International Journal of Pharmacy and Pharmaceutical Sciences

ISSN- 0975-1491 Vol 2, Suppl 3, 2010

ResearchArticle

COMPARATIVEEVALUATIONOFNATURALANDSYNTHETICSUPERDISINTEGRANTFOR PROMOTINGNIMESULIDEDISSOLUTIONFORFASTDISSOLVINGTECHNOLOGY
KALPESHK.MEHTA1*,HETULH.PATEL2,NITIND.PATEL1,CHINTANN.VORA1,N.J.PATEL1
1

DepartmentofPharmaceuticsandPharmaceuticalTechnology,S.K.PatelCollegeofPharmaceuticalEducationandResearch,Ganpat University,Kherva382711,Mehsana,Gujarat,India,2ShreeSwaminarayanPharmacyCollege,Kevadiacolony,Narmada,Gujarat. Email:kk30180@yahoo.com,nd121185@rediffmail.com Received:10April2010,RevisedandAccepted:29April2010

ABSTRACT ThepurposeofthisresearchwastodevelopfastdissolvingtabletsofNimesulidecontainingnaturalLepidiumsativum(family:Cruciferae)knownas asaliyo and widely used as herbal medicine and pharmaceutical excipient as disintegrating agent. The mucilage was extracted from seeds of Lepidiumsativumandwas usedtodevelop thefast dissolvingtabletofNimesulide.TheextractedmucilagewascharacterizedforWeight losson drying,Particlesize,pHofsolution,Swellingratio,Bulkandtappeddensity,Compressibilityindex,ViscosityandAngleofrepose.Thedisintegration propertyofextractedmucilageinFDTswascomparedwithwidelyusedsuperdisintegrantslikeSodiumstarchglycolate(SSG),KyronT314,AcDi Sol. The prepared FDTs were evaluated for Uniformity of weight, Hardness, Tablet thickness, Percentage friability, Wetting time, Invitro disintegration time and Invitro dissolution. From the study, it was concluded that higher dissolution of tablet could be obtained when mucilage concentrationis10%andalsothemannitolconcentrationwas10%.Promisingbatch(M5)exhibitedbetterdrugdissolution(79.9%)after30min thantheothertablets.ThedisintegrationandmeandissolutiontimeforbatchM5 was17secand5.27secrespectivelyisbetterthanothertablet preparedfromothersyntheticdisintegratingagent. Keywords:Lepidiumsativum,Nimesulide,KyronT314,FDT INTRODUCTION Nowadaysfastdissolvingtechnologyhasaniceapplicabilityincase of patient care. Because this type of formulation can disintegrate withinfewsecondsandreleasetheiractiveingredientveryfastand onset of action can be achieved in few minutes. Mostly superdisintegrants are added to the formulations to break up the tablet into small particle that can rapidly dissolve. Many synthetic substanceslikeSodiumStarchGlycolate,AcdiSol,Crossprovidone, and Kyron T314 have been used as a disintegrating agent in the tabletformulation.1Mucilageandgumshavebeenusedsinceancient times for their medicinal uses. In the modern era also they are widely used in the pharmaceutical industries as thickeners, water retention agents, emulsion stabilizers, suspending agents, binders and film formers. Apart from its use in finished medicines, newer uses have been found in the preparation of cosmetics, textiles, and paint paper. Mucilage of natural origin is preferred over synthetic and semisynthetic agent because they are cheaper, abundantly available, nontoxic and nonirritating in nature. Lepidium sativum (family:Cruciferae)isknownasasaliyoandiswidelyusedasherbal medicineinIndia.Itiswidelyavailableinmarketandhasverylow cost.Partsusedareleaves,root,oil,seedsetc.Seedscontainhigher amount of mucilage, dimeric imidazole alkaloids lepidine B, C, D, E andFandtwonewmonomericimidazolealkaloidssemilepidinoside AandB.MucilageofLepidiumsativumhasvariouscharacteristiclike binding, disintegrating, gelling etc.2 Hence in the present study, a methodisdevelopedtoisolatethemucilagefromseedsandits use todevelopthefastdissolvingtablet.Thedisintegration propertyof FDTs was compared with widely used superdisintegrants like Sodium starch glycolate (SSG), Kyron T314, Ac Di Sol. Nimesulide, chemically 4'nitro2'phenoxy methane sulfonanilide, is a weakly acidic nonsteroidal antiinflammatory drug falls under BCS class II drug , is selected as a model drug as it is widely used in the treatment of the management of a variety of painful and inflammatory conditions like post operative pain, primary dysmenorrhea and painful osteoarthritis. It shows high anti inflammatory,antipyretic,andanalgesicactivitiesinadditiontolow toxicity, a moderate incidence of gastric side effects, and a high therapeuticindex.310 MATERIALS Nimesulide (4'nitro2'phenoxy methane sulfonanilide) was gifted from Texas Laboratories Mehsana, Gujarat. Acdisol and SSG were supplied by Lincoln Pharmaceutical Ltd, Ahmedabad. Lepidium sativum seed was obtained from local market Mehsana. All other ingredientswereusedofanalyticalgrade. METHODS MethodologyforextractionofmucilageLepidiumsativum11 The seeds of Lepidium sativum contain the mucilage around the outer layer. The major problem in isolation of mucilage is that it swellsbutdoesnotseparatefromtheseeds.Becauseofthis,general methodsofseparationofmucilagearenotapplicabletoseparatethe seed mucilage and hence, different procedures were tried for the separationofmucilage. MethodA In first method (method A) the seeds (100 g) were boiled with distilled water (1 litre) for 15 minute and the mass was filtered throughBucknerfunnelwithoutfilterpaper.Theretainedresidues were boiled with distilled water (0.5 litre) for 15 minute and the combinedliquidwaspassedthrougheightfoldsofmuslincloth.The mucilage was precipitated from the filtrate by adding ethanol. The precipitated mucilage was dried in an oven at 450C till it was completelydried.Thepowderwaspassedthrough80#meshsieve andweighedtocalculatetheyield. MethodB Inthesecondmethod(methodB)theseeds(100g)weresoakedfor 12 hour in distilled water (1litre) and then added to a blender to separatemucilagefromseeds.Afterblendingfor15minutethemass was passed through eight folds of muslin cloth. The mucilage was precipitated from the filtrate by adding 1 liter of acetone. The powder was passed through 80 # mesh sieve and weighed to calculatetheyieldafterdryingat450Cfor6h. MethodC In third method (method C) the seeds (100 g) were soaked for 12 hourindistilledwater(1litre)andcrushedinblenderfor15minute. Thedispersionwasboiledfor30minutesandthemasswaspassed through eight folds of muslin cloth. The mucilage was precipitated fromthefiltratebyaddingacetone.Thepowderwaspassedthrough 80#meshsieveandweighedtocalculatetheyieldafterdryingat45oC for6hour.

