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International Journal of

PH RM CEUTIC LND BIOMEDIC L

RESE RCH

Research article

Formulation and evaluation of diclofenac potassium effervescent tablets

G. Rajalakshmi*, C.H. Vamsi, R. Balachandar, N. Damodharan

Department of Pharmaceutics, SRM College of Pharmacy, SRM University, Kattankulathur, Tamil Nadu, India, 603 203

Received: 18 Oct 2011 / Revised: 28 Oct 2011 / Accepted: 03 Nov 2011 / Online publication: 15 Nov 2011

ABSTRACT

In the present study, the design of an oral effervescent tablet of diclofenac potassium was carried out. Six differentformulations were prepared using different diluents, carbonates by wet granulation and direct compression method. The

prepared tablets were evaluated for various pre compression characteristics (like angle of repose, bulk density, tapped

density, cars index and hausners ratio) and post compression characteristics (like weight variation, hardness friability ,drug

content, disintegration, CO2content, effervescent time, particle size and in vitrodissolution studies). The dissolution test was

carried out in SIF without enzymes, 0.1N HCl and pH 4.8 acetate buffer. Among all the formulations, its F3 formulations

were better in all the terms of precompression and post compression parameters. In F3 formulations, F3A (by direct

compression) and F3B (by wet granulation method) were there. F3B (composed of active dextrates (Emdex), citricacid,

tartaric acid, effersoda and arginine) had given good pre formulation and post compression studies as F3A. Even the drug

release in the medium SIF pH6.8 without enzymes was 99.2% when compared to F3A (98.7%) and marketed tablet (98%).It

had all the qualities of a good effervescent tablet, based on this F3B formulation was selected as the best formulation, and it

was charged for stability studies. It had given better release profile in all the mediums when compared to marketed

conventional tablet (SUPANAC). A better therapeutic objective can be obtained by formulating effervescent tablet ofdiclofenac potassium that may help in obviating the demerits of slow release and slow absorption, gastrointestinal side effects

of normal tablets.

Key words: EMDEX, Effersoda, Wet granulation, Direct compression, Hausners ratio, Effervescent time, SIF.

1. INTRODUCTION

The oral dosage forms are the most popular way of taking

medication despite having some disadvantages like slow

absorption and thus onset of action is prolong. This can be

overcome by administrating the drug in liquid from but,

many APIs have limited level of stability in liquid form. For

achieving a prolonged and predictable drug delivery profile

in the gastrointestinal tract is to control the gastric residence

time using a gastro retentive dosage forms that will provide

as with new and important therapeutic options. The design of

oral controlled drug delivery system primarily is aimed at

achieving more predictable and increase availability of drugs.

However, the development process is precluded by several

physiological difficulties such as inability to restrain and

locates the controlled drug delivery system within the desired

region of gastrointestinal tract due to the variable gastric

emptying and motility [1]. So, effervescent tablets acts as an

alternative dosage form. The tablet is added into a glass of

water just before administration and the drug solution or

dispersion is to be drunk immediately. The tablet is quickly

broken apart by internal liberation of CO2 in water due to

interaction between tartaric acid and citric acid with alkali

metal carbonates or bicarbonates in presence of water.

Due to liberation in CO2 gas, the dissolution of API in

water as well as taste masking effect is enhanced. The

advantages of effervescent tablets compared with other oral

dosage forms includes an opportunity for formulator to

improve taste, a more gentle action on patients stomach and

marketing aspects. To manufacture these tablets, either wet

fusion or heat fusion is adopted. The tablets are compressed

soft enough to produce an effervescent reaction that isadequately rapid. Water soluble lubricants are used to prevent

an insoluble scum formation on water surface. To add

ISSN No: 0976-0350

Available online at

www.pharmscidirect.com

Int J Pharm Biomed Res2011, 2(4), 237-243

*Corresponding Author. Tel: 044 27453160, Fax:Email: [email protected]

2011 PharmSciDirect Publications. All rights reserved.

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G. Rajalakshmi et al., Int J Pharm Biomed Res 2011, 2(4), 237-243 238

sweetness to the formulation, saccharin is added since

sucrose is hygroscopic and add too much of bulk to the tablet.

