Formulation and evaluation of diclofenac ... - PharmSciDirect

Available online atwww.pharmscidirect.comInt J Pharm Biomed Res 2011, 2(4), 237-243Research articleInternational Journal ofPHARMACEUTICALAND BIOMEDICALRESEARCHISSN No: 0976-0350Formulation and evaluation of diclofenac potassium effervescent tabletsG. Rajalakshmi*, C.H. Vamsi, R. Balachandar, N. DamodharanDepartment of Pharmaceutics, SRM College of Pharmacy, SRM University, Kattankulathur, Tamil Nadu, India, 603 203Received: 18 Oct 2011 / Revised: 28 Oct 2011 / Accepted: 03 Nov 2011 / Online publication: 15 Nov 2011ABSTRACTIn 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. Theprepared tablets were evaluated for various pre compression characteristics (like angle of repose, bulk density, tappeddensity, cars index and hausner’s ratio) and post compression characteristics (like weight variation, hardness friability ,drugcontent, disintegration, CO 2 content, effervescent time, particle size and in vitro dissolution studies). The dissolution test wascarried out in SIF without enzymes, 0.1N HCl and pH 4.8 acetate buffer. Among all the formulations, its F3 formulationswere better in all the terms of precompression and post compression parameters. In F3 formulations, F3A (by directcompression) 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 drugrelease in the medium SIF pH6.8 without enzymes was 99.2% when compared to F3A (98.7%) and marketed tablet (98%).Ithad all the qualities of a good effervescent tablet, based on this F3B formulation was selected as the best formulation, and itwas charged for stability studies. It had given better release profile in all the mediums when compared to marketedconventional 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 effectsof normal tablets.Key words: EMDEX, Effersoda, Wet granulation, Direct compression, Hausner’s ratio, Effervescent time, SIF.1. INTRODUCTIONThe oral dosage forms are the most popular way of takingmedication despite having some disadvantages like slowabsorption and thus onset of action is prolong. This can beovercome by administrating the drug in liquid from but,many APIs have limited level of stability in liquid form. Forachieving a prolonged and predictable drug delivery profilein the gastrointestinal tract is to control the gastric residencetime using a gastro retentive dosage forms that will provideas with new and important therapeutic options. The design oforal controlled drug delivery system primarily is aimed atachieving more predictable and increase availability of drugs.However, the development process is precluded by severalphysiological difficulties such as inability to restrain and*Corresponding Author. Tel: 044 27453160, Fax:Email: rajalakshmig67@gmail.com©2011 PharmSciDirect Publications. All rights reserved.locates the controlled drug delivery system within the desiredregion of gastrointestinal tract due to the variable gastricemptying and motility [1]. So, effervescent tablets acts as analternative dosage form. The tablet is added into a glass ofwater just before administration and the drug solution ordispersion is to be drunk immediately. The tablet is quicklybroken apart by internal liberation of CO2 in water due tointeraction between tartaric acid and citric acid with alkalimetal carbonates or bicarbonates in presence of water.Due to liberation in CO 2 gas, the dissolution of API inwater as well as taste masking effect is enhanced. Theadvantages of effervescent tablets compared with other oraldosage forms includes an opportunity for formulator toimprove taste, a more gentle action on patient’s stomach andmarketing aspects. To manufacture these tablets, either wetfusion or heat fusion is adopted. The tablets are compressedsoft enough to produce an effervescent reaction that isadequately rapid. Water soluble lubricants are used to preventan insoluble scum formation on water surface. To add

G. Rajalakshmi et al., Int J Pharm Biomed Res 2011, 2(4), 237-243 238sweetness to the formulation, saccharin is added sincesucrose is hygroscopic and add too much of bulk to the tablet.The manufacturing shall be done under controlled climaticcondition to avoid effervescent reaction. The packaging isdone under 25% RH at 25ºC. Hands of the consumers andatmospheric moisture after opening the container can alsoresult in loss of product quality. The most commonly usedeffervescent tablet today is aspirin tablet [2].In the present study, the design of an oral effervescenttablet of Diclofenac potassium was carried out. DiclofenacPotassium is a nonsteroidal anti-inflammatory drug (NSAID)that exhibits anti-inflammatory, analgesic, and antipyreticactivities. It is used for treatment of primary dysmenorrhea,for relief of mild to moderate pain, for relief of the signs andsymptoms of osteoarthritis and rheumatoid arthritis.