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35 | P a g e International Standard Serial Number (ISSN): 2319-8141

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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:

[email protected]

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.

- 36 - | P a g e International Standard Serial Number (ISSN): 2319-8141


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.



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.



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.



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



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



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



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.



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.



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,



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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