The manufacturing shall be done under controlled climatic

condition to avoid effervescent reaction. The packaging is

done under 25% RH at 25C. Hands of the consumers and

atmospheric moisture after opening the container can also

result in loss of product quality. The most commonly used

effervescent tablet today is aspirin tablet [2].

In the present study, the design of an oral effervescent

tablet of Diclofenac potassium was carried out. Diclofenac

Potassium is a nonsteroidal anti-inflammatory drug (NSAID)

that exhibits anti-inflammatory, analgesic, and antipyretic

activities. It is used for treatment of primary dysmenorrhea,

for relief of mild to moderate pain, for relief of the signs and

symptoms of osteoarthritis and rheumatoid arthritis.[Mylan

drugs.com] The main objective of this work was to formulate

and evaluate Diclofenac potassium effervescent tablets by

using different ratios of carbonates and acids by wet

granulation and direct compression method that helps inobviating the demerits of slow release and slow absorption,

gastrointestinal side effects of normal tablets of Diclofenac

potassium and to increase the release and immediate effect.

Richard B Lipton [3] had worked on diclofenac potassium

oral solution seen that this diclofenac potassium has given

good therapeutic effect in the solution form, Wildgrubehj and

Terhaag B[4] had also worked on the effect of effervescent

tablets of Diclofenac sodium and shown that the gastro

intestinal side effects are reduced when compared to the

normal tablets of diclofenac . Different carbonates ,acids and

buffers were used to attain good effervescence in short timeand to obtain a clear solution , and to give maximum

therapeutic effect in short span of time when taken orally,

Diclofenac potassium is a weak acidic it gets ionized in the

stomach due to the neutralization capacity of the effervescent

solution stomach pH increases and it is in the ionized form

and gets absorbed. As the stomach pH starts to decrease it

gets absorbed through the permeation from the stomach walls

in the unionized form, CO2 released also helps in the

permeation of the drug .In case of normal tablets they remain

unionized in the stomach and absorb only through permeation

not through solubility as they are in the unionized form. In

case of effervescent tablets due to the initial raise of pH in the

stomach that help in the solubility of the drug and converts

the drug to ionized form, as the pH decreases again due to the

acids in the stomach the drug gets converted to unionized

form and get absorbed through the permeation and CO2

released helps in better permeation. These dosage form

process helps the drug to show better therapeutic effect

compared to the normal tablets.

An attempt was made to formulate effervescent tablet of

diclofenac potassium using different carbonates and acids by

wet granulation and direct compression method. The

prepared tablets were subjected to dissolution in variousmedia and the best formulation was selected for further

studies.

2. MATERIALS AND METHODS

2.1MaterialsDiclofenac potassium (Aptuit laurus Pvt Ltd) and all

excipients used were of analytical grade from S.D fine

chemicals and few as gift sample from Aptuit laurus Pvt Ltd

.All the instruments used for Preformulation study were from

Electrolab. All the glass wares used were of borosilicate,

Tablet compression machine was of Cadmach, Dissolution

apparatus USP type 2 was of Electrolab, UV

spectrophotometer was of PerkinElmer .Entire

Preformulation and post compression was performed in

40%RH to prevent moisture uptake from the atmosphere.

2.2 Wet granulation and direct compression methodAccurately measured quantities of drug and excipients

were taken as shown in Table 1. IPA was used as granulatingagent in case of wet granulation process. Mixture of drug and

excipients were taken for granulation. IPA was added until

wet mass was formed and passed through 20# to get the

required granules, Granules formed through wet granulation

were dried in oven till the moisture content was below

1%.Then the above dried granules were taken in to v cone

blender and flavor was added to it and blend for 15 min. The

formulation, F3B alone was done by direct compression

method. No granules were prepared in this case. Mixture of

drug and excipients were passed through 40# and were taken

in to v cone blender and flavor was added to it and blend

for 15 min and taken for compression. The tablets were

punched using Rotary compression machine (jaugur) of 25

mm punch. These compressed tablets were transferred in to

packing area and these tablets were packed in paper-

Aluminum packing with LDP coating.