[Mylandrugs.com] The main objective of this work was to formulateand evaluate Diclofenac potassium effervescent tablets byusing different ratios of carbonates and acids by wetgranulation and direct compression method that helps inobviating the demerits of slow release and slow absorption,gastrointestinal side effects of normal tablets of Diclofenacpotassium and to increase the release and immediate effect.Richard B Lipton [3] had worked on diclofenac potassiumoral solution seen that this diclofenac potassium has givengood therapeutic effect in the solution form, Wildgrubehj andTerhaag B[4] had also worked on the effect of effervescenttablets of Diclofenac sodium and shown that the gastrointestinal side effects are reduced when compared to thenormal tablets of diclofenac . Different carbonates ,acids andbuffers were used to attain good effervescence in short timeand to obtain a clear solution , and to give maximumtherapeutic effect in short span of time when taken orally,Diclofenac potassium is a weak acidic it gets ionized in thestomach due to the neutralization capacity of the effervescentsolution stomach pH increases and it is in the ionized formand gets absorbed. As the stomach pH starts to decrease itgets absorbed through the permeation from the stomach wallsin the unionized form, CO 2 released also helps in thepermeation of the drug .In case of normal tablets they remainunionized in the stomach and absorb only through permeationnot through solubility as they are in the unionized form. Incase of effervescent tablets due to the initial raise of pH in thestomach that help in the solubility of the drug and convertsthe drug to ionized form, as the pH decreases again due to theacids in the stomach the drug gets converted to unionizedform and get absorbed through the permeation and CO 2released helps in better permeation. These dosage formprocess helps the drug to show better therapeutic effectcompared to the normal tablets.An attempt was made to formulate effervescent tablet ofdiclofenac potassium using different carbonates and acids bywet granulation and direct compression method. Theprepared tablets were subjected to dissolution in variousmedia and the best formulation was selected for furtherstudies.2. MATERIALS AND METHODS2.1 MaterialsDiclofenac potassium (Aptuit laurus Pvt Ltd) and allexcipients used were of analytical grade from S.D finechemicals and few as gift sample from Aptuit laurus Pvt Ltd.All the instruments used for Preformulation study were fromElectrolab. All the glass wares used were of borosilicate,Tablet compression machine was of Cadmach, Dissolutionapparatus USP type 2 was of Electrolab, UVspectrophotometer was of PerkinElmer .EntirePreformulation and post compression was performed in40%RH to prevent moisture uptake from the atmosphere.2.2 Wet granulation and direct compression methodAccurately measured quantities of drug and excipientswere taken as shown in Table 1. IPA was used as granulatingagent in case of wet granulation process. Mixture of drug andexcipients were taken for granulation. IPA was added untilwet mass was formed and passed through 20# to get therequired granules, Granules formed through wet granulationwere dried in oven till the moisture content was below1%.Then the above dried granules were taken in to ‘v’ coneblender and flavor was added to it and blend for 15 min. Theformulation, F3B alone was done by direct compressionmethod. No granules were prepared in this case. Mixture ofdrug and excipients were passed through 40# and were takenin to ‘v’ cone blender and flavor was added to it and blendfor 15 min and taken for compression. The tablets werepunched using Rotary compression machine (jaugur) of 25mm punch. These compressed tablets were transferred in topacking 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, Carr’s indexand Hausner’s ratio. For determination of angle of repose (θ),the granules were poured through the walls of a funnel,which was fixed at a position such that its lower tip was ataheight of exactly 2.0cm above hard surface. The granuleswere poured till the time when upper tip of the pile surfacetouched the lower tip of the funnel. The tan -1 θ of the (heightof the pile / radius of its base) gave the angle of repose.2.3.2 Bulk and tapped densityGranules were poured gently through a glass funnel into agraduated cylinder cut exactly to 10 mL mark. Excessgranules were removed using a spatula and the weight of thecylinder with pellets required for filling the cylinder volume