K.Mehtaetal. IntJPharmacyandPharmSci,Vol2,Issue3,102108 Characterizationofmucilage2 ChemicalcharacterizationofLepidiumsativummucilage Thepresenceofmucilageinextractedmaterialwasconfirmedusing Molisch'stestandbytreatmentwithrutheniumred. PhysicochemicalcharacterizationofLepidiumsativummucilage Weightlossondrying:Weightlossondryingwasdeterminedforan appropriatequantityofmucilageat105Cfor2hourandpercentage lossofmoistureondryingwascalculatedusingtheformula. LOD(%)=(Weightofwaterinsample/Weightofdrysample)100 Particle size: The particle size of the driedpowder mucilage was determined by the microscopic method, and the study was carried outintriplicate. pH ofsolution: ThepH of the0.5%solution was measured with a pHmeter. Charring: A few milligrams of dried mucilage were placed in a meltingpoint apparatus. The temperature was taken and recorded whenthematerialstartedtochar. Swellingratio:Thestudywascarriedoutusinga100mlstoppered graduated cylinder. The initial bulk volume of 1 gm of dried mucilage was recorded. Water was added in sufficient quantity to yield 100 ml of a uniform dispersion. The sediment volume of the swollen mass was measured after 24 hour, stored at room temperature.Theswellingratiowascalculatedbytakingtheratioof theswollenvolumetotheinitialbulkvolume. Bulk and tapped density: A Preweighted, presieved quantity of dried mucilage was poured into a graduated cylinder, and the volume recorded. The cylinder was tapped until the powderbed volume reached a minimum value, and the tapped volume was recorded.Thebulkandtappeddensitieswerecalculated. Bulkdensity=Mass/Bulkvolume; Tappeddensity=Mass/Tappedvolume Compressibility Index: Compressibility index gives the important property of granules. It is also known as Carrs index. It can be calculated by following equation: It is a simple test to evaluate the LBDandTBDofapowderandtherateatwhichitpackeddown.The formulaforCarrsIndexisasbelow:19 CarrsIndex(%)=[(TBDLBD)x100]/TBD Viscosity: Rheological studies of dried mucilage were carried out using varying concentrations (0.10.5% w/v) prepared in distilled water.TheviscositiesweremeasuredusingaBrookfieldviscometer. Table1:Formulationforoptimizationofmannitolasasolubilizingagent Drug MCC Mannitol(%) SSG(%) MgStearate Talc TotalWeight *Allquantityinmg. PM0 100 129.5 0 5 3 5 250 PM1 100 117 5 5 3 5 250 PM2 100 104.5 10 5 3 5 250 PM3 100 92 15 5 3 5 250 PM4 100 79.5 20 5 3 5 250 AngleofRepose:Thefixedfunnelandfreestandingconemethods employafunnelthatissecuredwithitstipatgivenheight,H,which waskept2cm,abovegraphpaperthatisplacedonaflathorizontal surface.Withr,beingtheradiusofbaseofconicalpile,
ta n = h / r

