Asian Journal of Pharmaceutical and Clinical Research

Vol. 4, Issue 2, 2011

ISSN - 0974-2441

ResearchArticle

ENHANCEMENTOFSOLUBILITYANDDISSOLUTIONRATEOFIRBESARTANBYSOLID DISPERSIONTECHNIQUE

G.ASHWINIKUMAR*1,RAMKUMARCHOUDHARY1ANDCH.CHAITANYA2
1

DepartmentofPharmaceutics,BharatInstituteofTechnology(Pharmacy),Ibrahimpatnam,Hyderabad,AndhraPradesh,India. 2TherdosePharmaPvt.Ltd,Kukatpally,Hyderabad,AndhraPradesh,India Email:ashwinn4u@gmail.com

ABSTRACT The purpose of present work was to enhance the solubility and dissolution rate of Irbesartan by solid dispersion technology employing various superdisintegrantssuchassodiumstarchglycolate(SSG),crosspovidone(CP),croscarmellosesodium(CCS)andmicrocrystallinecellulose(MCC). Solid dispersions were prepared by physical mixing and solvent evaporation method. Various ratios of drug and carriers were used in the preparationintheratioof1:1,1:2and1:4.Phasesolubilitystudiesofpuredrugandsoliddispersionwasperformed.Itwasfoundthatsolubilityof Irbesartanwasincreased.Allthesoliddispersionspreparedwerefoundtobefinefreeflowingpowdersandthedrugcontentwasuniforminall batches. The results of the disintegration test revealed that F5 has faster disintegration and it disintegrates within two minutes (95secs). The dissolutionofIrbesartanfromallthesoliddispersionswasrapidandseveraltimeshigherthanthedissolutionofthecorrespondingpuredrugand followedfirstorderkinetics.Allthedissolutionparametersestimatedi.e.T50, T90,DE30%valuesindicatedrapidandhigherdissolutionofthedrug (Irbesartan) from solid dispersions than that of corresponding pure drug. CP showed highest enhancement of dissolution rate and efficiency of Irbesartan.Ineachcasethedissolutionrate(K1)andDE30%wereincreasedastheconcentrationofsuperdisintegrantsinthesoliddispersionswas increased. The order of increase in dissolution rate with various superdisintegrants CP > SSG > CCS > MCC with Irbesartan. Among all inhouse formulationsF5showedmaximumdissolutioni.e.4.25and6.15foldincreaseinDE30%anddissolutionrate(K1)wereobservedwithformulation F5.FTIRstudiesrevealedthattherewasnochemicalinteractionbetweendrugandcarrierwhenformedassoliddispersion. Keywords:Superdisintegrants,soliddispersions,crosspovidone,Microcrystallinecellulose. INTRODUCTION Solid dispersion technology is the science of dispersing one or more active ingredients in an inert matrix in the solid state in order to achieve increased dissolution rate, sustained release of drugs,alteredsolidstatepropertiesandenhancedreleaseofdrugs fromointmentandsuppositorybasesandimprovedsolubilityand stability1. The enhancement of oral bioavailability of poorly soluble drugs remainsoneofthemostchallengingaspectsofdrugdevelopment. Althoughsaltformation,solubilizationandparticlesizereduction havecommonlybeenusedtoincreasedissolutionrateandthereby oral absorption and bioavailability of such drugs, there are some practicallimitationsofthesetechniques 2. Incaseofsalts,theincreaseddissolutionrateinthegastrointestinal tractmay notbeachieved becauseofthereconversion ofsalts into aggregates of their respective acid (or) base forms. Further solubilization of drugs in organic solvents or in aqueous media by the use of surfactants and cosolvents leads to liquid formulations that are usually undesirable from patient acceptability