Indo American Journal of Pharmaceutical Research, 2014

FORMULATION
AND
CHARACTERIZATION
LEVOSALBUTAMOL SULPHATE
*

OF

BUCCAL

ISSN NO: 2231-6876

TABLETS

OF

Dr. S.S. Thonte, V. V. Garud, R.S. Pentewar, B. K. Sugave

Channabasweshwar Pharmacy College, Kava Road, Latur- 413512 (M.S.) India.

ARTICLE INFO
Article history
Received 10/12/2014
Available online
31/12/2014

Keywords
Chitosan,
HPMC K4M,
Mucoadhesive Drug Delivery
System,
Levosalbutamol Sulphate.

ABSTRACT
The buccal route of administration has a number of advantages including bypassing the
gastrointestinal tract and the hepatic first pass effect. The successful delivery of drugs across
the oral mucosa represents a continuing challenge, as well as a great Opportunity. The
Levosalbutamol sulphate is a adreno-receptor agonist used for the maintenance, treatment
of chronic asthma attacks and to relieve Chronic obstructive pulmonary diseases (COPD)
Because of poor bioavailability of Levosalbutamol sulphate by oral route, there is a need to
increase its bioavailability by formulating it into buccal dosage forms. The buccal tablets of
Levosalbutamol sulphate were prepared by direct compression method. The tablets were
evaluated based on their physical characteristics like, weight variation, thickness, hardness;
their mechanical properties are found within the prescribed limits. Swelling index of all the
formulations were between ranges of 18.560.55 to 89.310.07. Surface pH, friability, like in
vitro residence time and their evaluations like, drug content uniformity are found within the
ranges, the ranges of (F1- F6) and in vitro study shows 50.09% to 78.78% among these the
formulation (F4) shown highest drug release of 78.782.00% at the end of 8 hours. The FTIR
study reveals that there was no interaction between API and excipients. It was observed that
all preformulation and formulation parameters were acceptable with reasonable limits of
standards required for buccal tablets which may enhance the absorption of drug with
increased residence time in buccal cavity avoiding first pass metabolism may also leads to
increased bioavailability.

Copy right 2014 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical
Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Please cite this article in press as Dr. S. S. Thonte et al. Formulation and Characterization of Buccal Tablets of Levosalbutamol
Sulphate. Indo American Journal of Pharm Research.2014:4(12).

5885

Corresponding author
Dr.S.S.Thonte
Principal
Channabasweshwar Pharmacy College,
Kava Road, Latur 413512
Contact No. 2382-641008
ssthonte@gmail.com

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INTRODUCTION
The cost involved both in terms of money and time in the development of a single new chemical entity has made it
mandatory for pharmaceutical companies to reconsider delivery strategies to improve the efficacy of drugs that have already been
approved. However, despite the tremendous advances in drug delivery, the oral route remains the preferred route for the
administration of therapeutic agents due to low cost, ease of administration and high level of patient compliance. Our intent, therefore,
is to utilize the implication of various approaches for buccal adhesive delivery strategies applied for the systemic delivery of orally
less/in efficient drugs, in addition to the widely used local drug delivery [1, 2].
In recent years, the interest in novel routes of drug administration occurs from their ability to enhance the bioavailability of
drugs. Drug delivery via the buccal route using bioadhesive dosage forms offers such a novel route of drug administration [3]. The
mucosal lining of oral cavity offers some distinct advantages. It is richly vascularised and more accessible for the administration and
removal of a dosage form. Additionally, buccal drug delivery has high patient acceptability compared to other non-oral routes of drug
administration4. Various advantages and other aspects of this route are elucidated of the following:
1. Ease of administration.
2. Permits localization of the drug in the oral cavity for a prolonged period of time.
3. Offers excellent route for systemic delivery of drugs with high first pass metabolism, thereby offering a greater
bioavailability.
4. A significant reduction in dose can be achieved, thereby reducing dose dependent side effects.
5. Drugs which are unstable in acidic environment of the stomach or are destroyed by the enzymatic or alkaline environment of
the intestine.
6. The presence of saliva ensures relatively large amount of water for drug dissolution unlike the case of rectal and transdermal
routes.
7. It offers passive system for drug absorption and does not require any activation.
8. It can be made unidirectional to ensure only buccal absorption.
9. The buccal mucosa is highly perfused with blood vessels and offers greater permeability than the skin.
10. Therapeutic serum concentrations of the drug can be achieved more rapidly.
11. Better patient compliance than vaginal, rectal and nasal route of administration.
12. Termination of therapy is easy.
13. Can be administered to unconscious patients.
14. Increased patients compliance.

