Development and in vitro evaluation of mucoadhesive buccal tablets ...

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Int J Pharm Biomed Res 2013, 4(3), 149-154
Research article
International Journal
of PHARMACEUTICAL
AND BIOMEDICAL
RESEARCH
ISSN No: 0976-0350
Development and in vitro evaluation of mucoadhesive buccal tablets of
Labetalol hydrochloride
Vishal Kadam*, R.P.Umbare, S.M.Patil, Vijay Chakote
ASPM’S K.T.Patil College of Pharmacy, Siddharth nagar, Barshi road, Osmanabad-413 501, Maharashtra, India
Received: 21 Jun 2013 / Revised: 05 Jul 2013 / Accepted: 09 Jul 2013 / Online publication: 25 Jul 2013
ABSTRACT
The present investigation is concerned with development and evaluation of mucoadhesive buccal tablets containing
antihypertensive drug, Labetalol hydrochloride to circumvent the first pass effect and to improve its bioavailability with
reduction in dosing frequency and dose related side effects. The tablets were prepared by direct compression method. 12
formulations were developed using various concentrations of carbopol 934P as primary polymer along with any of the
secondary polymers viz., HPMC K4M, sodium alginate, xanthan gum and guar gum. The tablets were tested for weight
variation, hardness, surface pH, drug content uniformity, swelling index, and bioadhesive strength and in vitro drug
dissolution study. FTIR studies showed no evidence on interactions between drug and polymers. The in vitro release of
Labetalol hydrochloride was performed under sink conditions (Phosphate buffer pH 6.8, 37±0.5ºC, 50rpm) using USP-XXIV
dissolution apparatus type II. The best in vitro drug release profile was achieved with the formulation F4 which contains the
drug, Carbopol 934P and Sodium alginate. The surface pH, bioadhesive strength and swelling index of formulation F4 was
found to be 6.53, 31.40g and 85.81%, respectively. The formulation F4, containing 50mg of Labetalol hydrochloride
exhibited 8h sustained drug release i.e. 93.83% with desired therapeutic concentration. The in vitro release kinetics studies
reveal that all formulations fits well with zero order kinetics followed by Korsmeyer-Peppas, first order and then Higuchi’s
model and the mechanism of drug release is non-Fickian diffusion.
Key words: Labetalol hydrochloride, Mucoadhesive buccal tablet, Surface pH, Bioadhesive strength, Swelling index, In vitro
drug release
1. INTRODUCTION
Buccal delivery of drugs provides an attractive alternative
to the oral route of drug administration. Problems such as
first pass metabolism and drug degradation in the GIT
environment can be circumvented by administering the drug
via buccal route. Moreover, the oral cavity is easily
accessible for self medication and be promptly terminated in
case of toxicity by removing the dosage form from buccal
cavity [1-3]. Labetalol hydrochloride has a short biological
half-life 4 to 6 hours and 50% protein binding with a daily in
divided doses [4]. Because of high frequency of
administration and short biological half-life with low plasma
*Corresponding Author. Tel: +91 9730069337 Fax:
Email: vishal.kadam1986@gmail.com
Table
©2013
1
PharmSciDirect Publications. All rights reserved.
protein binding, Labetalol hydrochloride is an ideal drug for
designing a mucoadhesive buccal tablet for buccal delivery.
Prolonged release of the drug and increased bioavailability
leads to the significant reduction in the dose and hence dose
related side effects.
Hence, in the present work an attempt was made to
formulate mucoadhesive buccal tablet of Labetalol
hydrochloride using different mixtures of polymers in order
to avoid extensive first pass metabolism, degradation in the
stomach and prolonged effect.