and commercialization. Particle size reduction is commonly used to increase the dissolution rate and there is a practical limit to how much size reduction can be achieved by such commonly used methodsascontrolledcrystallizationandgrinding3. A solid dispersion may be obtained in different ways e. g. by employing organic solvents or by dispersing or dissolving the activesubstanceinanothersuitablemedium(e.g.anoilymaterial that is in liquid form at room temperature or at elevated temperatures). Solid dispersions (solvent method) are prepared by dissolving a physical mixture of the active substance (e.g. a drug substance) and the carrier in a common organic solvent, followed by evaporation of the solvent4. The carrier is often a hydrophilic polymer. Suitable organic solvents include pharmaceuticalacceptablesolventinwhichtheactivesubstanceis solublesuchasmethanol,ethanol,methylenechloride,chloroform, ethylacetateandacetone. The enhancement of oral bioavailability of poorly soluble drugs remainsoneofthemostchallengingaspectsofdrugdevelopment. Although salt formation solubilization and Size reduction have commonlybeenusedtoincreasedissolutionrateandtherebyoral absorption and bioavailability of such drugs 5. There are some practical limitations of these techniques. The solid dispersion approach has been widely and successfully applied to improve solubility,dissolutionrateand consequentlythe bioavailabilityof poorlysolubledrugs6.ManyhydrophilicexcipientslikePEG4000, PEG6000,Mannitol,PVP,andpoloxamerscanbeusedtoenhance the dissolution of drug 7. In the present study, an attempt was made to increase solubility and dissolution of drugs by solid dispersion technique using sodium starch glycolate (SSG), crosspovidone (CP), croscarmellose sodium (CCS) and microcrystalline cellulose (MCC) by physical mixing and solvent evaporationmethods. The drug Irbesartan was selected for enhancement of solubility and dissolution rate as it is a poorly water soluble (BCS class II) anti hypertensivedrug.Oneofthemajorproblems of thisdrug is low solubility in biological fluids, which results into poor bioavailabilityafteroraladministration 8,9. Due to poor solubility of drug, its bioavailability rate (26%) is limited by drug dissolution. Therefore, in the present study, an attempthasbeenmadetoincreasesolubilityofIrbesartanbysolid dispersion using physical mixing (PM) and solvent evaporation (SE) technique of Irbesartan with SSG, CP, CCS and MCC and to improvethedissolutionofdrug.Theaimofthepresentworkisto enhance the solubility, dissolution rate and oral bioavailability of poorly soluble drug Irbesartan by solid dispersion technology usingvariouscarriers. MATERIALSANDMETHODS IrbesartanwasreceivedasagiftsamplefromMatrixLaboratories Ltd, Hyderabad. Microcrystalline cellulose was procured from Kemphasol,Mumbai.Sodiumstarchglycolatewaspurchasedfrom Central Drug House, New Delhi. Crosspovidone procured from Ozone International, Mumbai. Croscarmellose sodium (procured from Ozone International, Mumbai). Methanol (Qualigens chemicals Ltd., Mumbai). Lactose anhydrous (Sd fine chemicals Ltd.,Mumbai).Mannitol(SdfinechemicalsLtd.,Mumbai).Talc(Sd fine chemicals Ltd., Mumbai). Magnesium stearate (Sd fine chemicals Ltd., Mumbai). The commercial products of Irbesartan