Differential scanning calorimetry (DSC) studies: DSC study was carried out using DSCTA60 instrument (M/s Shimadzu, Japan) to check the compatibility of ingredients. DSC thermograms of pure drug (Nimesulide), Mucilage (Lepidium sativum) were individually taken for their identical endothermic reaction. Finally physical mixtureofallaboveingredientswasscannedforDSC. Fourier transforms infrared (FTIR) spectral studies: Fourier transform infrared (FTIR) spectral data were taken on a Shimadzu (model FTIR8300) instrument to find out chemical stability of the excipients. FTIR spectra of pure drug, mucilage and mixture were obtained.Allthesampleswerecrushedwithpotassium bromideto get pellets at 1 ton/cm2. Spectral scanning was done in the range between4000400cm1. Preparationoffastdissolvingnimesulidetablets12 Different fast dissolving tablet formulations were prepared by directcompressionmethod. All the powders were passed through 80 # sieve to decrease the particle size. Required quantity of drug and excipients mixed thoroughly. The blend was compressed using Rotary Tablet Machine12Station.Eachtabletcontained100mgofNimesulideand otherpharmaceuticalingredients. Formulation for optimization of mannitol as a solubilizing agent Compositionforoptimizationofmannitolasasolubilizingagentfor fastdissolvingformulationisshowninTable1. Formulationofpreliminarytrialbatchestochecktheactivityof mucilageasdisintegratingagent13 Composition of preliminary trials batches to check the activity of mucilageasdisintegratingagentisshowninTable2. Optimization of mucilage concentrations as dissolution and disintegrationenhancingagent Composition for optimization of mucilage as a disintegrating agent forfastdissolvingformulationisshowninTable3. FormulationforcomparisonofmucilagewithSSGandAcdisol superdisintegrants ComparisonofmucilagewithSSGandAcdiSolasadisintegrating agentforfastdissolvingformulationisshowninTable4.