2.3 Preformulation studies2.3.1 Angle of repose [5]

The flow properties of granules (before compression)

were characterized in terms of angle of repose, Carrs indexand Hausners ratio. For determination of angle of repose (),

the granules were poured through the walls of a funnel,

which was fixed at a position such that its lower tip was at

aheight of exactly 2.0cm above hard surface. The granules

were poured till the time when upper tip of the pile surface

touched the lower tip of the funnel. The tan-1of the (height

of the pile / radius of its base) gave the angle of repose.

2.3.2 Bulk and tapped density

Granules were poured gently through a glass funnel into a

graduated cylinder cut exactly to 10 mL mark. Excessgranules were removed using a spatula and the weight of the

cylinder with pellets required for filling the cylinder volume

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Table 1

Optimized formula for diclofenac potassium effervescent tablets 50mg

Sl No Ingredients F1A F1B F2A F2B F3A F3B

1 Diclofenac potassium B.P 0.05 0.05 0.05 0.05 0.05 0.05

2 Effersoda 2.01 1.98 1.98 1.98 1.98 1.983 Citric acid 0.42 0.25 0.35 0.41 0.3 0.3

4 Tartaric acid 0.25 0.44 0.45 0.39 0.48 0.45

5 Sodium citrate 0.38 0.58 -- -- -- --6 Glycine -- -- 0.3 0.5 -- --

7 Arginine -- -- -- -- 0.18 0.4

8 EMDEX -- -- -- -- 0.948 0.765

9 Sugar -- -- 0.815 -- --10 Dextrose -- -- -- 0.641 -- --

11 Mannitol 0.831 0.641 -- -- -- --

12 Povidone K 30 -- -- -- -- -- --13 sun set yellow 0.001 0.001 0.005 0.005 0.004 0.005

14 lemon flavor -- -- -- -- -- 0.005

15 org flavor 0.008 0.008 0.04 0.004 0.008 0.00516 Acesulfame K -- -- -- -- -- 0.02

17 Aspartame 0.05 0.05 -- -- -- --

18 Sucralose -- -- 0.01 0.02 0.05 0.02Total 4 4 4 4 4 4

was calculated. The cylinder was then tapped from a height

of 2 cm until the time when there was no more decrease in

the volume. Bulk density and tapped density were calculated.

Hausners ratio and Carrs index were calculated.

2.4Evaluation of effervescent tablets [6]The prepared diclofenac potassium effervescent tablets

were evaluated for uniformity of weight using 20 tablets,

hardness and friability using 10 tablets, drug content,

disintegration, CO2 content, particle size and in vitrodissolution studies.

2.4.1 Tablet hardness

The resistance of tablet for shipping or breakage, under

conditions of storage, transportation and Handling, before

usage, depends on its hardness. The hardness of tablet of each

formulation was measured by using Pfizer hardness tester.

2.4.2 Tablet thickness

Thickness of tablets was important for uniformity oftablet size. Thickness was measured by using screw gauze on

3 randomly selected samples.

2.4.3 Friability

Friability is the measure of tablet strength. Roche

Friabilator was used for testing the friability using the

following procedure. Twenty tablets were weighed accurately

and placed in the plastic chamber that revolves at 25 rpm for

4 minutes dropping the tablets through a distance of six

inches with each revolution. After 100 revolutions the tablets

were reweighed and the percentage loss in tablet weight was

determined.

% loss = 100tabletsofwtInitial

tabletsofwt.Final-tabletsofwt.Initialx

2.4.4 Weight variation [7]

Twenty tablets were weighed individually and the average

weight was determined. Then percentage deviation from the

average weight was calculated. According to IP standards,

not more than two of the individual weight deviates from the

average weight by more than the percentage shown in the

(Table 3) and none deviates by more than twice thatpercentage.

2.4.5 CO2content [8]

Tablet was placed in 100 mL of 10%sulphuric acid

solution, difference in weight after and before was calculated

the resulted weight was the amount of CO2 released. The

drug content in each formulation was determined by 20

tablets and powder equivalent to average weight was added

in 100 mL of methanol, followed by stirring for 30 min. The

solution was filtered through a 0.45membrane filter, diluted

suitably and the absorbance of resultant solution wasmeasured spectrophotometrically at 276 nm using methanol

as blank.

