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International Journal of Universal Pharmacy and Bio Sciences 2(6): November-December 2013
INTERNATIONAL JOURNAL OF UNIVERSAL
PHARMACY AND BIO SCIENCES IMPACT FACTOR 1.89***
ICV 3.00*** Pharmaceutical Sciences RESEARCH ARTICLE……!!!
FORMULATION AND EVALUATION OF SUBLINGUAL TABLETS OF
OXAZEPAM
Gangadhara Rao. K*1, Lakshmana Rao Potti
1, Rama Kotaiah. M
1, Prasada Rao.M
1,
Siva Sankar.R.Beera valli2, Kameswara Rao.S
3.
*1 Department of Pharmaceutics, M.A.M College of Pharmacy, Kesanupalli, Narasarao Pet,
Guntur (dt), Andhra Pradesh, India. 2Fredrick Burg, Virgina.
3Srisiddhartha Pharmacy College, Nuzivid.
KEYWORDS:
Oxazepam,
Croscarmellose, Sodium
Starch Glycollate,
Crospovidone.
For Correspondence:
Gangadhara Rao.K
Address: Department of
Pharmaceutics, M.A.M
college of Pharmacy,
Kesanupalli, Narasarao
Pet, Guntur(dt),Andhra
Pradesh, India.
Email-ID:
ramavathnag@gmail.com
ABSTRACT
The objective of the current study was to develop and optimize a
sublingual tablet of Oxazepam which is an effective drug in the
treatment of anxiety and insomnia. Oxazepam containing tablets were
prepared by direct compression method using different superdisintigrents
such as Crosspovidone, Sodium Starch Glycollate, Crosspovidone. The
tablets were evaluated for both pre compressional parameters like bulk
density, tapped density, angle of repose, compressability index and
hausners ratio and post compressional parameters like Hardness, Weight
variation, Thickness, Friability, Drug content, Wetting time, Water
absorption ratio, In-vitro disintegration time, In-vitro dissolution study
and also Drug release kinetic study. The Hardness, Weight variation,
Thickness, Friability and Drug content of tablets were found to be
acceptable according to pharmacopoeial limits. An optimized tablet
formulation i.e. F3 was found, which provided short wetting time of 19
sec and In-vitro disintegration time of 17 sec. From the above results, it
indicated that the amount of superdisintegrant i.e. sodium starch
glycollate was significantly affected the dependent variables like wetting
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
in-vitro drug release data of all oxazepam sublingual tablets were
subjected to goodness of fit test by linear regression analysis according
to Zero order equation, Ist order equation, Higuchi’s 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, 45°C, 37°C, 40°C/ 75% RH.
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INTRODUCTION:
Tablets that disintegrate or dissolve rapidly in the patient’s 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 gamma-
aminobutyric 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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Table.No.1: FORMULATION TABLE
F.No OX
(%)
MCC
(%)
LAC
(%)
MAN
(%)
DEX
(%)
SSG
(%)
CSS
(%)
CPV
(%)
TAL
(%)
FLO
(%)
Twt
(mg)
F1 10 28 - 60.6 - 1 - - 0.2 0.2 100
F2 10 28 - 59.6 - 2 - - 0.2 0.2 100
F3 10 28 - 58.6 - 3 - - 0.2 0.2 100
F4 10 28 - - 58.6 3 - - 0.2 0.2 100
F5 10 28 58.6 - - 3 - - 0.2 0.2 100
F6 10 28 - 57.6 - - 2 2 0.2 0.2 100
F7 10 28 57.6 - - - 2 2 0.2 0.2 100
F8 10 28 - - 57.6 - 2 2 0.2 0.2 100
F9 10 28 - - 59.6 - 1 1 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. Carr’s 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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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. Bulk
Density
(gm/ml)
Tapped Density
(gm/ml)
Carr’s
Index
Hausner
Ratio
Angle of
Repose
01 0.5144 0.5896 14.61 1.1461 19
02 0.5102 0.5952 16.66 1.1666 18
03 0.5122 0.5814 14.03 1.1351 16
04 0.5208 0.5966 14.6 1.1455 14
05 0.5081 0.6053 19.13 1.1913 34
06 0.5091 0.5924 16.36 1.1636 17
07 0.5197 0.5966 14.79 1.1479 28
08 0.5144 0.5980 16.26 1.1625 19
09 0.5319 0.6024 13.25 1.1325 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. Thickness7
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)
Weight
variation
Friability
(%)
Disintegration
(Seconds)
Wetting
Time
(Seconds)
Assay
(%)
w/w
F1 2.5 2.62 101.2 0.3412 38 52 93.51
F2 4.0 2.67 99.8 0.0942 29 36 94.82
F3 4.0 2.63 102.3 0.1970 17 19 95.91
F4 4.0 2.63 100.2 0.0104 118 107 96.20
F5 3.0 2.70 99.6 0.1023 17 24 95.04
F6 3.5 2.64 99.8 0.3241 25 19 96.28
F7 3.0 2.67 102.3 0.1226 21 19 96.50
F8 4.0 2.67 98.4 0.0140 114 150 95.62
F9 3.0 2.68 98.9 0.0462 46 25 95.11
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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
5 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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Fig.No.2: Dissolution profiles of F. No 01-03,
Fig.No.2: Dissolution profiles of F. No 04-06,
Fig.No.3: Dissolution profiles of F. No 07-09
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35
% C
DR
time in min
%CDR1
%CDR2
%CDR3
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35
% C
DR
time in min
%CDR4
%CDR5
%CDR6
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35
% C
DR
time in min
%CDR7
%CDR8
%CDR9
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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 / Mα 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 zero-
order 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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Table 4: Regression analysis of Formulation No.1-9
Formulation
No.
Regression Coefficient
Zero order
First order
Higuchi
Korsemeyer
Peppas
F1 0.9032 0.9834 0.9654 0.9649
F2 0.8891 0.8954 0.9875 0.9485
F3 0.9159 0.9452 0.9863 0.9830
F4 0.9110 0.9750 0.9679 0.9636
F5 0.9214 0.9654 0.9759 0.9751
F6 0.9413 0.9826 0.9748 0.9625
F7 0.8925 0.9212 0.9629 0.959
F8 0.9089 0.9326 0.9547 0.9517
F9 0.9234 0.9486 0.9738 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 45°C, 37°C, 40°C/ 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
TIME (MIN) % Cumulative Drug Release
Initial 30 Days 60 Days 90 Days
5 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 λmax 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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The powder parameters like bulk density, bulkiness, carr’s 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, Carr’s index: 14.03-19.13, Hauser’s ratio: 1.1325-
1.1666, 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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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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