2. MATERIALS AND METHODS
2.1. Materials
Labetalol hydrochloride was a gift sample from Emcure
Pharmaceuticals, Pune. Carbopol 934P, HPMC K4M,

Vishal Kadam et al, Int J Pharm Biomed Res 2013, 4(3), 149-154 150
Table 1
Composition of Labetalol hydrochloride buccal tablets
Ingredients
Formulation code (mg)
F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12
Labetalol Hcl 50 50 50 50 50 50 50 50 50 50 50 50
Carbopol 934P 30 40 50 30 40 50 30 40 50 30 40 50
HPMC K4M 70 60 50 - - - - - - - - -
Sodium alginate - - - 70 60 50 - - - - - -
Xanthan gum - - - - - - 70 60 50 - - -
Guar gum - - - - - - - - - 70 60 50
Lactose 15 15 15 15 15 15 15 15 15 15 15 15
MCC 30 30 30 30 30 30 30 30 30 30 30 30
Saccharin sodium 1 1 1 1 1 1 1 1 1 1 1 1
Mag. Stearate 2 2 2 2 2 2 2 2 2 2 2 2
Talc 2 2 2 2 2 2 2 2 2 2 2 2
Average weight 200 200 200 200 200 200 200 200 200 200 200 200
sodium alginate, xanthan gum and guar gum were purchased
from S.D.Fine Chemicals Ltd., Mumbai. All other reagents
used were of analytical grade.
2.2. Compatibility studies
I.R spectroscopy can be used to investigate and predict
any physiochemical interaction between different polymers.
Infrared spectra matching approach was used for detection of
any possible chemical interaction between the drug and
polymer. The drug-excipient compatibility studies were
carried out using Fourier Transform Infrared
Spectrophotometer (FTIR). Infra red spectra of pure drug and
mixture of drug and polymer were recorded.
2.3. Formulation of mucoadhesive buccal tablets
The drug, polymers and excipients were mixed
homogeneously in a glass mortar for 15 min (Table 1). The
mixture (200mg) was then compressed using 8mm,
biconcave punch in a single-stroke using 10-station rotary
machine (The Rimek Mini Press-1).
2.4. Evaluation of mucoadhesive buccal tablets
2.4.1. Weight variation
Ten tablets from each formulation (F1 to F12) were
weighed using an electronic balance and the average weight
was calculated [5].
2.4.2. Hardness
The hardness of the tablets was determined using
Monsanto hardness tester. It is expressed in Kg/cm 2 . Three
tablets were randomly picked from each formulation and the
mean and standard deviation values were calculated [6,7].
2.4.3. Friability
Roche type friabilator was used for testing the friability.
Five tablets were weighed accurately and placed in the
tumbling apparatus that revolves at 25rpm, dropping the
tablets through a distance of six inches with each revolution.
After 4min, the tablets were weighed and the percentage loss
was determined [6,7].
2.4.4. Thickness
The thickness of three randomly selected tablets from
each formulation was determined in mm using a vernier
caliper (Pico India). The average values were calculated
[6,7].
2.4.5. Content uniformity
Weigh and powder 5 tablets, weigh accurately a quantity
of the powder equivalent to 50mg of Labetalol
Hydrochloride, shake with 150mL of phosphate buffer
pH 6.8 for 10 min, add sufficient phosphate buffer pH 6.8 to
produce 200mL and filter. Dilute 10mL of filtrate to 100mL
with water and measure the absorbance of the resulting
solution at maximum at about 302nm [5,6].
2.4.6. Surface pH
The surface pH of the buccal tablets was determined in
order to investigate the possibility of any side effects in vivo.
As an acidic or alkaline pH may cause irritation to the buccal
mucosa, it was determined to keep the surface pH as close to
neutral as possible. The method adopted by Battenberg et al
was used to determine the surface pH of the tablet. A
combined glass electrode was used for this purpose. The
tablet was allowed to swell by keeping it in contact with 5mL
of phosphate buffer (pH 6.8) for 2h at room temperature. The
pH was measured by bringing the electrode in contact with
the surface of the tablets and allowing it to equilibrate for
1min [8].