TYPES OF BUCCAL DRUG DELIVERY SYSTEM:

1. Buccal patches/films
2. Buccal gels and ointments
3. Buccal tablets

The purpose of the buccal tablet is absorption of the drug through the lining of
the mouth. Buccal tablets can be most easily held between the gum and cheek.
The daily total salivary secretion volume is between 0.5 and 2.0 l. However, the volume of saliva constantly present in the mouth
is around 1.1 ml, thus providing a relatively low fluid volume available for drug release from delivery systems compared to the GI
tract.. In addition, saliva is a weak buffer with a pH around 5.5 7.0. Ultimately the pH and salivary compositions are dependent on

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Graph 1: Design of buccal mucoadhesive dosage forms.

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Buccal mucoadhesive dosage forms can be categorized into three types based on their geometry (Graph 1).
Type I: It is a single layer device with multidirectional drug release.
Type II: It is a device in which an impermeable backing layer is superimposed on top of the drug loaded bioadhesive layer creating a
double-layered device and preventing drug loss from the top surface into the oral cavity.
Type III: It is a unidirectional drug release device, from which drug loss is minimal, since the drug is released only from the
side adjacent to the buccal mucosa. [4].

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the flow rate of saliva which in turn depends upon three factors: the time of day, the type of stimulus and the degree of
stimulation. For example, at high flow rates, the sodium and bicarbonate concentrations increase leading to an increase in the pH
[6-8].
Levosalbutamol sulphate is chosen as a drug candidate, which is widely prescribed in the elderly patients as anti
asthmatic agent. Levosalbutamol sulphate, (R)-l-{4-hydroxy-3-hydroxymethyl phenyl)-2-(tert-butylamino) ethanol sulphate, a receptor agonist, is most widely used as a sympathomimetic for the treatment of acute as well as chronic asthma. Generally, it is
given through the inhalation route but is also effective after oral administration. But it undergoes first pass metabolism. Hence in
the present study an attempt was made to prepare the buccal tablets of Levosalbutamol sulphate.
The polymer should possess sufficient flexibility to penetrate the mucus network, be biocompatible, nontoxic and economically
favourable [9]. According to the literature mucoadhesive polymers are divided into first generation mucoadhesive polymers and
second generation novel mucoadhesive polymers. The anionic and cationic polymers exhibit stronger mucoadhesion [10].
Typical examples include polyacrylic acid (PAA) and its weakly cross-linked derivatives and sodium carboxymethyl
cellulose (Na CMC). PAA and Na CMC possess excellent mucoadhesive characteristics. Chitosan is a cationic polysaccharide,
produced by the deacetylation of chitin, the most abundant polysaccharide in the world, next to cellulose. Chitosan is a popular
polymer to use due to its biocompatibility, biodegradability and favourable toxicological properties. Chitosan has been reported to
bind via ionic interactions between primary amino functional groups and the sialic acid and sulphonic acid substructures of mucus
[11] - [15].
Permeation enhancers
Membrane permeation is the limiting factor for many drugs in the development of buccal adhesive delivery devices. The
epithelium that lines the buccal mucosa is a very effective barrier to the absorption of drugs. Substances that facilitate the
permeation through buccal mucosa are referred as permeation enhancers [16]. The goal of designing penetration enhancers, with
improved efficacy and reduced toxicity profile is possible by understanding the relationship between enhancer structure and the
effect induced in the membrane and of course, the mechanism of action. However, the selection of enhancer and its efficacy
depends on the physicochemical properties of the drug, site of administration, nature of the vehicle and other excipients. In some
cases usage of enhancers in combination has shown synergistic effect than the individual enhancers. The efficacy of enhancer in
one site is not same in the other site because of differences in cellular morphology, membrane thickness, enzymatic activity, lipid
composition and potential protein interactions are structural and functional properties. Penetration enhancement to the buccal
membrane is drug specific [17].
Effective penetration enhancers for transdermal or intestinal drug delivery may not have similar effects on buccal drug
delivery because of structural differences; however, enhancers used to improve drug permeation in other absorptive mucosa
improve drug penetration through buccal mucosa. These permeation enhancers should be safe and non-toxic, pharmacologically
and chemically inert, non-irritant, and non-allergenic [18]. However, examination of penetration route for transbuccal delivery is
important because it is fundamental to select the proper penetration enhancer to improve the drug permeability. The different
permeation enhancers are available [14-18].
Chelators: EDTA, citric acid, sodium salicylate, methoxy salicylates.
Surfactants: sodium lauryl sulphate, polyoxyethylene, Polyoxyethylene-9-laurylether, Polyoxythylene-20-cetylether,
Benzalkonium chloride, 23-lauryl ether, etc.
Bile salts: sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium glycodeoxycholate, sodium
taurodeoxycholate.
Non-surfactants: unsaturated cyclic ureas.
Inclusion complexes: cyclodextrins.
Thiolated polymers: chitosan-4-thiobutylamide, chitosan- 4-thiobutylamide/GSH, chitosan-cysteine, Poly (acrylicacid)homocysteine, polycarbophil-cysteine,
Polycarbophil- cysteine/GSH, chitosan-4-thioethylamide/GSH, chitosan-4-thioglycholic acid.

