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Int J Pharm Biomed Res 2011, 2(4), 237-243

International Journal of
PHARMACEUTICAL AND BIOMEDICAL RESEARCH ISSN No: 0976-0350

Research article

Formulation and evaluation of diclofenac potassium effervescent tablets

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 different formulations 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, CO2 content, effervescent time, particle size and in vitro dissolution 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 of diclofenac 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
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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 is adequately rapid. Water soluble lubricants are used to prevent an insoluble scum formation on water surface. To add

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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 in obviating 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 time and 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 various media and the best formulation was selected for further studies.

2. MATERIALS AND METHODS 2.1 Materials Diclofenac 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 method Accurately measured quantities of drug and excipients were taken as shown in Table 1. IPA was used as granulating agent 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 paperAluminum packing with LDP coating. 2.3 Preformulation studies 2.3.1 Angle of repose [5] The flow properties of granules (before compression) were characterized in terms of angle of repose, Carrs index and 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-1 of 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. Excess granules were removed using a spatula and the weight of the cylinder with pellets required for filling the cylinder volume

G. Rajalakshmi et al., Int J Pharm Biomed Res 2011, 2(4), 237-243 Table 1 Optimized formula for diclofenac potassium effervescent tablets 50mg Sl No 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Ingredients Diclofenac potassium B.P Effersoda Citric acid Tartaric acid Sodium citrate Glycine Arginine EMDEX Sugar Dextrose Mannitol Povidone K 30 sun set yellow lemon flavor org flavor Acesulfame K Aspartame Sucralose Total F1A 0.05 2.01 0.42 0.25 0.38 -----0.831 -0.001 -0.008 -0.05 -4 F1 B 0.05 1.98 0.25 0.44 0.58 -----0.641 -0.001 -0.008 -0.05 -4 F2 A 0.05 1.98 0.35 0.45 -0.3 --0.815 ---0.005 -0.04 --0.01 4 F2 B 0.05 1.98 0.41 0.39 -0.5 --0.641 --0.005 -0.004 --0.02 4 F3 A 0.05 1.98 0.3 0.48 --0.18 0.948 ----0.004 -0.008 --0.05 4

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F3 B 0.05 1.98 0.3 0.45 --0.4 0.765 ----0.005 0.005 0.005 0.02 -0.02 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. 2.4 Evaluation 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 vitro dissolution 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 of tablet 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 =

Initial wt. of tablets - Final wt. of tablets x100 Initial wt of tablets

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 that percentage. 2.4.5 CO2 content [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 0.45 membrane filter, diluted suitably and the absorbance of resultant solution was measured 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 =
V X F X 100 Weight of sample in mg

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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 0.45 membrane 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 contained for 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 suitable dilutions 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 was measured 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 the formulations. The drug content was in the range of 99.42100.54 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 was 0.5%,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

G. Rajalakshmi et al., Int J Pharm Biomed Res 2011, 2(4), 237-243 Table 2 Pre compression parameters of diclofenac potassium effervescent tablet blend Sl. No 1 2 3 4 5 Pre compression and post compression studies Angle of repose() Bulk density in g/mL Tap density ing/mL Compressibility index in % Hausners ratio F1A 31.96 0.5 0.61 17.94 1.21 F1B 32.15 0.53 0.62 14.28 1.167 F2A 29.62 0.7 0.66 14.94 1.16 F2B 29.62 0.8 0.6 18.91 1.233 F3A 31.51 0.53 0.62 13.11 1.15

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F3B 31.08 0.5 0.5 16.36 1.19

Table 3 Post compression study of diclofenac potassium effervescent tablets Sl No 1 2 3 4 5 6 7 8 9 10 11 Pre compression and post compression studies Weight variation in % Content uniformity in % Friability in % Hardness in KP Thickness of tablet in mm Diameter of tablet in mm CO2 content in mg Moisture content in % pH Disintegration time (900 mL water) in sec at 37C Effervescent time (200 mL water)in sec F 1A 2.24 99.70 1.16 10 5.6 25 262 0.50 6.8 43 52 F1 B 2.83 100.25 0.24 12 5.9 25 261 0.5 6.8 54 64 F2 A 1.73 99.42 0.12 16 5.9 25 262 1.2 6.8 45 51 F2 B 1.76 100.5 0.2 15 6 25 260 1.3 6.8 48 51 F3 A 2.87 99.85 0.1 16 5.9 25 260 0.7 6.8 48 52 F3 B 2.8 100.5 0.2 14 5.96 25 261 0.7 6.8 48 50

Table 4 Stability data for F3B formulation Sl No 1 2 3 4 5 6 7 8 Post compression studies of stability sample F3B Content uniformity Friability Hardness in Kp CO2 content in mg Moisture content in % pH Disintegration time in sec Effervescent time in sec 1 Month 25C/60%RH 99.50% 0.2 14 260 0.7 6.8 48 50 40C /75%RH 100% 0.23 14 260 0.75 6.8 48 50 2 Month 25C/60%RH 100.50% 0.2 14 260 0.7 6.8 48 50 40C /75%RH 99.70% 0.25 13 256 0.8 6.8 50 52 3 Month 25C/60%RH 99.10% 0.2 14 2.58 0.7 6.8 48 51 40C /75%RH 99.60% 0.3 13 253 0.8 6.8 50 52