G. Rajalakshmi et al., Int J Pharm Biomed Res 2011, 2(4), 237-243 239Table 1Optimized formula for diclofenac potassium effervescent tablets 50mgSl No Ingredients F 1 A F 1 B F 2 A F 2 B F 3 A F 3 B1 Diclofenac potassium B.P 0.05 0.05 0.05 0.05 0.05 0.052 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 0.34 Tartaric acid 0.25 0.44 0.45 0.39 0.48 0.455 Sodium citrate 0.38 0.58 -- -- -- --6 Glycine -- -- 0.3 0.5 -- --7 Arginine -- -- -- -- 0.18 0.48 EMDEX -- -- -- -- 0.948 0.7659 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 0.00514 lemon flavor -- -- -- -- -- 0.00515 org flavor 0.008 0.008 0.04 0.004 0.008 0.00516 Acesulfame K -- -- -- -- -- 0.0217 Aspartame 0.05 0.05 -- -- -- --18 Sucralose -- -- 0.01 0.02 0.05 0.02Total 4 4 4 4 4 4was calculated. The cylinder was then tapped from a heightof 2 cm until the time when there was no more decrease inthe volume. Bulk density and tapped density were calculated.Hausner’s ratio and Carr’s index were calculated.2.4 Evaluation of effervescent tablets [6]The prepared diclofenac potassium effervescent tabletswere evaluated for uniformity of weight using 20 tablets,hardness and friability using 10 tablets, drug content,disintegration, CO 2 content, particle size and in vitrodissolution studies.2.4.1 Tablet hardnessThe resistance of tablet for shipping or breakage, underconditions of storage, transportation and Handling, beforeusage, depends on its hardness. The hardness of tablet of eachformulation was measured by using Pfizer hardness tester.2.4.2 Tablet thicknessThickness of tablets was important for uniformity oftablet size. Thickness was measured by using screw gauze on3 randomly selected samples.2.4.3 FriabilityFriability is the measure of tablet strength. RocheFriabilator was used for testing the friability using thefollowing procedure. Twenty tablets were weighed accuratelyand placed in the plastic chamber that revolves at 25 rpm for4 minutes dropping the tablets through a distance of sixinches with each revolution. After 100 revolutions the tabletswere reweighed and the percentage loss in tablet weight wasdetermined.Initial wt.of tablets-Final wt.of tablets% loss = x 100Initial wt of tablets2.4.4 Weight variation [7]Twenty tablets were weighed individually and the averageweight was determined. Then percentage deviation from theaverage weight was calculated. According to IP standards,not more than two of the individual weight deviates from theaverage weight by more than the percentage shown in the(Table 3) and none deviates by more than twice thatpercentage.2.4.5 CO 2 content [8]Tablet was placed in 100 mL of 10%sulphuric acidsolution, difference in weight after and before was calculatedthe resulted weight was the amount of CO 2 released. Thedrug content in each formulation was determined by 20tablets and powder equivalent to average weight was addedin 100 mL of methanol, followed by stirring for 30 min. Thesolution was filtered through a 0.45μ membrane filter, dilutedsuitably and the absorbance of resultant solution wasmeasured spectrophotometrically at 276 nm using methanolas blank.2.4.6 Moisture contentTake around 50 mL of methanol in titration vessel of KarlFischer titrator and titrate with Karl Fischer reagent to endpoint. In a dry mortar grind the pellets to fine powder .Weighaccurately about 0.5 g of the sample, transfer quickly to thetitration vessel, stir to dissolve and titrate with Karl Fischerreagent to end point.Moisture content =V X F X100Weight of sample in mg

G. Rajalakshmi et al., Int J Pharm Biomed Res 2011, 2(4), 237-243 240where, F= factor of Karl Fischer reagent, V=volume in mL ofKarl Fischer reagent consumed for sample titration.2.4.7 Drug contentTablet was placed in 100 mL of 10%sulphuric acidsolution, difference in weight after and before was calculatedthe resulted weight was the amount of CO 2 released. Thedrug content in each formulation was determined by 20tablets and powder equivalent to average weight was addedin 100 mL of methanol, followed by stirring for 30 min. Thesolution was filtered through a 0.45μ membrane filter, dilutedsuitably and the absorbance of resultant solution wasmeasured spectrophotometrically at 276nm using methanol asblank.2.4.8 Content uniformityIn 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 unitoutside the range of 85 to 115% of the label claim and nounits is outside 75 to 125% or if RSD>6% or if bothconditions prevail, test 20 additional units.2.4.9 Disintegration testIt was performed in disintegration apparatus at 300Ctemperature and time was noted. Place one tablet into eachtube and