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FORMULATION:
Method of Preparation of mucoadhesive buccal tablets:
Direct compression method was employed to prepare buccal tablets of Levosalbutamol sulphate using, chitosan, HPMC K4M
as polymers. All the ingredients including drug, polymer and excipients were weighed accurately according to the batch formula
(Table 1). The drug and all the ingredients except lubricants were taken on a butter paper with the help of a stainless steel spatula and
the ingredients were mixed in the order of ascending weights and blended for 10 min in an inflated polyethylene pouch. After uniform
mixing of ingredients, lubricant was added and again mixed for 2 min. The prepared blend of each formulation was pre-compressed
by using different punches ( 6 mm) according to their weights on a single stroke tablet punching machine (Rimek Press Minipress II)
at a pressure of 0.5 ton and turret speed of 2 rpm to form a buccal tablet.

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MATERIAL AND METHODS:

Levosalbutamol sulphate (LVS) was received as Gift Sample by Glenmark Pharmaceuticals Industries Ltd, Nashik. Polymers
like Chitosan, PVP K30 and HPMC K4M were obtained from Ozone International, Mumbai and magnesium stearate was received
from Meher Chemie, Mumbai and Lactose was received from Thomas Baker, Mumbai. All chemicals used for this study were of
analytical reagent grade. Freshly prepared distilled water was used throughout the work.

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Table 1: Formulation of single mucoadhesive buccal tablet of Levosalbutamol sulphate.

Ingredients (mg/tablet)
Levosalbutamol sulphate
Chitosan
HPMC K4M
PVP K-30
Lactose
MCC
Mg. Stearate
Talc
Total

Formulation code
F1
F2
F3
2
2
2
15.60 31.20 46.80
---4.88
4.88
4.88
34.13 24.38 14.63
21.44 15.59 9.74
1.17
1.17
1.17
0.78
0.78
0.78
80.00 80.00 80.00

F4
2
15.60
15.60
4.88
24.38
15.59
1.17
0.78
80.00

F5
2
31.20
15.60
4.88
14.63
9.74
1.17
0.78
80.00

F6
2
46.80
15.60
4.88
5.85
2.92
1.17
0.78
80.00

Table 2: Pre compression parameter for F1-F6.

Batch code
F1
F2
F3
F4
F5
F6

Bulk density
0.75
0.73
0.75
0.73
0.70
0.69

Tapped density
0.81
0.80
0.82
0.82
0.77
0.77

Carrs index
7.40
8.75
8.53
10.97
9.09
10.08

Hausners ratio
1.08
1.09
1.09
1.03
1.05
1.11

Angle of repose
32
29
31
33
31
32

200

150

100

50
30
4000

3000
2000
Wavenumber [cm-1]

1000

400

Graph 1: FTIR spectra of Levosalbutamol Sulphate.

