±0
15 20 0±0 0±0
16 24 0±0 0±0
Mean ± SD, n = 6
 129

TABLE 5.41: COMPARISON OF PHARMACOKINETIC PARAMETERS FOR

PARACETAMOL FROM BUCCAL PATCH (TPF14) AND ACUVIN.
Acuvin
S. No Parameters Buccal patch (TPF14) (Marketed
product)
1 Cmax (ng/ml) 424.11±0.01 314.32±0.04
2 AUC 0-t (ng h/ml) 4135.65±0.12 3223.25±0.02
3 AUC0-∞ (ng h/ml) 6167.75±0.14 4945.14±0.02
4 Tmax (h) 1.02±0.14 2.00±0.12
5 t 1/2 (h) 1.5±0.014 3.05±0.05

TABLE 5.42: COMPARISON OF PHARMACOKINETIC PARAMETERS OF

TRAMADOL HCL FROM BUCCAL PATCH (TPF14) AND ACUVIN.
Acuvin
S. No Parameters Buccal patch (TPF14) (Marketed
product)
1 Cmax (ng/ml) 624.31±0.01 514.33±0.04
2 AUC 0-t (ng h/ml) 7315.32±0.12 6723.15±0.02
3 AUC0-∞ (ng h/ml) 10163.15±0.14 8945.14±0.02
4 Tmax (h) 1.52±0.12 2.00±0.14
5 t 1/2 (h) 2.0±0.014 3.55±0.05

Bioavailability Parameters

Plasma concentration profiles of prepared paracetamol and tramadol

hydrochloride buccal patch formulation TPF14 and marketed conventional product are
presented in figures 5.63 and 5.64. Paracetamol and tramadol hydrochloride buccal patch
formulation TPF14 releases maximum concentration of both drugs within 90 minutes of
administration when compared to 120 minutes from marketed product (Acuvin). All the
pharmacokinetic parameters are tabulated in tables 5.41 and 5.42. In this study the
immediate drug absorption was achieved with the test formulation. The average peak
 130

concentration of the marketed product was lower than that of the buccal patch TPF14 for
paracetamol (314.32±0.04ng/ml versus 424.11±0.01ng/ml) and even for tramadol
hydrochloride (514.33±0.04ng/ml versus 624.31±0.01ng/ml). AUC0-inf for formulation
TPF14 was higher for both the drugs than those from marketed product (Acuvin).
Statistically, AUC0-t of the optimized preparation was significantly higher (p<0.05) as
compared to marketed product. The results indicated that the test formulation TPF14
could increase the bioavailability of both paracetamol and tramadol hydrochloride in vivo
effectively. In this study, the buccal patches produced higher bioavailability and
immediate release than that of the marketed product.
5.8 STABILITY STUDIES
Short term stability studies were performed for 3 months. Data obtained was
given in tables 5.43 to 5.50

TABLE 5.43: STABILITY STUDIES DATA FOR TF3 AT 25°C / 60% RH

S. No Time Weight Drug Folding Physical
Interval Variation* Content* Endurance* appearance
(days) (mg) %
1 0 166±0.01 94.21±0.01 410±3 Uniform
2 15 164±0.02 96.25±0.04 403±2 Uniform
3 30 162±0.05 92.30±0.02 410±6 Uniform
4 60 163±0.07 92.11±0.01 410±3 Uniform
5 90 162±0.01 90.31±0.10 410±3 Uniform
Mean ± SD, n = 3
 131

TABLE 5.44: STABILITY STUDIES DATA FOR TF3 AT 40°C / 75% RH

S. No Time Weight Drug Folding Physical
Interval Variation* Content* Endurance* appearance
(days) (mg) %
1 0 166±0.01 94.21±0.01 411±4 Uniform
2 15 168±0.02 96.25±0.04 408±2 Uniform
3 30 158±0.05 92.30±0.02 405±5 Uniform
4 60 160±0.07 92.11±0.01 405±7 Uniform
5 90 160±0.01 90.31±0.10 402±2 Uniform
Mean ± SD, n = 3