2.4.6 Moisture content

Take around 50 mL of methanol in titration vessel of Karl

Fischer titrator and titrate with Karl Fischer reagent to end

point. In a dry mortar grind the pellets to fine powder .Weigh

accurately about 0.5 g of the sample, transfer quickly to the

titration vessel, stir to dissolve and titrate with Karl Fischer

reagent to end point.

Moisture content =mginsampleofWeight

100XFXV

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where, F= factor of Karl Fischer reagent, V=volume in mL of

Karl Fischer reagent consumed for sample titration.

2.4.7 Drug content

Tablet was placed in 100 mL of 10%sulphuric acid

solution, difference in weight after and before was calculated

the resulted weight was the amount of CO2 released. The

drug content in each formulation was determined by 20

tablets and powder equivalent to average weight was added

in 100 mL of methanol, followed by stirring for 30 min. The

solution was filtered through a 0.45membrane filter, diluted

suitably and the absorbance of resultant solution was

measured spectrophotometrically at 276nm using methanol as

blank.

2.4.8 Content uniformity

In this test, 30 tablets were randomly selected containedfor sample, and 10 tablets should contain not less than 85.0 %

and not more than 115.0 % of the label claim. If one unit

outside the range of 85 to 115% of the label claim and no

units is outside 75 to 125% or if RSD>6% or if both

conditions prevail, test 20 additional units.

2.4.9 Disintegration test

It was performed in disintegration apparatus at 300C

temperature and time was noted. Place one tablet into each

tube and suspend the assembly in to the 1000 mL beaker

containing water maintained at 372C, 252C and operate

the apparatus. Remove the assembly form the liquid. Observe

the tablets, if one or two tablets fail to disintegrate

completely; repeat the test on 12 additional tablets. The

requirement is met if not less than 16 of the total of 18 tablets

tested are disintegrated [9,10].

2.4.10 Invitro release studies

The dissolution test was carried out in SIF without

enzymes, 0.1N HCl, and 4.8 pH acetate buffer. Samples were

taken at predetermined time intervals and after suitabledilutions absorbance were measured with the help of UV

spectrophotometer at 276 nm and the percentage drug

released at various time intervals were calculated. The release

rate of diclofenac potassium from tablets was determined

using United States Pharmacopeia (USP) Dissolution Testing

Apparatus 2. The dissolution test was performed using 900

mL of 0.1N HCl, 4.5 acetate buffer, 6.8 SIF at 370.5C and

50 rpm. A sample (10 mL) of the solution was withdrawn

from the dissolution apparatus hourly and the samples were

placed with fresh dissolution medium. The samples were

filtered through a 0.45 membrane filter and diluted to a

suitable concentration. Absorbance of these solutions wasmeasured at 265 nm using spectrophotometrically at 276nm

using respective buffer as blank. Cumulative percentage drug

release was calculated using an equation obtained from a

standard curve.

2.5 Stability studies[11]The promising formulation was tested for a period of

three months at 25C/60%RH and 40C/75%RH, for their

drug content and other parameters.

3. RESULTS AND DISCUSSION

3.1 Preformulation studies

The results of micrometric properties are presented in

Table 2. The flow property was found to be good in all the

formulation. In particular, F2A, F2B showed excellent flow

property. [12]. In case of bulk density and tapped density all

the formulation were within the range of 0.5-0.8g/dl.

Compressibility Index was found to be good in case of F1B,F2A F3A and fair in case of F1A, F2B and F3B. In case of

Hausners ratio, F1B, F2A and F3A had shown good and

F1A, F2B and F3B were fair compared to others.