suspend the assembly in to the 1000 mL beakercontaining water maintained at 37±2°C, 25±2°C and operatethe apparatus. Remove the assembly form the liquid. Observethe tablets, if one or two tablets fail to disintegratecompletely; repeat the test on 12 additional tablets. Therequirement is met if not less than 16 of the total of 18 tabletstested are disintegrated [9,10].2.4.10 Invitro release studiesThe dissolution test was carried out in SIF withoutenzymes, 0.1N HCl, and 4.8 pH acetate buffer. Samples weretaken at predetermined time intervals and after suitabledilutions absorbance were measured with the help of UVspectrophotometer at 276 nm and the percentage drugreleased at various time intervals were calculated. The releaserate of diclofenac potassium from tablets was determinedusing United States Pharmacopeia (USP) Dissolution TestingApparatus 2. The dissolution test was performed using 900mL of 0.1N HCl, 4.5 acetate buffer, 6.8 SIF at 37±0.5°C and50 rpm. A sample (10 mL) of the solution was withdrawnfrom the dissolution apparatus hourly and the samples wereplaced with fresh dissolution medium. The samples werefiltered through a 0.45μ membrane filter and diluted to asuitable concentration. Absorbance of these solutions wasmeasured at 265 nm using spectrophotometrically at 276nmusing respective buffer as blank. Cumulative percentage drugrelease was calculated using an equation obtained from astandard curve.2.5 Stability studies[11]The promising formulation was tested for a period ofthree months at 25°C/60%RH and 40°C/75%RH, for theirdrug content and other parameters.3. RESULTS AND DISCUSSION3.1 Preformulation studiesThe results of micrometric properties are presented inTable 2. The flow property was found to be good in all theformulation. In particular, F2A, F2B showed excellent flowproperty. [12]. In case of bulk density and tapped density allthe 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 ofHausner’s ratio, F1B, F2A and F3A had shown good andF1A, F2B and F3B were fair compared to others.3.2 Physical evaluation of tabletsThe formulated floating tablets met the pharmacopoeialrequirement of uniformity of weight. All the tablet confirmedto the requirement of assay as per I.P. Hardness, % Friability,Thickness, Weight Variation and content uniformity werewithin acceptable limit. Results are shown in the Table 3. Itwas 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 otherformulations. The moisture content was 1.20% and 1.30% incase of F2A and F2B which is a problem in effervescentdosage form .The reason for these variations is due to sugarand dextrose used in the respective formulations. Drying timefor all the formulations is around 2h at 50°C , in case of F2A and F2B, it required more than 2h for the moisture contentto become less than 1% extending drying time lead to colorchange .In case of F1A and F1B the moisture content was0.5%,and in case of F3Aand F3B it was 0.7%. In case ofhardness it was around 10-16Kp. F2A and F3A hadmaximum hardness of 16KP and F1A had least hardness of10Kp due to lack of binder. F3B had given good hardness of14Kp after which Friability and moisture content were also inthe limit. The comparative study of hardness, moisturecontent and friability for all the formulation are showed inFig.1.The thickness of the tablet was between 5.6 and 6mm. Allthe formulated tablets had 25mm diameter .The formulationshad pH of 6.8. The effervescent test was carried out in 200mlwater and all the formulations showed effervescence within50 to 64 sec. The formulation F1B took maximum time of 64sec to effervescence whereas the formulation F3B the least

G. Rajalakshmi et al., Int J Pharm Biomed Res 2011, 2(4), 237-243 241Table 2Pre compression parameters of diclofenac potassium effervescent tablet blendSl. No Pre compression and post compression studies F1A F1B F2A F2B F3A F3B1 Angle of repose(Ø) 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 0.53 Tap density ing/mL 0.61 0.62 0.66 0.6 0.62 0.54 Compressibility index in % 17.94 14.28 14.94 18.91 13.11 16.365 Hausner’s ratio 1.21 1.167 1.16 1.233 1.15 1.19Table 3Post compression study of diclofenac potassium effervescent tabletsSl No Pre compression and post compression studies F 1 A F 1 B F 2 A F 2 B F 3 A F 3 B1 Weight variation in % 2.24 2.83 1.73 1.76 2.87 2.82 Content uniformity in % 99.70 100.25 99.42 100.5 99.85 100.53 Friability in % 1.16 0.24 0.12 0.2 0.1 0.24 Hardness in KP 10 12 16 15 16 145 Thickness of tablet in mm 5.6 5.9 5.9 6 5.9 5.966 Diameter of tablet in mm 25 25 25 25 25 257 CO 2 content in mg 262 261 262 260 260 2618 Moisture content in % 0.50 0.5 1.2 1.3 0.7 0.79 pH 