TABLE 5.45: STABILITY STUDIES DATA FOR LF3 AT 25°C / 60% RH

S. No Time Weight Drug Folding Physical
Interval Variation* Content* Endurance* appearance
(days) (mg) %
1 0 98±0.02 95.12±0.01 342±2 Uniform
2 15 95±0.05 95.52±0.08 344±5 Uniform
3 30 96±0.06 95.26±0.03 342±6 Uniform
4 60 98±0.03 95.11±0.10 343±3 Uniform
5 90 98±0.07 95.17±0.05 342±3 Uniform
Mean ± SD, n = 3

TABLE 5.46: STABILITY STUDIES DATA FOR LF3 AT 40°C / 75% RH

S. No Time Weight Drug Folding Physical
Interval Variation* Content* Endurance* appearance
(days) (mg) %
1 0 96±0.01 96.21±0.01 341±4 Uniform
2 15 98±0.02 95.25±0.04 340±2 Uniform
3 30 98±0.05 96.30±0.02 342±5 Uniform
4 60 96±0.07 94.11±0.01 340±7 Uniform
5 90 96±0.01 95.31±0.10 342±2 Uniform
Mean ± SD, n = 3
 132

TABLE 5.47: STABILITY STUDIES DATA FOR AF4 AT 25°C / 60% RH

S. No Time Weight Drug Folding Physical
Interval Variation* Content* Endurance* appearance
(days) (mg) %
1 0 98±0.02 95.12±0.01 342±2 Uniform
2 15 95±0.05 95.52±0.08 344±5 Uniform
3 30 96±0.06 95.26±0.03 342±6 Uniform
4 60 98±0.03 95.11±0.10 343±3 Uniform
5 90 98±0.07 95.17±0.05 342±3 Uniform
Mean ± SD, n = 3

TABLE 5.48: STABILITY STUDIES DATA FOR AF4 AT 40°C / 75% RH

S. No Time Weight Drug Folding Physical
Interval Variation* Content* Endurance* appearance
(days) (mg) %
1 0 96±0.01 96.21±0.01 341±4 Uniform
2 15 98±0.02 95.25±0.04 340±2 Uniform
3 30 98±0.05 96.30±0.02 342±5 Uniform
4 60 96±0.07 94.11±0.01 340±7 Uniform
5 90 96±0.01 95.31±0.10 342±2 Uniform
Mean ± SD, n = 3
 133

TABLE 5.49: STABILITY STUDIES DATA FOR TPF14 AT 25°C / 60% RH

S. No Time Physical Drug Weight Folding
Interval appearance Content* Variation* Endurance*
(days) % (mg)
TRM PAR
1 0 Uniform 93.12±0.01 98.8±0.02 435±0.02 510±5
2 15 Uniform 93.52±0.03 98.4±0.03 436±0.02 514±7
3 30 Uniform 93.26±0.07 97.7±0.08 439±0.05 512±2
4 60 Uniform 93.11±0.08 98.2±0.02 436±0.07 513±4
5 90 Uniform 93.17±0.03 98.6±0.07 438±0.02 510±6
Mean ± SD, n = 3

TABLE 5.50: STABILITY STUDIES DATA FOR TPF14 AT 40°C / 75% RH

S. No Time Physical Drug Weight Folding
Interval appearance Content* Variation* Endurance*
(days) % (mg)
TRM PAR
1 0 Uniform 93.42±0.05 98.2±0.01 435±0.04 508±2
2 15 Uniform 93.32±0.03 97.9±0.04 435±0.03 512±4
3 30 Uniform 93.56±0.06 98.7.±0.06 434±0.05 510±6
4 60 Uniform 93.31±0.02 98.4±0.02 435±0.08 514±3
5 90 Uniform 93.27±0.04 98.8±0.03 436±0.03 510±4
Mean ± SD, n = 3

Stability studies for the prepared buccal patches were carried out according to
ICH guidelines at different temperature and RH conditions for 90 days. From the data
obtained it was very clear that there was no change in physical parameters of the buccal
patches at the same time the patches did not show any loss in their drug content.