Table2:Twotrialbatchestochecktheactivityofmucilageasdisintegratingagent Drug MCC Mannitol Mucilage SSG MgStearate Talc TotalWt. *AllQuantityinmg PM 100 107 25 5% 3 5 250 PS 100 107 25 5% 3 5 250

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K.Mehtaetal. IntJPharmacyandPharmSci,Vol2,Issue3,102108 Table3:Optimizationofmucilageconcentrationasdissolutionanddisintegrationtimeenhancingagent Drug MCC Mannitol Mucilage(%) MgStearate Talc TotalWeight *AllQuantityinmg Table4:ComparisonofmucilagewithSSGandAcdiSolasadisintegratingagent Formulation Nimesulide MCC Mannitol Mucilage SSG AcdiSol MgStearate Talc TotalWeight *AllQuantityinmg Evaluation of physical parameter of preparedmucilage FDT of Nimesulide14 Preparedtabletswereevaluatedforcertainphysicalpropertieslike uniformityofweight,hardness,friabilityanddissolutionstudy. Uniformityofweight15

M1 100 112 25 2 3 5 250

M2 100 108 25 4 3 5 250

M3 100 104 25 6 3 5 250

M4 100 100 25 8 3 5 250

M5 100 96 25 10 3 5 250

M6 100 92 25 12 3 5 250

M7 100 88 25 14 3 5 250

M(Mucilage) 100 96 25 10% 3 5 250

S(SSG) 100 107 25 5% 3 5 250

A(Acdisol) 100 108 25 4% 3 5 250

InvitrodissolutionprofileofpreparedNimesulideFDT18 The release rate Nimesulide from fast dissolving tablets was determined using United State Pharmacopoeia (USP) XXIV dissolutiontestingapparatusII(paddlemethod). The dissolution test was performed using 900 ml of phosphate buffer(pH7.4)at370Cand50rpm.Asample(10ml)ofthesolution waswithdrawnfromthedissolutionapparatusat2,5,10,15,20,25 and 30 min. The samples were replaced with fresh dissolution mediumofsamequantity.Thesampleswerefilteredthrougha0.45 mmembranefilter.Absorbanceofthesesolutionswasmeasuredat 392 nm using a Shimadzu UV1601 UV/Vis double beam spectrophotometer. Cumulative percentage of drug release was calculatedusinganequationobtainedfromastandardcurve. RESULTANDDISCUSSION Characterizationofmucilage ChemicalcharacterizationofLepidiumsativummucilage Thepresenceofmucilageinextractedmaterialwasconfirmedusing Molisch'stestandbytreatmentwithrutheniumred.Bothtestswere positiveforthepresenceofmucilage. PhysiochemicalcharacterizationofLepidiumsativummucilage The results of other investigations (percentage yield, particle size, pHofsolution,lossondrying)areshowninTable5. Table5:PhysicochemicalpropertyofdriedmucilageLepidium sativum Percentageyield pH Particlesize Lossondrying Theweightlossondryingindicatestheamountofmoisturepresent in the material available to interact with other material. For dried mucilage,thelossondryingwas17.53%. Swellingratio The swelling ratio of mucilage, determined in distilled water was 3.7. There was a significant change in swelling by the end of the 22% 6.2 189.57m

Everyindividualtabletina batch shouldbeinuniformweight and weight variation in within permissible limits. The weights were determinedtowithin1mgbyusingSartoriousbalance(BT124S). Weight control is based on a sample of 20 tablets. Determinations weremadeintriplicate. Hardness

The hardness of the tablets was determined by diametric compressionusingaHardnesstestingapparatus(MonsantoType).A tablet hardness of about 45 kg/cm2 is considered adequate for mechanicalstability.Determinationsweremadeintriplicate.

