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International Standard Serial Number (ISSN): 2319-8141

International Journal of Universal Pharmacy and Bio Sciences 2(6): November-December 2013

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES
Pharmaceutical Sciences

IMPACT FACTOR 1.89***

ICV 3.00***
RESEARCH ARTICLE!!!

FORMULATION AND EVALUATION OF SUBLINGUAL TABLETS OF

OXAZEPAM
Gangadhara Rao. K*1, Lakshmana Rao Potti1, Rama Kotaiah. M1, Prasada Rao.M1,
Siva Sankar.R.Beera valli2, Kameswara Rao.S3.
*1
Department of Pharmaceutics, M.A.M College of Pharmacy, Kesanupalli, Narasarao Pet,
Guntur (dt), Andhra Pradesh, India.
2
Fredrick Burg, Virgina.
3
Srisiddhartha Pharmacy College, Nuzivid.
ABSTRACT
The
objective
of
the
current
study was to develop and optimize a
KEYWORDS:
sublingual tablet of Oxazepam which is an effective drug in the
treatment of anxiety and insomnia. Oxazepam containing tablets were
Oxazepam,
prepared by direct compression method using different superdisintigrents
Croscarmellose, Sodium
such as Crosspovidone, Sodium Starch Glycollate, Crosspovidone. The
tablets were evaluated for both pre compressional parameters like bulk
Starch Glycollate,
density, tapped density, angle of repose, compressability index and
Crospovidone.
hausners ratio and post compressional parameters like Hardness, Weight
variation, Thickness, Friability, Drug content, Wetting time, Water
For Correspondence:
absorption ratio, In-vitro disintegration time, In-vitro dissolution study
Gangadhara Rao.K
and also Drug release kinetic study. The Hardness, Weight variation,
Thickness, Friability and Drug content of tablets were found to be
Address: Department of
acceptable according to pharmacopoeial limits. An optimized tablet
Pharmaceutics, M.A.M
formulation i.e. F3 was found, which provided short wetting time of 19
college of Pharmacy,
sec and In-vitro disintegration time of 17 sec. From the above results, it
Kesanupalli, Narasarao
indicated that the amount of superdisintegrant i.e. sodium starch
Pet, Guntur(dt),Andhra
glycollate was significantly affected the dependent variables like wetting
Pradesh, India.
time and In-vitro disintegration time. The best in-vitro drug release was
found to be in Batch.No.3 i.e.101.75% during the end of 15th min. The
Email-ID:
in-vitro drug release data of all oxazepam sublingual tablets were
ramavathnag@gmail.com
subjected to goodness of fit test by linear regression analysis according
to Zero order equation, Ist order equation, Higuchis equation and
Krosmeyer-Peppas equation to ascertain the mechanism of drug release.
Hence the drug release followed the Ist order release kinetics with
diffusion mechanism. Compatability studies reveal that there was no
interaction between the drug and polymers. The tablets showed no
significant change either in physical appearance or in dissolution pattern
after storing at room temperature, 45C, 37C, 40C/ 75% RH.
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International Standard Serial Number (ISSN): 2319-8141

INTRODUCTION:
Tablets that disintegrate or dissolve rapidly in the patients mouth are convenient for young children,
the elderly and patients with swallowing difficulties, and in situations where potable liquids are not
available. For these formulations, the small volume of saliva is usually sufficient to result in tablets
disintegration in oral cavity. The medication can then be absorbed partially or
entirely into the systemic circulation from blood vessels in the sublingual mucosa, or it can be
swallowed as a solution to be absorbed from gastrointestinal tract. The sublingual route usually
produces a faster onset of action than orally ingested tablets and the portion absorbed through
sublingual blood vessels bypass the hepatic first pass metabolic processes.1-3 Oxazepam4 is used in
the treatment of Anxiety and exerts its anxiolytic effects by potentiating the effect of gammaaminobutyric acid (GABA) on GABA-A receptors through a cooperative mechanism of action. The
bioavailability of Oxazepam following oral administration is very low. Oxazepam is absorbed
rapidly on oral administration. When administered orally, frequent dosing is needed due to its short
biological half life. Secondly drug undergoes high hepatic first pass metabolism. Various techniques
can be used to formulate rapidly disintegrating or dissolving tablets. 5,6 Direct compression is one of
these techniques which require incorporation of a superdisintegrant into the formulation, or use of
highly water soluble excipients to achieve fast tablet disintegration. Extremely fast tablets
disintegration would be required to enhance the release of Oxazepam from tablets for rapid
absorption by the sublingual mucosa blood vessels. It was decided that Oxazepam could be
formulated into fast disintegrating tablets for sublingual administration as potential emergency
treatment of anxiety.
MATERIALS AND METHODS:
MATERIALS:
Oxazepam was obtained as a gift sample from sunpharma, Ahmedabad. Croscarmellose sodium,
Crosspovidone XL-10, Sodium Starch Glycolate, Talc, mg stearate , mannitol, lactose, aspartame
were procured from Hetero labs, jeedimetla. All the chemicals and solvents used were of analytical
grade.
METHOD:
Oxazepam sublingual tablets prepared by the direct compression method using different excipients.
Different concentration of excipients was used to prepare different group of sublingual tablets.
Compositions of various formulations are shown in Table-1. All the ingredients were weighed
accurately and passed through sieve # 40. Oxazepam was taken and was mixed with this all
ingredients in geometrical ratio in polythene bag. Finally the talc was added and mixed thoroughly
to get free flowing powder. The blends were compressed using 6.5mm standard concave punches.
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International Standard Serial Number (ISSN): 2319-8141