6.8 6.8 6.8 6.8 6.8 6.810 Disintegration time (900 mL water) in sec at 37°C 43 54 45 48 48 4811 Effervescent time (200 mL water)in sec 52 64 51 51 52 50Table 4Stability data for F3B formulationSl No Post compression studiesof stability sample F3B1 Month 2 Month 3 Month25°C/60%RH 40°C /75%RH 25°C/60%RH 40°C /75%RH 25°C/60%RH 40°C /75%RH1 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 0.33 Hardness in Kp 14 14 14 13 14 134 CO 2 content in mg 260 260 260 256 2.58 2535 Moisture content in % 0.7 0.75 0.7 0.8 0.7 0.86 pH 6.8 6.8 6.8 6.8 6.8 6.87 Disintegration time in sec 48 48 48 50 48 508 Effervescent time in sec 50 50 50 52 51 52Table 5Dissolution profile for stability sample (F 3 B)Sl No. Time 1 month 2 month 3 month%CDR25°C/60%RH%CDR40°C /75%RH%CDR25°C/60%RH%CDR40°C /75%RH%CDR25°C/60%RH1 0 0 0 0 0 0 02 5 100.2 99.7 100 100.2 100.1 99.63 10 100.5 100.1 100.5 100.3 100.3 100.34 15 100 99.5 100 99.6 100.1 1005 30 99.8 99.3 99.5 99.2 99.6 99.3%CDR40°C /75%RH50 sec. This may be due to absence of either GlycineArginine or EMIDEX in F1A, F1B. The disintegration testwas performed in 900 mL of water at 37°C in these F3B hadtaken less time to disintegrate, The formulation F1B hadtaken maximum time to disintegrate it took 54 sec at 37°Cand 62 sec at 25°C whereas F1A and F2B took 52 sec andF3A took 51 sec. In case of CO 2 content F1A, F2A hasreleased maximum of 262mg. In F1B and F3B 261mg of CO 2was released. The effervescent time, CO 2 content,disintegration time of all formulations is shown in Fig.2.3.3 Invitro dissolution studiesThe dissolution test was carried out in SIF withoutenzymes, 0.1N HCl and pH4.8 acetate buffer. These revealedthe amount of drug absorbed from the released drug atdifferent pH conditions in the body. All the formulation hadgiven good release as shown in the figures. As all theformulation had disintegration time less than 1 minimmediate release of drug was seen .The results werecompared with the marketed tablet SUPANAC (immediate

G. Rajalakshmi et al., Int J Pharm Biomed Res 2011, 2(4), 237-243242Fig.1. Comparative study of hardness, moisture content and friability of allthe formulationsFig.5. Dissolution profile in pH 6.8 SIF without enzymesFig.2. Comparative study of effervescent time, CO2 content, disintegrationtime of all the formulationsFig.3. Dissolution profile in 0.1NHCl pH1.2Fig.4. Dissolution profile in pH 4.5 acetate bufferrelease diclofenac potassium). In case of 0.1N HCl (pH1.2)alll the formulation showed only 10-12 % drug release at thiscondition. The reason for poor drug release is due to thepoorsolubility of thedrug in this medium. But when compared totheMarket tablet the releasee was more due to neutralizationofpH1.2 in the effervescent formulation. The dissolutionprofile 0.1 N HCl is shown inFig.3.In case of acetate buffer pH 4.5 all the formulationsshowed 40-50%of drug release. But when compared to theMarket tablet the release was more due to neutralization ofpH4.5 acetate buffer in theeffervescent formulation. Thedissolution profile in pH 4.5 acetate buffer is shown in Fig.4.When the dissolution is carried in pH6.8 SIF withoutenzymes, all the formulation had given good release. Asshown in Fig.5,all the formulations released 98-100%drugrelease at this pH condition due to the solubility of thedrugin this medium.As SIF had given 100% drug release it wasselected as thedissolution medium. Marketed Immediaterelease diclofenac potassium50mg tablett (SUPANAC) wascompared withall the formulation, inwhich preparedformulations had shown rapid release compared tothemarketed tablets in all the mediums.Among all theformulations, itsF3 formulations were better in all the termsofprecompression and post compression parameters. In F3formulations there were F3Aand F3B out of which F3Awasprepared by wet granulationn method which had given goodflow properties and post compressionstudies all theparameters likehardness, friability, moisture contenandeffervescent time were good.F3B (composed of active dextrates (Emdex), citricacid,tartaric acid, effersoda and arginine) which was prepared bydirect compression method had given good pre formulationand post compression studiess as F3A. Even the drug releasein the medium SIF pH6.8 without enzymes was 99.2% whencompared to F3A (98.7%) and marketed tablet (98%). It wasprepared by direct compression method, which reduces thestep of granulation preventthe drying time, spray dried(EMDEX) usedhad given good flow properties all theparameters suchas hardness ,friability ,moisture content,effervescence time and disintegration time were within theselected range. It had all the qualities of a good effervescent