3.2 Physical evaluation of tablets

The formulated floating tablets met the pharmacopoeial

requirement of uniformity of weight. All the tablet confirmed

to the requirement of assay as per I.P. Hardness, % Friability,

Thickness, Weight Variation and content uniformity were

within acceptable limit. Results are shown in the Table 3. It

was clear that weight variation holds good for all theformulations. The drug content was in the range of 99.42-

100.54 for all the six formulations. In case of Friability,

formulation F1A had very high % of friability than other

formulations. The moisture content was 1.20% and 1.30% in

case of F2A and F2B which is a problem in effervescent

dosage form .The reason for these variations is due to sugar

and dextrose used in the respective formulations. Drying time

for all the formulations is around 2h at 50C , in case of F2

A and F2B, it required more than 2h for the moisture content

to become less than 1% extending drying time lead to color

change .In case of F1A and F1B the moisture content was0.5%,and in case of F3Aand F3B it was 0.7%. In case of

hardness it was around 10-16Kp. F2A and F3A had

maximum hardness of 16KP and F1A had least hardness of

10Kp due to lack of binder. F3B had given good hardness of

14Kp after which Friability and moisture content were also in

the limit. The comparative study of hardness, moisture

content and friability for all the formulation are showed in

Fig.1.

The thickness of the tablet was between 5.6 and 6mm. All

the formulated tablets had 25mm diameter .The formulations

had pH of 6.8. The effervescent test was carried out in 200ml

water and all the formulations showed effervescence within

50 to 64 sec. The formulation F1B took maximum time of 64

sec to effervescence whereas the formulation F3B the least

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Table 2

Pre compression parameters of diclofenac potassium effervescent tablet blend

Sl. No Pre compression and post compression studies F1A F1B F2A F2B F3A F3B

1 Angle of repose() 31.96 32.15 29.62 29.62 31.51 31.08

2 Bulk density in g/mL 0.5 0.53 0.7 0.8 0.53 0.5

3 Tap density ing/mL 0.61 0.62 0.66 0.6 0.62 0.5

4 Compressibility index in % 17.94 14.28 14.94 18.91 13.11 16.365 Hausners ratio 1.21 1.167 1.16 1.233 1.15 1.19

Table 3

Post compression study of diclofenac potassium effervescent tablets

Sl No Pre compression and post compression studies F1A F1B F2A F2B F3A F3B

1 Weight variation in % 2.24 2.83 1.73 1.76 2.87 2.8

2 Content uniformity in % 99.70 100.25 99.42 100.5 99.85 100.5

3 Friability in % 1.16 0.24 0.12 0.2 0.1 0.24 Hardness in KP 10 12 16 15 16 14

5 Thickness of tablet in mm 5.6 5.9 5.9 6 5.9 5.96

6 Diameter of tablet in mm 25 25 25 25 25 257 CO2content in mg 262 261 262 260 260 261

8 Moisture content in % 0.50 0.5 1.2 1.3 0.7 0.7

9 pH 6.8 6.8 6.8 6.8 6.8 6.8

10 Disintegration time (900 mL water) in sec at 37C 43 54 45 48 48 4811 Effervescent time (200 mL water)in sec 52 64 51 51 52 50

Table 4

Stability data for F3B formulation

Sl No Post compression studiesof stability sample F3B

1 Month 2 Month 3 Month

25C/60%RH 40C /75%RH 25C/60%RH 40C /75%RH 25C/60%RH 40C /75%RH

1 Content uniformity 99.50% 100% 100.50% 99.70% 99.10% 99.60%

2 Friability 0.2 0.23 0.2 0.25 0.2 0.3

3 Hardness in Kp 14 14 14 13 14 134 CO2content in mg 260 260 260 256 2.58 253

5 Moisture content in % 0.7 0.75 0.7 0.8 0.7 0.8

6 pH 6.8 6.8 6.8 6.8 6.8 6.8

7 Disintegration time in sec 48 48 48 50 48 508 Effervescent time in sec 50 50 50 52 51 52

Table 5

Dissolution profile for stability sample (F3B)

Sl No. Time 1 month 2 month 3 month

%CDR

25C/60%RH

%CDR

40C /75%RH

%CDR

25C/60%RH

%CDR

40C /75%RH

%CDR

25C/60%RH

%CDR

40C /75%RH

1 0 0 0 0 0 0 0

2 5 100.2 99.7 100 100.2 100.1 99.6

3 10 100.5 100.1 100.5 100.3 100.3 100.34 15 100 99.5 100 99.6 100.1 100

5 30 99.8 99.3 99.5 99.2 99.6 99.3

50 sec. This may be due to absence of either Glycine

Arginine or EMIDEX in F1A, F1B. The disintegration test

was performed in 900 mL of water at 37C in these F3B had

taken less time to disintegrate, The formulation F1B had

taken maximum time to disintegrate it took 54 sec at 37C

and 62 sec at 25C whereas F1A and F2B took 52 sec and

F3A took 51 sec. In case of CO2 content F1A, F2A has

released maximum of 262mg. In F1B and F3B 261mg of CO2was released. The effervescent time, CO2 content,

disintegration time of all formulations is shown in Fig.2.