Table 3: Values for IR spectrum of LVS.
Functional group
C-H of 30 carbon
N-H bending of 20 amine
C-O of phenol
C-O of primary alcohol
C-H stretching

Reported Frequency
(cm-1)
1400-1375
1640-1530
1200-1240
1260-1000
3000-2840

Obtained Frequency
(cm-1)
1376.93
1627.63
1203.36
1153.22
2985.27

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%T

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Sr.no
1
2
3
4
5
6

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Graph 2: U.V. absorption spectrum of Levosalbutamol sulphate in Phosphate buffer (pH 6.8).
Solubility of Levosalbutamol Sulphate in different solvents:
Solvent
Water
Ethanol 95%
Ether
Dichloromethane

Solubility
Freely soluble
Slightly soluble
Slightly soluble
Very slightly soluble

Table 4: Evaluation parameters of mucoadhesive buccal tablets of Levosalbutamol Sulphate

Thickness
(mm)
1
2
2
2
1
2

Diameter
(mm)
2.5
2.4
2.4
2.6
2.5
2.5

Friability
(%)

Hardness
(kg/cm2)

0.88
0.85
0.89
0.85
0.86
0.85

3
3
4
4
4
3

Disintegration Time
(Min./Sec.)
9
10
9
9
9
9

Drug
content
(%)
94
93
96
98
97
97

Surface
pH
6.8
6.7
6.8
6.8
6.8
6.8

Graph 3: FTIR spectra of Levosalbutamol Sulphate with Chitosan.

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F1
F2
F3
F4
F5
F6

Weight
variation
(mg)
82
82
84
86
85
83

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Formulation
code

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Graph 4: FTIR spectra of Levosalbutamol Sulphate with HPMC K4M.

Graph 5: FTIR spectra of Formulation of Levosalbutamol Sulphate buccal Tablet.

RESULTS:
Table 5: Swelling data of mucoadhesive buccal tablets of Levosalbutamol Sulphate containing Chitosan (F1, F2 & F3).
Time (h)
1
2
3
4
5
6
7
8

Percentage weight change

F1
F2
31.900.60 23.060.05
40.210.78 30.350.25
48.570.95 36.880.90
55.790.05 41.010.65
61.460.56 46.490.52
66.880.89 49.290.44
70.800.43 52.160.27
72.710.15 54.420.11

F3
15.530.15
19.140.40
24.950.78
27.280.32
31.430.14
34.050.65
36.070.54
38.060.23

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(n=3, MeanSD)

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Percent Weight Change

80
60
40
20
0
0

2
F1

4Time (h)
F2

10

F3

Graph 6: Swelling data of mucoadhesive buccal tablets of Levosalbutamol Sulphate containing chitosan (F1, F2 & F3).
Table 6: Swelling data of mucoadhesive buccal tablets of Levosalbutamol Sulphate containing chitosan and HPMC K4M (F4,
F5 & F6).
Time (h)
1
2
3
4
5
6
7
8

Percentage weight change

F4
F5
30.890.15 25.220.25
49.870.21 41.150.25
59.910.86 47.480.91
68.520.61 53.080.83
75.380.28 58.400.57
82.170.16 62.640.72
85.070.15 65.830.24
89.310.07 68.060.47

F6
18.560.55
23.990.70
30.150.17
34.100.45
38.600.57
41.930.49
44.840.54
46.840.69

(n=3, MeanSD)

100

Percent Weight Change

80
60
40

20
0
0

4
F4

Time (h)
F5

10

F6

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Graph 7: Swelling data of mucoadhesive buccal tablets of Levosalbutamol Sulphate containing chitosan and HPMC K4M (F4,
F5 & F6).

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Table 7: In vitro release data of Levosalbutamol Sulphate from mucoadhesive buccal tablets containing chitosan (F1, F2 &
F3).
Time (h)
0
1
2
3
4
5
6
7
8

In vitro release
F1
F2
0.00
0.00
15.12 14.88
22.63 21.60
32.75 31.22
38.21 37.72
41.35 42.21
50.40 49.08
55.39 51.10
69.43 68.39

F3
0.00
15.48
20.55
32.25
39.07
44.86
48.12
54.55
63.99

Graph 8: in vitro drug release profiles of formulation F1-F3 containing Chitosan.

Table 8: In vitro release data of Levosalbutamol sulphate from mucoadhesive buccal tablets containing chitosan and HPMC
K4M (F4, F5 & F6).