Table.No.1: FORMULATION TABLE

F.No

OX
(%)

MCC
(%)

LAC
(%)

F1

10

28

F2

10

28

F3

10

F4

DEX
(%)

SSG
(%)

CSS
(%)

CPV
(%)

60.6

59.6

28

58.6

10

28

F5

10

28

F6

10

28

F7

10

28

F8

10

28

F9

10

28

58.6
57.6

MAN
(%)

58.6

TAL
(%)

FLO
(%)

Twt
(mg)

0.2

0.2

100

0.2

0.2

100

0.2

0.2

100

0.2

0.2

100

0.2

0.2

100

57.6

0.2

0.2

100

0.2

0.2

100

57.6

0.2

0.2

100

59.6

0.2

0.2

100

OX: oxazepam, MAN: Mannitol DC, LAC: Lactose, CPV: Crosspovidone XL-10. CSS:
Crosscarmellose Sodium, SSG: Sodium Starch glycolate, DEX: Dextrose anhydrous, Twt: Total
weight of Tablet, TAL: Talc, MCC: Microcrystalline cellulose PH 200, FLO: Flavor orange.
Precompression parameters
Properties of powder, which are of most importance, are Residual moisture content, Bulk density,
Bulkiness, Hausner ratio and Compressibility index. These parameters were evaluated on a
laboratory scale for optimum production with respect to quality and quantity.
1. Bulk density (Do): It is the ratio of bulk volume to the total mass of the powder taken. It is
measured by pouring the weighed powder into a graduated cylinder and the volume was noted. It is
given by
Do = M/Vo
Where M is the mass of powder,
Vo is the Bulk Volume of powder; it is expressed in gm/ml.
2. Tapped density (Dt): It is the ratio of mass of the powder to the tapped volume of the powder.
The tapped volume was measured by bulk density apparatus in which the powders were tapped for
predetermined number of taps until the volume remained constant. It is given by
Dt = M/Vt
Where M is the mass of powders
Vt is the tapped volume of powders; it is expressed in gm/ml.
3. Carrs index
It indicates the ease, which a material can be introduced to flow. It is given by
I = (Dt-Do/Do) x 100
Where Dt is tapped density
Do is bulk density; it is expressed in terms of percentage.
4. Hausner ratio: It is the ratio of tapped density to untapped density. It is given by
H = Dt/Do
Where Dt is the tapped density of powders
Do is the untapped density of powders.
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International Standard Serial Number (ISSN): 2319-8141

5. Angle of Repose: The angle of internal friction is a measure of internal stress distribution and is
the angle at which an applied stress diverges as it passes through the bed. It is the least slope at
which a powder will slide down an inclined plane surface. The typical method is to pour the powder
in a conical heap on a level, flat surface and measure the included angle with the horizontal. It is
denoted by q.
tan q = h/r
Where, q -angle of repose, h- height in cm, r- radius.
The powder mixture was allowed to pass through the funnel fixed to a stand at definite height. The
angle of repose was then calculated by measuring the height and radius of the heap of powder
formed.
Table.No.2: Pre-compression parameters of all batches
Formu.No.