3.3 Invitro dissolution studies

The dissolution test was carried out in SIF without

enzymes, 0.1N HCl and pH4.8 acetate buffer. These revealed

the amount of drug absorbed from the released drug at

different pH conditions in the body. All the formulation had

given good release as shown in the figures. As all the

formulation had disintegration time less than 1 minimmediate release of drug was seen .The results were

compared with the marketed tablet SUPANAC (immediate

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tablet, based on this F3B formulation was selected as the best

formulation, and it was charged for stability studies.

3.4 Stability studiesF3B formulation was charged for stability studies at

25C/60%RH and 40C /75%RH. The results are presented

in Table 4 and 5. There were no significant changes in the

stability results of F3B formulation, content uniformity was

within the limits .In case of hardness and friability there was

no change in 25C/60%RH conditions. In case of 40C

/75%RH stability condition there was slight increase in the

friability and decrease in hardness due to the increase in

moisture content, but the changes were within the limits. No

major changes were seen in case of disintegration and

effervescent time. Release profile was similar as the initial

data in both 25C/60%RH, 40C /75%RH condition.

4. CONCLUSIONS

The diclofenac potassium effervescent tablets had been

prepared by wet granulation and direct compression method

with an objective to prevent the side effects like gastric ulcer

of normal conventional tablets of Diclofenac potassium. The

prepared effervescent formulation was thought to be patient

friendly in case of swallow ability and show better

therapeutic effect due to fast release compared to the

marketed tablets of diclofenac potassium.

After performing the precompatibility studies, acids like

(citric acid, tartaric acid), bases like (effersoda), buffers like

(sodium citrate, glycine, arginine), diluents like (mannitol,

sugar, dextrose and dextrates) were selected due to their

better drug - excipient compatability. With the aid of above

information many formulations had been prepared in these

F1A had failed in case of hardness, F1B had failed in case of

effervescent time, F2A and F2B had failed in case of

moisture content, F3 formulation had shown good results in

preformulation and post compression studies all the results.

Among all the formulations, F3 formulations were better in

all the terms of precompression and post compression

parameters. In F3 formulation there were F3A and F3B out of

which F3Awas prepared by wet granulation method which

had given good flow properties and post compression studies

all the parameters like hardness, friability, moisture content

and effervescent time were good.

F3B (composed of active dextrates (Emdex), citric acid

,tartaric acid, effersoda and arginine) which was prepared by

direct compression method had given good pre formulation

and post compression studies than F3A and it was charged

for stability studies and had given good stability data with

respect to all the evaluation parameters.

In conclusion F3B can be easily prepared on the

commercial scale. It had given better release profile

compared to the marketed immediate release tablets of

diclofenac potassium (Supanac 50 mg).

5. ACKNOWLEDGEMENT

Authors are thankful to Aptuit laurus Pvt Ltd and Senior

General Manager Sandeep Kachwaha for providing the

facilities (punching), drug and excipients for this researchproject.

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[6] Lachman, L., Lieberman, H.A., Kanig, J.L., The Theory and Practice ofIndustrial Pharmacy. 3rdMumbai: Vargheese Publishing House 1991.pp. 296-302.

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[8] Yanze, F.M., Duru., C., Jacob., M., Pharma Belg2000, 55, 53-56.[9] Basawaraj S. Patil,J Pharm Sci & Res 2011, 3, 1245-1252

[10] World Health Organisation Document., Revision of Monograph ofTablets., March 2011 QAS/09.324/Final

[11] Carstensen, J.T., Drug Stability: Principle and Practices, MarcelDekker, 2nd Edn., 1995, pp.538- 550.

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