F6
0.00
16.04
26.42
35.22
43.06
50.09
56.59
62.71
68.15

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0
1
2
3
4
5
6
7
8

In vitro release
F4
F5
0.00
0.00
18.77 17.32
28.07 27.05
37.09 36.45
46.12 45.32
55.58 53.03
63.82 60.33
71.32 66.49
78.78 71.44

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Time (h)

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Graph 9: In-vitro drug release profiles of formulation F4-F6 containing Chitosan & HPMC K4M.
Table 9: Regressional analysis of the in vitro release data according to various release kinetic models.
Formulation code
F1
F2
F3
F4
F5
F6

Zero order
r2
0.976
0.968
0.973
0.974
0.974
0.973

First order
r2
0.932
0.914
0.977
0.977
0.997
0.998

Higuchi
r2
0.976
0.946
0.968
0.981
0.979
0.981

Korsmeyer-Peppas
r2
0.908
0.936
0.924
0.946
0.917
0.908

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Graph 10: Log cumulative % drug remaining Vs time plots (First order) of formulations F1, F2, & F3.

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Graph 11: Log cumulative % drug remaining Vs time plots (First order) of formulations F4, F5, & F6.

Graph 13: Log cumulative % drug release Vs log of time plots (Korsmeyer-Peppas) of formulations F4, F5, & F6.

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Graph 12: Log cumulative % drug release Vs log of time plots (Korsmeyer-Peppas) of formulations F1, F2, & F3.

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Graph 14: Log cumulative % drug release Vs square root of time plots (Higuchi) of formulations F1, F2, & F3.

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DISCUSSION
Levosalbutamol sulphate is 5HT1 receptor agonist with low oral bioavailability due to extensive first pass metabolism. We
have tried to prepare mucoadhesive drug delivery system using Levosalbutamol as a drug and chitosan, HPMC as a mucoadhesive and
release retardant polymers over a period of 8 hours which bypasses first pass metabolism and may enhance bioavailability.
The drug-polymer interaction was studied using FTIR spectroscopy for selected combination of drug with different polymers
used. The FTIR spectra obtained is illustrated in graph 1-4 reveals that Levosalbutamol sulphate was in the free form and no drugpolymer and polymer-polymer interactions took place during formulation development.
Precompressional Parameters were evaluated for bulk density, tapped density, Carrs index, Hausners ratio and angle of repose.
Results were represented in Table 2. Postcompressional parameters were studied and represented in Table 4. The drug content was
from 97.95% to 103.36% suggested uniform mixing of drug. The surface pH for all the buccal tablets was from 6.68 to 7.04 which
were nearer to salivary pH (6.5-7.5) suggesting that the prepared buccal tablets can be used without the risk of mucosal irritation and
discomfort.
The swelling index of the prepared formulations was in the range of 34.100.45 to 89.310.07. The results are presented as
percentage weight change with respect to time in Table 5-6 and in graph 6-7. The swelling of all the tablets was increased as the time
proceeds because the polymer gradually absorbs water due to hydrophilicity of the polymer. The swelling index was 38.06% to
72.71% for the formulation which contains only chitosan. As the concentration of chitosan increased alone and in combination of
secondary polymers, the swelling was decreased because of more viscous layer formation.
The in vitro release data was represented in Table 7-8 and illustrated in graph 8-9. The buccal tablets containing chitosan
alone showed initially a rapid burst release of the drug followed by > 90% release within 4 h. The addition of secondary polymer like
HPMC K4M along with chitosan as primary polymer in formulations F4 to F6 prolonged the release of Levosalbutamol sulphate from

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Graph 15: Log cumulative % drug release Vs square root of time plots (Higuchi) of formulations F4, F5 & F6.

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6 to 8 h. The buccal tablets containing HPMC K4M showed a maximum release of 68.15% to 78.78% because HPMC with a grade of
K4M has a hydrophilic gel forming matrix which was used as a release retardant.
The in vitro release data was subjected to zero order, first order, Higuchi, Korsemeyer-Peppas, Hixson Crowell and erosion
model in order to establish the drug release mechanism and kinetics of drug release from the buccal tablets in Table 9 and illustrated in
graph10-15. The results of in-vitro study are promising and reveals that the formulation may enhance the bioavailability and the data
can be used for further in-vivo study and these tablets can be option for the conventional Levosalbutamol with increased patient
compliance.
CONCLUSION
Buccal Tablets were prepared using Chitosan and HPMC as polymer. So lastly we conclude that, Buccal tablets of
Levosalbutamol sulphate containing Chitosan and HPMC can meet the ideal requirements for buccal release intra-oral devices, which
can be good way to bypass the extensive hepatic first pass metabolism and may increase bioavailability.

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5896

ACKNOWLEDGEMENT:
Authors are thankful to management of Channabasweshwar Pharmacy College, Latur, Maharashtra, India for providing facilities.

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