Vishal Kadam et al, Int J Pharm Biomed Res 2013, 4(3), 149-154 151
2.4.7. Mucoadhesion studies
Mucoadhesion strength of the tablet was measured on a
modified physical balance employing the method using sheep
buccal mucosa as model mucosal membrane [9]. Fresh sheep
buccal mucosa was obtained from a local slaughter house and
was used within 2h of slaughtering. The mucosal membrane
was washed with distilled water and then with phosphate
buffer pH 6.8. A double beam physical balance was taken
and to the left arm of balance a thick thread of suitable length
was hanged and to the bottom side of thread a glass stopper
with uniform surface was tied. The buccal mucosa was tied
tightly with mucosal side upward using thread over the base
of inverted 50mL glass beaker which was placed in a 500mL
beaker filled with phosphate buffer pH 6.8 kept at 37°C such
that the buffer reaches the surface of mucosal membrane and
keeps it moist. The buccal tablet was then stuck to glass
stopper from one side membrane using an adhesive
(Feviquick). The two sides of the balance were made equal
before the study, by keeping a weight on the right hand pan.
A weight of 5g was removed from the right hand pan, which
lowered the glass stopper along with the tablet over the
mucosal membrane with a weight of 5g. The balance was
kept in this position for 3min. Then, the weights were
increased on the right pan until tablet just separated from
mucosal membrane. The excess weight on the right pan i.e.
total weight minus 5g was taken as a measure of the
mucoadhesive strength. The mean value of three trials was
taken for each set of formulations. After each measurement,
the tissue was gently and thoroughly washed with phosphate
buffer and left for 5min before placing a new tablet to get
appropriate results for the formulation. After calculating
mucoadhesion strength the force of adhesion and bond
strength parameters were calculated from following equations
as;
Force of Adhesion (N) =Mucoadhesive strength × 9.8 / 1000
Bond Strength (N/m 2 ) = Force of adhesion / Surface area.
paddle method was used to study the drug release from the
tablets. The dissolution medium consisted of 900mL of
phosphate buffer (pH 6.8). The release was performed at
37°C ± 0.5°C, at a rotation of speed of 50rpm. 5mL samples
were withdrawn at predetermined time intervals (1 to 8h) and
the volume was replaced with fresh medium. The samples
were filtered through Whitman filter paper No.40 and
analyzed for Labetalol hydrochloride after appropriate
dilution by UV spectrophotometer at 302nm. The % drug
release was calculated using the calibration curve of the drug
in phosphate buffer pH 6.8.
2.4.10. Release kinetic studies
To find out the mechanism of drug release from
hydrophilic matrices, the in vitro release data was treated
with different kinetic models, namely zero order, first order,
Higuchi and Korsemeyer-Peppas.
3. RESULTS AND DISCUSSION
3.1. Compatibility studies
The spectral data of pure drug and various drug-polymer
mixtures are presented in Fig.1-5. The results indicate that
there was no chemical incompatibility between drug and
polymers used in the formulation.
2.4.8. Swelling studies
The swelling index of the buccal tablet was evaluated in
phosphate buffer pH 6.8 [10]. The initial weight of the tablet
was determined (W1) and then tablet was placed in 6mL
phosphate buffer pH 6.8 in a petridish and then was
incubated at 37 ± 1 o C. The tablet was removed at different
time intervals (1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0 and 8.0h) from
the Petri dish and excess water was removed carefully using
the filter paper. The swollen tablet was then reweighed (W2)
and the percentage hydration was calculated using the
following formula
Percentage hydration = [(W2-W1)/ W1] ×100
Fig.1. IR spectra of Labetalol Hcl
2.4.9. In vitro dissolution studies
The in vitro dissolution study was conducted as per the
United State Pharmacopoeia (USP) XXIV. The rotating
Fig.2. IR spectra of Labetalol Hcl, Carbopol 934P and HPMC K4M

Vishal Kadam et al, Int J Pharm Biomed Res 2013, 4(3), 149-154 152
3.4. Friability test
The friability test for all the formulations were done as
per the standard procedure of Indian Pharmacopoeia. The
results of the friability test were tabulated in Table 2. The
data indicates that the friability was less than 1% in all
formulations.
3.5. Thickness
Fig.3. IR spectra of Labetalol HCl,Carbopol 934P and Sodium alginate
The thickness of the tablet was found to be almost
uniform in all formulations F1 to F12. The thickness was
found to be in the range of 3.0 to 3.25mm.
3.6. Drug content
Percentage of drug content was found to be 95.41% to
99.50%. Hence it is concluded that all the formulations are
following acceptable limits as per Indian Pharmacopoeia i.e.