Friability

The friability of the tablets was measured in a Roche friabilator (CampbellElectronics,Mumbai).Tabletsofaknownweight(W0)or asample of 20tablets are dedusted ina drum for afixedtime and weighed (W) again. Percentage friability was calculated from the lossinweightasgiveninequationasbelow.Theweightlossshould notbemorethan1%.
% Friability = W 0 W W 0 100

Invitrodisintegrationtest16 The test was carried out on 6 tablets using Tablet disintegration tester ED20 (Electrolab, Mumbai, India) distilled water at 37C 2Cwasusedasadisintegrationmediaandthetimeinsecondtaken for complete disintegration of the tablet with no palable mass remainingintheapparatuswasmeasuredinseconds. Wettingtime17 The wetting time of the tablets can be measured using a simple procedure. Five circular tissue papers of 10 cm 2 diameter were placed in a petridish with a 10 cm2 diameter. Ten millimeters of watercontainingEosin,awatersolubledye,wasaddedtopetridish. Atabletwascarefullyplacedonthesurfaceofthetissuepaper.The time required for water to reach upper surface of the tablet was notedasawettingtime.

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K.Mehtaetal. IntJPharmacyandPharmSci,Vol2,Issue3,102108 study, which indicated that the mucilage had excellent swelling properties. Viscosity Theviscosityoftheextracteddriedmucilagewas8.05cpsfor0.5% solution. It can be concluded that mucilage has a viscosity of such typethatissuitableforfastdissolvingdrugdelivery. Flowproperty The flow properties and compressibility of the dried mucilage, includingbulkandtappeddensity,Carr'sindex,theHausnersratio, and the Angle of repose are shown in Table 7. It can be concluded thatthedriedmucilagehasagoodflowpropertieswhichissuitable foradirectcompressionformulation. DSCstudy DSC curves obtained for pure Nimesulide, Mucilage (Lepidium sativum), Nimesulide + mucilage is shown in figure 1. Pure powdered Nimesulide showed a melting endotherm at 152.95C. DSC thermo grams of physical mixture of drug and excipients showed the melting peak of the drug at 152.15C. Presence of all peaksindicatesthatallingredientswerecompatible. The FTIR astudy was carried out for the drug,mucilage(Lepidium sativum), and mixture of both drug and mucilage. IR spectrum for thepuredrug,mucilageandmixtureareindicatedinFigures2.The peaks of all the functional groups lie within the limit. From the IR studiesitwasfoundthattherewasnointeractionofthe functional groupsofdrugwiththemucilageincaseoffastdissolvingtabletof nimesulide. Table6:RheologicaldataofdriedmucilageLepidiumsativum Concentration 0.1% 0.2% 0.3% 0.4% 0.5% Table7:FlowpropertiesofdriedmucilageLepidiumsativum Bulkdensity(g/ml) Tappeddensity(g/ml) Carrsindex(%) Hausnersratio Angleofrepose(0) 0.37 0.62 40.32 1.67 36.14 Viscosity 1.95cps 2.85cps 3.35cps 6.15cps 8.05cps

Fig1:DSCSpectraofNimesulide(1),Mucilage(2),Nimesulide+Mucilage(3)

Fig2:FTIRSpectraofNimesulide(A),Mucilage(B),Nimesulide+Mucilage(C) Characterizationofpreparedtablet Optimizationofmannitolasasolubilizeagent In preliminary study, different batches were prepared as per the compositiongiveninTable1.Differentotherevaluationparameters were also studied. Considering release profile, batches PM0 PM4 shows drug release with slight variations. From all batches, it was 105

K.Mehtaetal. IntJPharmacyandPharmSci,Vol2,Issue3,102108 foundthatBatchPM2givesdesirablefastreleaseaction.Moreover, Therefore,themannitolconcentration10%wasselectedforfurther hardness,disintegrationtimeoftabletwerefound40.2kg/Cm 2,42 work. sec, it gives 65.22% release of drug with in 30 minute (Figure 3). Table8:EvaluationparametersofNimesulidefastdissolvingtablet Batchcode PM0 PM1 PM2 PM3 PM4 Hardness(n=5)kg/cm2 4.361.20 4.090.89 4.000.55 4.510.89 4.461.20 DTtime(Sec) 47 44 42 40 37 Wettingtime(Sec) 51 48 50 47 41 %Friability 0.42 0.51 0.35 0.40 0.42 WeightVariation 2482.50 2512.00 2492.74 2492.15 2532.54