01
02
03
04
05
06
07
08
09

Bulk
Density
(gm/ml)
0.5144
0.5102
0.5122
0.5208
0.5081
0.5091
0.5197
0.5144
0.5319

Tapped
(gm/ml)

Density

0.5896
0.5952
0.5814
0.5966
0.6053
0.5924
0.5966
0.5980
0.6024

Carrs
Index
14.61
16.66
14.03
14.6
19.13
16.36
14.79
16.26
13.25

Hausner
Ratio

Angle of
Repose

1.1461
1.1666
1.1351
1.1455
1.1913
1.1636
1.1479
1.1625
1.1325

19
18
16
14
34
17
28
19
18

Post compression parameters

1. Hardness as per IP7
The hardness of the tablet is a official Test for the tablets as per IP and it was determined for all the
formulations by using Monsanto type hardness tester and the results shown in table.no.3.
2. Friability7
The friability of the tablet is not a official test but as it is required for the shipment of the product, so
it was carried out by using Friabilator. The 10 tablets were weight (W initial) and transferred into the
friabilator. The friabilator was operated at 25 rpm for 4 minutes. Then the tablets were weighed
again after friabilation (W final). And the results shown in table.no.3.The % friability was then
calculated using the formula
% F= W initial Wfinal
W initial
3. Weight variation as per IP8
The weight variations of the sublingual tablets were carried out using 10 tablets by taking the
Average weight of 10 tablets and the results shown in table.no.3.
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4. Thickness

The thickness of the tablet was measured by using digital vernier scale. The limit for this was
average thickness 0.2mm and the results shown in table.no.3.
5. Disintegration time10
The disintegration time for sublingual tablets was determined by using USP disintegration test
apparatus. The limit for disintegration was not more than 2 minutes at 370 C.
Procedure:
Six tablets were placed individually in each tube of disintegration test apparatus and discs were
placed. The water bath was maintained at 370 C _0.50C and the time taken for all tablets to
disintegrate completely were noted and the results shown in table.no.3.
6. Wetting time9
Wetting time was determined by placing a piece of tissue paper folded twice in small petridish
having internal diameter of 6.5 cm. 10 ml of water was added. A tablet was placed on the paper and
time for complete wetting of tablet was measured in seconds and the results shown in table.no.3. The
photographs of wetting time of sublingual tablets were shown in fig.no.1
7. Assay
10 tablets weighed and triturated. The tablet triturate equivalent to 100 mg of the drug was weighed
accurately, dissolved in Methanol and further dilutions were made using the same and the
absorbance were measured at 295 nm against the reagent blank and the concentration of oxazepamin
mcg/ml was determined using the regression equation and the results shown in table.no.3.
Y = 0.036X
Drug content in mcg / tab = conc. mcg / ml* dilution factor
% drug content = drug content in mg* 100 / label claim.
Table.No.3: Post compression parameters
FORM.No.

Hardness
(kg/cm2)

Thickness
(mm)

F1
F2
F3
F4
F5
F6
F7
F8
F9

2.5
4.0
4.0
4.0
3.0
3.5
3.0
4.0
3.0

2.62
2.67
2.63
2.63
2.70
2.64
2.67
2.67
2.68

Weight
variation

101.2
99.8
102.3
100.2
99.6
99.8
102.3
98.4
98.9

Friability
(%)

Disintegration
(Seconds)

Wetting
Time
(Seconds)

Assay
(%)
w/w

0.3412
0.0942
0.1970
0.0104
0.1023
0.3241
0.1226
0.0140
0.0462

38
29
17
118
17
25
21
114
46

52
36
19
107
24
19
19
150
25

93.51
94.82
95.91
96.20
95.04
96.28
96.50
95.62
95.11

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International Standard Serial Number (ISSN): 2319-8141

Initially

Started wetting
Swelling
Fig.No.1: wetting images of sublingual tablets
8. Invitro dissolution study
The dissolution was carried out to determine the rate of drug release at different time intervals. The
sublingual tablets were subjected for dissolution study by using modified USP dissolution apparatus.
The tablet was placed in the basket and the dissolution was carried out using Phosphate Buffer pH
6.8 as medium. Aliquots of 5ml were withdrawn at every 5 minutes interval and were replaced by
same solution. The drug content was analyzed spectrophotometrically at 230nm against reagent
blank. The results were shown in table.No.4. % Cumultive drug release and time curve dissolution
graphs were visualized in fig.no.2 to 4
Table.No.4: % Cumulative drug release profile of all formulations
Time
(min)