± 5%.
3.7. Surface pH
Fig.4. IR spectra of Labetalol HCl, Carbopol 934P and Xanthan gum
Surface pH of all the formulations F1 to F12 was found to
be 6.17 to 6.70, which is well within the limit of acceptable
salivary pH range of 5.6 to 7.0 (Table 2). Hence, it was
concluded that all formulations could not produce any local
irritation to the mucosal surface.
3.8. Bioadhesive strength
Fig.5. IR spectra of Labetalol HCl, Carbopol 934P and Guar gum
3.2. Weight variation test
The weight variation test was conducted for each batch of
all formulations F1 to F12 as per I.P and the results are
shown in Table 2. The weight variation test for all the
formulations complies with the IP limit (± 10%).
3.3. Hardness test
The measured hardness of the tablets of each batch of all
formulations i.e. F1 to F12 were ranged between 4.5 to 5.5
Kg/cm 2 and the results are shown in Table 2.
The bioadhesion characteristics were affected by the
concentration of the bioadhesive polymers. Increase in
concentration of polymer increases bioadhesive strength of
formulation. The formulations (F1, F2, F3) with Carbopol
934P and HPMC K4M showed the bioadhesive strengths of
26.60, 24.50, 23.10g, respectively. The formulations (F4, F5,
F6) with Carbopol 934P and sodium alginate showed the
bioadhesive strengths of 31.40, 29.50, 27.60g, respectively.
The formulations (F7, F8, F9) with Carbopol 934P and
Xanthan gum showed the bioadhesive strengths of 16.20,
14.60, 12.10g, respectively. The formulations (F10, F11,
F13) with Carbopol 934P and Guar gum showed the
bioadhesive strengths of 22.00, 19.40, 17.80g, respectively.
3.9. Swelling studies
The swelling studies were conducted for all formulations
i.e. F1 to F12. All the formulations were hydrated generally
by keeping the tablets in contact with phosphate buffer pH
6.8 for 1 to 8h. The highest hydration (swelling) i.e. 85.81%
was observed with the formulation F4 (Fig.6).
3.10. In vitro release studies
The in vitro cumulative drug release profile of
formulations F1, F2, F3 (containing Carbopol 934P and

Vishal Kadam et al, Int J Pharm Biomed Res 2013, 4(3), 149-154
153
Table 2
Physico-chemical parameters of Labetalol hydrochloride buccal tablets
Formulation code (mg) Average weight Hardness (Kg/cm 2 ) Friability (%)
F1
F2
F3
F4
F5
F6
F7
F8
F9
F10
F11
F12
198.5±0.2
4.7± 0.10
199.1±0. 1 4.5± 0.05
198.7±0.4
4.6± 0.06
199.0±0.2
4.8± 0.04
200.2±0.22 5.3± 0.07
198.8±0. 6 5.1± 0.03
201.2±0.4
4.6± 0.02
199.3±0. 3 4.5± 0.03
200.1±0. 1 4.8± 0.05
199.4±0.2
5.5± 0.07
198.7±0. 7 5.2± 0.06
199.3±0. 3 4.8± 0.04
0.61
0.40
0.71
0.50
0.70
0.50
0.70
0.40
0.60
0.51
0.51
0.81
Thickness (mm) Surface pH
3.00±0.02
3.06±0.01
3.12±0.02
3.16±0.06
3.25±0.05
3.10±0.04
3.02±0.02
3.00±0.01
3.10±0.03
3.13±0.05
3.20±0.03
3.10±0.04
6.30
6.25
6.34
6.53
6.40
6.41
6.24
6.17
6.29
6.65
6.70
6.55
Drug content
99.24
95.41
99.50
96.87
97.71
98.47
96.45
98.98
95.97
97.33
98.41
97.07
Mucoadhesive
strength
26.60±0.10
24.50±0.15
23.10±0.21
31.40±0.16
29.50±0.20
27.60±0.25
16.20±0.10
14.60±0.23
12.10±0.15
22.00±0.20
19.40±0.30
17.80±0.27
Fig.6. Percentage swelling of mucoadhesive Labetalol Hcl buccal tablets
100
90
Cumulative % drug release
Cumulative % drug release
Percent weight change
80
70
60
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8 9
Time in hours
Fig.7. In vitro drug releasee profile of formulations F1 to F3
100
90
80
70
60
50
40
30
20
10
0
F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12
Formulation code
90
80
70
60
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8
Time in hours
Fig.8. In vitro drug releasee profile of formulations F4 to F6
F1
F2
F3
F4
F5
F6
9
HPMC K4M) showed 84.17% %, 82.34%, 77.22%, respectively
(Fig.7). Among these three formulations, F1 was found
to be