70 60 50 %CDR 40 30 20 10 0 0

Comparision of dissolution profile for Manitol batch

PM0 PM1 PM2 PM3 PM4

10

20 Time(min)

30

40

Fig3:Drugreleaseprofilesofdifferentmannitolbatches Preliminary trails batches to check the activity of mucilage as disintegratingagent In present investigation attempt was made to prepare Fast Dissolving tablet formulation of Nimesulide using mucilage as a disintegrating agent in one batch and in another batch SSG batch tabletswerepreparedbydirectcompressionmethod.Inpreliminary study,differentbatcheswerepreparedasperthecompositiongiven in Table 2. From the obtain result, it was found that 5 % mucilage batch gives desirable fast release action compared to 5% SSG (Figure4). Optimization of mucilage concentration as a super disintegratingagent In preliminary study, different batches were prepared as per the composition given in Table 3. All the batches were evaluated for invitro dissolution study (Figure 5) and other evaluation parameters(Table9).Fromallbatches,itwasfoundthatBatchM5 (Table 3) gives desirable fast release action. Moreover, hardness, disintegration time of tablet were found 40.2 kg/cm 2, 17 sec, it gives 79.90% release of drug with in 30 minute. Therefore, the mucilageconcentration10%wasselectedforfurtherwork.

Comparision of dissolution profile for 5% SSG & 5% Mucilage Batch

80 60 40 20 0 0 10 20 30 40

% CDR

PS PM

Time(min)
Fig4:ComparativecumulativedrugreleaseprofileformucilageandSSG 106

K.Mehtaetal. IntJPharmacyandPharmSci,Vol2,Issue3,102108 Table9:EvaluationparametersofNimesulidefastdissolvingtabletusingmucilage Batchcode M1 M2 M3 M4 M5 M6 M7 Hardness(n=5)kg/cm2 4.061.17 4.110.78 4.020.49 4.140.75 4.000.20 4.231.08 4.121.15 DTtime(Sec) 37 34 31 24 17 16 16 Wettingtime(Sec) 40 37 35 27 19 21 22 %Friability (n=10) 0.43 0.46 0.45 0.43 0.47 0.44 0.47 WeightVariation(n=20) 2492.48 2501.00 2511.64 2491.15 2501.45 2491.89 2491.40

Comparision of Dissolution profile for Mucilage batches 90 80 70 60 50 40 30 20 10 0 0 10 20 Time(min) 30

M1 M2 M3 M4 M5 M6 M7 40

Fig5:Comparativecumulativedrugreleaseprofilefordifferentmucilagebatches Table10:EvaluationparametersofNimesulidefastdissolvingtabletusingMucilage,SSG,andAcdiSolBatches Batchcode M(Mucilage) S(SSG) A(Acdisol) Hardness(n=5)kg/cm2 4.000.20 4.810.78 4.200.49 DTtime(Sec) 17 39 36 Wettingtime(Sec) 19 42 39 %Friability (n=10) 0.39 0.45 0.37 WeightVariation(n=20) 2521.45 2491.75 2501.54

% CDR

Fig6:Comparisonofcumulativedrugreleaseprofileofmucilagewithdifferentsuperdisintegratingagents