%CDR
F1

%CDR
F2

%CDR
F3

%CDR
F4

%CDR
F5

%CDR
F6

%CDR
F7

%CDR
F8

%CDR
F9

66.67

77.24

84.93

63.99

96.28

74.85

78.85

55.86

61.3

10

74.1

82.28

94.38

75.83

99.87

82.24

86.37

67.68

68.48

15

80.9

86.03

101.75

81.66

99.99

89

91.45

76.42

73.48

20

87.81

90.36

88.02

95.83

97.46

87.01

80.62

25

96.53

94.64

93.91

100.58

100.08

96.02

88.29

30

101.86

99.03

99.93

99.02

99.42

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International Standard Serial Number (ISSN): 2319-8141

120

% CDR

100
80

%CDR1

60

%CDR2

40

%CDR3

20
0
0

10

15

20

25

30

35

time in min

Fig.No.2: Dissolution profiles of F. No 01-03,

120

% CDR

100
80
60

%CDR4

40

%CDR5

20

%CDR6

0
0

10

15

20

25

30

35

time in min

Fig.No.2: Dissolution profiles of F. No 04-06,

120

% CDR

100
80
60

%CDR7

40

%CDR8

20

%CDR9

0
0

10

15

20

25

30

35

time in min

Fig.No.3: Dissolution profiles of F. No 07-09

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DRUG RELEASE KINETICS:

To examine the release mechanism of Oxazepam from the prepared sublingual tablets, the results
were analyzed according to the following equation Where Mt / M is the fractional drug released at
time t, k is a kinetic constant incorporating structural and geometrical characteristics of the
drug/polymer system [device], and n is the diffusional exponent that characterizes the mechanism of
drug release. It is known that for non-swelling tablets, the drug release can generally be expressed
by the Fickian diffusion mechanism, for which n = 0.5, whereas for most erodible matrices, a zeroorder release rate kinetics is followed, for which n = 1. For non-Fickian release, the n value falls
between 0.5 and 1.0 [0.5 < n < 1.0]; whereas in the case super case II transport n >1.
The data of the in-vitro release was fit into different equations and kinetic models to explain the
release kinetics of Oxazepam from sublingual tablets. The kinetic models used were zero-order
equation12 (eq. 1), first-order equation13 (eq. 2), Higuchi equation14 (eq. 3) and Krosmeyer-Peppas
equation15 (eq. 4).
Qt = K0t ----------- (1)
Qt = Q0 (1- e-k1t) ----------- (2)
Qt = KH.t1/2 ----------- (3)
Qt / Q = Kk tn ----------- (4)
Where,
Qt ------- Is the amount of drug release in time t
Q0 ------- Is the initial amount of the drug
n ------- Exponent value
And K0, K1, KH, and Kk are release rate constants for Zero-order, First-order, Higuchi, and
Krosmeyer-Peppas model respectively. Zero order represents an ideal release profile in order to
achieve the pharmacological prolonged action. This is applicable to dosage forms like transdermal
systems, coated forms, osmotic systems, as well as matrix tablets with low soluble drugs. First order
is applicable to study hydrolysis Kinetics and to study the release profiles of pharmaceutical dosage
forms such as those containing water-soluble drugs in porous matrices.
Higuchi Matrix is applicable to systems with drug dispersed in uniform swellable polymer matrix as
in case of matrix tablets with water-soluble drug. Krosmeyer-Peppas equation is widely used; when
the release mechanism is not well known or when more than one type of release phenomena could
be involved. Data of the in-vitro release was fit into different equations and kinetic models to
explain the release kinetics of Oxazepam from sublingual tablets. The data are presented in Table
06.

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Formulation
No.

F1
F2
F3
F4
F5
F6
F7
F8
F9

International Standard Serial Number (ISSN): 2319-8141

Table 4: Regression analysis of Formulation No.1-9
Regression Coefficient

Zero order
0.9032
0.8891
0.9159
0.9110
0.9214
0.9413
0.8925
0.9089
0.9234

First order
0.9834
0.8954
0.9452
0.9750
0.9654
0.9826
0.9212
0.9326
0.9486

Higuchi
0.9654
0.9875
0.9863
0.9679
0.9759
0.9748
0.9629
0.9547
0.9738

Korsemeyer
Peppas
0.9649
0.9485
0.9830
0.9636
0.9751
0.9625
0.959
0.9517
0.9721

STABILITY STUDIES:
The selected formulations were packed in the strip packaging, which were packed in the card board
box and labeled. They were then stored at 45C, 37C, 40C/ 75% RH and Room Temp. Kept for
three months and evaluated for their physical appearance band drug release at specific intervals of
time per ICH Guide lines. The values were shown in table.No.6 & table.No.7.
Table.No.6: Dissolution Profile: B .No. 03
% Cumulative Drug Release
TIME (MIN)
Initial