highest
percentage
drug release. Similarly,
in vitro
cumulative drug
release profile of formulations F4, F5, F6
(containing Carbopol 934P and sodium
alginate) showed
93.83%, 90.02% %, 86.78%, respectively (Fig.8). Among these
three formulations, F4 was found to be highest percentage
drug release. During the study, it was observed that the tablet
formulations F1-F6 initially swell and non-erodible over the
period of 8h. The in vitro cumulative drug
release profile of
formulations F7, F8, F9 (containing Carbopol 934P
and
xanthum
gum) showed 78.27%, 75.96%, 71.07%,
respectively (Fig.9). Among these three formulations, F7 was
found to be highest percentage drug release. The in vitro
cumulative drug release profile of formulations F10,
F11,
F12 (containing
Carbopol 934P and guar gum) showed
82.76%, 78.69%, 75.69%, respectively (Fig.10). Among
these three formulations, F10 was found to be highest
percentage drug
release. It was concludedd that by increasing
the
concentration of Carbopol 934P in the formulation, the
drug release rate from the tablets was found to be decreased.
But when the concentration of secondary polymers increased,
the
drug releasee rate was found to be increased. This may be
due to increased hydration or swelling characteristics of
polymers with increased concentrations.
From the overall
data it was found that the formulation
F4 showed the
maximum percentage of drug
release i.e. 93.83% at the end
of
8h.
3.11. Drug release kinetics
In vitro drug
release data of F1 to F12 were fitted to
zero
order, first order, Higuchi and Korsmeyer-Peppas equations
to ascertain the pattern of drug release. The R 2 values
were
found to be higher in zero-order and then Higuchi, which indicates all the
followed by Korsmeyer-
Peppas, first order
formulations followed zero-order release pattern. According
to Korsmeyer-Peppas equation, the release exponent “n”
value is > 0.5, which indicates the mechanism of drug release
for
all formulations is non-Fickian diffusion type.

Vishal Kadam et al, Int J Pharm Biomed Res 2013, 4(3), 149-154 154
Cumulative % drug release
Cumulative % drug release
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8 9
Time in hours
Fig.9. In vitro drug release profile of formulations F7 to F9
0 1 2 3 4 5 6 7 8 9
Time in hours
Fig.10. In vitro drug release profile of formulations F10 to F12
4. CONCLUSIONS
Mucoadhesive buccal tablets of Labetalol HCl could be
prepared using Carbopol 934P as primary polymer in
combination of secondary polymers such as HPMC K 4M,
sodium alginate, xanthan gum and guar gum by direct
compression method. IR spectroscopic studies indicated that
there was no drug-polymer and polymer-polymer interaction.
F7
F8
F9
F10
F11
F12
All the prepared tablets were in acceptable range of weight
variation, hardness, thickness, friability and drug content as
per pharmacopoeial specification. The buccal tablets showed
good swelling upto 8h in phosphate buffer pH 6.8
maintaining the integrity of formulation which is required for
bioadhesion. The increase in concentration of secondary
polymer significantly increases the swelling. The surface pH
of prepared buccal tablets was in the range of salivary pH,
suggested that prepared tablets could be used without risk of
mucosal irritation. It can be seen that by increasing the
concentration of Carbopol 934P in the formulation, the drug
release rate from the tablets was found to be decreased. But
when the concentration of secondary polymer increased, the
drug release rate was found to be increased.
ACKNOWLEDGEMENTS
Authors wish to thank K.T. Patil College of Pharmacy,
Osmanabad, Maharashtra, for providing research laboratory
to carry out this project work.
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