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K.Mehtaetal. IntJPharmacyandPharmSci,Vol2,Issue3,102108 FormulationforcomparisonofmucilagewithSSGandAcdiSol superdisintegrants Different batches were prepared as per the composition given in Table4.Allthebatcheswereevaluatedforinvitrodissolutionstudy (Figure 6) and other evaluation parameters (Table 10). From all batches, it was found that Batch M (Figure 6 and Table 10) gives desirablefastreleaseaction,DTtimeandWettingtime. CONCLUSION In the all above formulation mucilage was incorporated as a disintegratingagenttoreducethedisintegrationtimeandmannitol was incorporated to increase the solubility of mucilage. Based on result, it was concluded that higher dissolution of tablet could be obtainedwhenmucilageconcentrationis10%andalsothemannitol concentrationwas10%.Promisingbatch(M5)exhibitedbetterdrug dissolution (79.9%) after 30 min than the other tablets. The disintegrationandmeandissolutiontimeforbatchM(mucilage) was 17secondsand5.27secondsrespectively,isbetterthanothertablet preparedfromothersyntheticdisintegratingagent.Fromtheobtain result,itwasfoundthatmucilage batchgivesdesirablefastrelease actionascomparetoAcdiSolandSSG. REFERENCES 1. 2. 3. BiY.Preparationandevaluationofacompressedtabletrapidly disintegrating in the oral cavity. Chem. Pharm. Bull. 1996; 44 (11):21212127. DMPatel,DGPrajapati,NMPatel,SeedmucilagefromOcimum americanum linn. As disintegrant in tablets: Separation and evaluation,IJPS:2007,Volume:69(3):431435. Bianchi M and Broggini M. A Randomized, DoubleBlind, Clinical Trial Comparing the Efficacy of Nimesulide, Celecoxib and Rofecoxib in osteoarthritis of the Knee. Drugs, 2003; 63, Suppl.1:3746. RoserBJ,BlairJ.Rapidlysolubleoraldosageforms,methodof making same, and composition thereof. US patent 5 762 961. June9,1998. Wallace JL. Prostaglandins, NSAIDs and cytoprotection. GastroenterolClin.NorthAm.1992;21:631641. Singla AK, Chawla M, Singh A. Nimesulide: some pharmaceutical and pharmacological aspects and update. J PharmPharmacol.2000;52:467486. Dapino P, Ottonello L, Dallegri F. The antiinflammatory drug Nimesulide inhibits neutrophil adherence to and migrations 10. 11. 8. across monolayers of cytokineactivated endothelial cells. Respiration.1994;61:336341. PielG,PirotteI,DelnevvileI,NevenP,DelattreL.Studyof the influence of both cyclodextrin and Llysine on the aqueous solubility of Nimesulide: isolation and characterization of nimesulideLlysinecyclodextrincomplexes.J.PharmSci.1997; 86:475480. NalluriBN,ChowdaryKPR,MurthyKVR,HaymanAR,BecketG. Physicochemicalcharacterizationanddissolutionpropertiesof nimesulide cyclodextrin binary systems.AAPS PharmSciTech. 2003;4(1):E2. SeedherN,BhatiaS.Solubilityenhancementofcox2inhibitors using various solvent systems. AAPS PharmSciTech. 2003; 4(3):E33. Koji Hasegawa, Junya mizutani, Seiji Kosemura and Shosuke Yamamura. Isolation and Identification of lepidimoide, a new allelopathic substance from mucilage of germinated cress seeds.PlantPhysiol.,1992;100:10591061. Watanabe Y. New compressed tablet rapidly disintegrating in saliva in the mouth using crystalline cellulose and a disintegrant.Biol.Pharm.Bull.1995;18(9):13081310. Augsberger LL, Hahm HA, Brzecko AW, Shah U. Superdisintegrants: characterization and function. In: Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, 2nd edi. New York: Marcel Dekker, 2002: 2623 2638 ChangRK,GuoX,BurnsideB,CouchR.Fastdissolvingtablets. PharmTechnol.2000;24(6):5258. Pharmacopoeia of India, New Delhi, Ministry of Health and Family Welfare, Government of India, Controller of Publications,1996. Koizumi K. New method of preparing porosity saliva soluble compressed tablets using mannitol with camphor. Int. J. Pharm,1997;152:12731. Bi YX, Sunada H, Yonezawa Y, Danjo K. Evaluation of rapidly disintegratingtabletspreparedbydirectcompressionmethod. Chem.PharmBull1996;44:21215. The United States Pharmacopoeia24/ National Formulary19, Asian Edition; US Pharmacopoeial Convention Inc: Rockville, MD;2000:19451946. Aulton ME, Wells TI. Pharmaceutics: The Science of Dosage FormDesign.ChurchillLivingstoneLondon,England,1988.

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