Table 5 Dissolution profile for stability sample (F3B) Sl No. Time 1 month %CDR 25C/60%RH 0 100.2 100.5 100 99.8 %CDR 40C /75%RH 0 99.7 100.1 99.5 99.3 2 month %CDR 25C/60%RH 0 100 100.5 100 99.5 %CDR 40C /75%RH 0 100.2 100.3 99.6 99.2 3 month %CDR 25C/60%RH 0 100.1 100.3 100.1 99.6 %CDR 40C /75%RH 0 99.6 100.3 100 99.3

1 2 3 4 5

0 5 10 15 30

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 CO2 was 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 min immediate release of drug was seen .The results were compared with the marketed tablet SUPANAC (immediate

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F Fig.1. Comparativ ve study of hardn ness, moisture con ntent and friabilit ty of all the fo ormulations

Fig.5. Dis ssolution profile i in pH 6.8 SIF wit thout enzymes

F Fig.2. Comparativ ve study of efferv vescent time, CO2 content, disintegration time of all the formulations s

Fi ig.3. Dissolution profile p in 0.1NHC Cl pH1.2

Fig.4 4. Dissolution pro ofile in pH 4.5 acetate buffer

rel lease diclofen nac potassium m). In case of 0.1N 0 HCl (pH H 1.2) all l the formulation showed o only 10-12 % drug release at a this condition. The reason r for poo or drug release is due to the e poor solubility of the e drug in this medium. But when compa ared to the e Market tablet the release e was more du ue to neutraliz zation of f pH1.2 in th he effervescen nt formulation. The disso olution pro ofile 0.1 N HC Cl is shown in n Fig.3. In case of acetate buffe er pH 4.5 al ll the formulations showed 40-50% % of drug rele ease. But whe en compared to the Market tablet th he release wa as more due to t neutralizati ion of pH H 4.5 acetate buffer in the e effervescen nt formulation n. The dis ssolution prof file in pH 4.5 a acetate buffer is shown in Fig.4. F When the dissolution d is carried in pH H 6.8 SIF without w en nzymes, all th he formulatio on had given good release. As shown in Fig.5, , all the form mulations relea ased 98-100% % drug rel lease at this pH p condition due to the sol lubility of the e drug in this medium. . As SIF had given 100% drug release it i was sel lected as the e dissolution medium. Ma arketed Immediate rel lease diclofen nac potassium m 50mg tablet t (SUPANAC C) was compared with h all the fo ormulation, in n which pre epared rmulations had h shown ra apid release compared to o the for ma arketed table ets in all th he mediums. . Among al ll the for rmulations, its s F3 formulat tions were bet tter in all the terms of f precompression and post compression parameters. In F3 for rmulations the ere were F3A A and F3B out of which F3A A was pre epared by we et granulation n method whic ch had given good flo ow properties and post compression n studies al ll the pa arameters like e hardness, f friability, moi isture conten nt and eff fervescent tim me were good. F3B (compo osed of active dextrates (E Emdex), citricacid, tar rtaric acid, eff ffersoda and a arginine) whic ch was prepar red by dir rect compress sion method h had given goo od pre formu ulation an nd post compr ression studies s as F3A. Eve en the drug re elease in the medium SIF S pH6.8 wi ithout enzyme es was 99.2% when compared to F3 3A (98.7%) an nd marketed tablet (98%). It I was pre epared by dir rect compress sion method, which reduce es the ste ep of granula ation prevent t the drying time, spray dried (E EMDEX) used d had given good flow properties al ll the pa arameters such h as hardne ess ,friability ,moisture co ontent, eff fervescence ti ime and disin ntegration tim me were withi in the sel lected range. It had all the qualities of a good efferve escent

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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 studies F3B 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 research project. REFERENCES
[1] Leon Lachman, Herbert Liberman, Joseph L. Kanig, in: Theory and Practice of Industrial Pharmacy, 2nd Edn. Varghese Publication, 1985. [2] Mohrle, R., in: Liberman, Lachman L. Schwartz. Pharmaceutical Dosage Form, Vol 1, Marcel Decker Inc., New York, 2005, pp. 285292. [3] Richard B Lipton, Brian, Richard, P., Sage Journals Online, 2010, 30, 1336-1346 [4] Terhaag, B., Hoffmann, A., Barkworth, M., Int J Clin Pharmacol Ther., 2000, 38, 546-551. [5] Gunn, C. Carter, S.J., Ed. Tutorial Pharmacy, CBS Publishers and Distributors, 1986, pp. 211-233. [6] Lachman, L., Lieberman, H.A., Kanig, J.L., The Theory and Practice of Industrial Pharmacy. 3rd Mumbai: Vargheese Publishing House 1991. pp. 296-302. [7] Indian Pharmacopoeia, Government of India Ministry of Health and Family Welfare. Delhi: Controller of Publications 1996, 2, pp. 182. [8] Yanze, F.M., Duru., C., Jacob., M., Pharma Belg 2000, 55, 53-56. [9] Basawaraj S. Patil, J Pharm Sci & Res 2011, 3, 1245-1252 [10] World Health Organisation Document., Revision of Monograph of Tablets., March 2011 QAS/09.324/Final [11] Carstensen, J.T., Drug Stability: Principle and Practices, Marcel Dekker, 2nd Edn., 1995, pp.538- 550. [12] USP (30), 2007 The United States Pharmacopeial convention, Twin brook park way, Rockville MD 20852, 2, 12601.