30 Days

60 Days

90 Days

84.93

86.01

85.00

84.8

10

94.38

93.07

93.0

92.9

15

101.75

100.49

100.20

100.05

DISCUSSION:
The sample of Oxazepam tested for physicochemical properties complies as per BP specifications.
The estimation of Oxazepam by UV spectrophotometric method at max 230 nm in Methanol. The
correlation coefficient for the standard curve was found to be 0.999, at concentration range, 0.5 18mcg/ml. The resulting tablets were evaluated considering the disintegration time as the main
criteria. Initially the formulation was prepared by using different concentrations of crosscarmellose
sodium and crosspovidone each individually, and the resulting tablet DT was found to be high. The
expected DT was obtained when the combination of crosscarmellose sodium and crosspovidone
(XL-10) were used. Similarly, the other formulation was prepared by using lower concentration of
sodium starch glycolate, the DT was found to be higher, but by increasing the concentration of
sodium starch glycolate, expected DT was obtained with optimum tablet characteristic.

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International Standard Serial Number (ISSN): 2319-8141

The powder parameters like bulk density, bulkiness, carrs index and Hauser ratio were carried out
for all 9 formulations of the powder blend ready for compression. The values are found to be, Bulk
density 0.5081-0.5319, tapped density 0.5814-0, Carrs index: 14.03-19.13, Hausers ratio: 1.13251.1666, Angle of repose: 16-34 . The post compressional parameters reveals that Weight variation
was between: 97.88-103.04mg, Thickness was varied: 2.62-2.70, Hardness was between: 2.5-4.0 all
the parameters meets the acceptable limits. Disintegration time (in seconds) for all the formulation
batches was evaluated .Based on the study it was found that formulation F. No 4 and F. No 8
exhibited a disintegration time (in seconds) more than 100 seconds, which may be due to the
presence of dextrose as diluent, though it may contain different types of disintegrating agents. If
lactose is used as diluent and containing a combination of disintegrating agent such as
croscarmellose sodium and crospovidone XL-10, the DT was slightly higher when compared to that
of formulation B. No 5, which contained sodium starch glycolate as disintegrating agent at a
concentration of 3%. The formulation B. No 3 and B. No 5 showed a low DT value among the all
formulation prepared which may be due to the presence of appropriate concentration of sodium
starch glycolate as disintegrating agent. Finally it may be concluded that sodium starch glycolate at
concentration of 3% with either lactose or mannitol may be considered as best diluents. Similarly
results to those for DT were found to be significant for wetting time. Thus it may be concluded that
formulation B. No 3.6 and 7 showed low wetting time values. Formulations Batch no 03 and 05,
showed rapid dissolution rate, the percentage cumulative drug release (%CDR) after 5 minutes
found to be more than 80% and complete dissolution was achieved within 15minutes. Thus it may
be concluded that formulation B. no 3 may be considered as best formulation with respect to in vitro
drug release profile.
Based on pre-compression parameters formulation No 3 was considered as best formulations. With
respect to post-compression parameters like disintegration time, wetting time and dissolution study
(in vitro) formulation No 3, 5, 6 and 7 were considered as best formulation. The release kinetics
reveals that the drug release followed the Ist order release kinetics with diffusion mechanism. In
present study short term physical stability and drug content and dissolution profile were carried out
of formulation batch no 03, and 06. The results of drug content in all the formulations inferred no
significant deviation from the initial values this indicates the stability of drug in all the batches of
tablets.
CONCLUSION:
The sublingual tablets of F3 was contain 10mg of Oxazepam 28mg of MCC PH 200 and 58.6mg of
mannitol (DC) and sodium starch glycolate 3mg, talc 0.2mg and flavor orange 0.2mg considered to
be the best among all other nine formulations of tablets since it exhibited a good dissolution profile,
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International Standard Serial Number (ISSN): 2319-8141

disintegration time, appearance, uniformity of drug content, taste and further good stability and In
vivo absorption profile.
ACKNOWLEDGEMENT:
The author was very thankful to Sunpharma hyderabd and Hetero labs, jeedimetla for providing
Oxazepam as a gift sample and other excipients.
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