Kumaretal. AsianJPharmClinRes,Vol4,Issue2,2011,3640 wereprocuredfromthelocalmarket.Allotherchemicals/solvents usedwereofARgrade. PreparationofIrbesartansoliddispersions ThesoliddispersionsofIrbesartanwerepreparedin1:1,1:2and1:4 ratiosbytwomethodsasshowninTable1. Physicalmixingmethod: Irbesartan and each of surface active carriers (MCC, CCS, SSG and CP) were weighed accurately and mixed thoroughly in mortar and pestlewithtrituratingforabout10min.Thesemixtureswere then passed through sieve number #60 and finally, stored in air tight containerstillfurtheruse. Solventevaporationmethod10: Irbesartan and each of surface active carriers (MCC, CCS, SSG and CP)wereweighedaccuratelyinvariousratios(1:1,1:2and1:4)and transferredtochinadishcontainingsufficientquantityofmethanol todissolve.Methanolwasevaporatedonheatingmantleat600C.The resulting solid dispersions were stored for 24 hrs in dessicator to congeal. The mass obtained was crushed, pulverized. Finally, dispersionswerepassedthroughsievenumber#60andwerestored inairtightcontainerstillfurtheruse. Table1:ListofIrbesartansoliddispersionspreparedandtheir compositions Formulationcode PM1 PM2 PM3 PM4 PM5 PM6 PM7 PM8 PM9 PM10 PM11 PM12 SE1 SE2 SE3 SE4 SE5 SE6 SE7 SE8 SE9 SE10 SE11 SE12 Carrier MCC MCC MCC CCS CCS CCS SSG SSG SSG CP CP CP MCC MCC MCC CCS CCS CCS SSG SSG SSG CP CP CP Drug:Carrier 1:1 1:2 1:4 1:1 1:2 1:4 1:1 1:2 1:4 1:1 1:2 1:4 1:1 1:2 1:4 1:1 1:2 1:4 1:1 1:2 1:4 1:1 1:2 1:4 Table2:FormulaeofIrbesartantabletsemployingsolid dispersions Ingredients (mg/tablet) PureIrbesartan SE3 SE6 SE9 SE12 Lactose anhydrous MCC Manitol Magnesium stearate Talc Totalweightof tablet(mg) EvaluationofIrbesartanSolidDispersions Solubilitystudies11 Solubility study was performed according to method reported by Higuchi and Connors12,13. Excess (usually more than1mg/ml concentration) of solid dispersions were added to 25ml distilled water taken in stopper conical flasks and mixture were shaken for 24hrs in rotary flask shaker. After shaking to achieve equilibrium, 2ml aliquots were withdrawn at 1hr intervals and filtered through Whatmann filter paper. The filtrate was diluted if necessary and analyzed by UV spectrophotometer at 244 nm. Shaking was continueduntilthreeconsecutivereadingsweresame. DrugcontentEstimation14 The percentage drug content in physical mixtures and solvent evaporative dispersions was estimated by dissolved 50 mg quantitiesofphysicalmixturesandsolventevaporativedispersions inmethanol,mixedthoroughlybyshakingandthevolumewasmade up to the mark with solvent (0.1N HCl). The solution was filtered and the filtrate was diluted suitably with 0.1N HCl (1.2 pH) and absorbance was measured at 244 nm using UV/Visible spectrophotometer. Preformulation studies of Irbesartan and optimized Solid Dispersions Preformulationstudiessuchasangleofrepose,bulkdensity,tapped density;CarrsindexandHausnersratiowereperformed. EvaluationofIrbesartantablets: Various physical parameters such as hardness, friability, disintegrationtimewereevaluated Contentofactiveingredient15 For drug content analysis, twenty tablets were accurately weighed andfinelypowdered.Thequantityofpowder,equivalentto150mg ofIrbesartanwastakenina100mlvolumetricflaskandfilteredthe solution, 1ml of the filtrate was dissolved in 10ml of 0.1N HCl (1.2 pH) and assayed for drug content at 244nm, using spectrophotometer. Disintegrationtest16 One tablet was placed in each tube of disintegration apparatus (Thermonic model) and the test was carried out using distilled waterasDisintegrationmediumat250C.ThetimeforDisintegration wasnotedineachtestproductforsixtablets. InvitrodissolutionstudyofIrbesartantablets Invitro dissolution study of tablets was conducted using USP dissolution apparatus II (lab India DISSO 2000, eight stages) at 244nm, using 0.1 N HCl (1.2pH) maintained at 370.5 0C. Aliquot equal to 5 ml was withdrawn at regular time intervals (10, 20, 30, 37 F1 150 707 30 10 2 1 900 F2 750 107 30 10 2 1 900 F3 750 107 30 10 2 1 900 F4 750 107 30 10 2 1 900 F5 750 107 30 10 2 1 900

PM=PhysicalMixingandSE=SolventEvaporation Preformulation studies of Irbesartan and optimized Solid Dispersions Preformulationstudiessuchasangleofrepose,bulkdensity,tapped density;CarrsindexandHausnersratiowereperformed. FormulationofIrbesartantablets1,5 Based on maximum solubility, optimized solid dispersions were formulated as tablets and the composition of tables is shown in Table2.Directcompressionmethodwasusedforthepreparationof tablets. In this, microcrystalline cellulose (MCC) was used as direct compressible vehicle, mannitol was used as diluent and talc, magnesium stearate as lubricant and glidants respectively. All the ingredients were blended in a closed dry plastic container. The blend of powder was compressed into tablets to a hardness of 24 kg/cm2 on a Cadmach single punch tablet machine. In each case thirty tablets were prepared. The tablets were stored in a tightly closed container and evaluated for following characteristics in triplicate.

Kumaretal. AsianJPharmClinRes,Vol4,Issue2,2011,3640 40, 50, 60 min), an equal volume of fresh dissolution medium was replacedtomaintainthesinkconditionandaliquotsweremeasured at 244 nm UV/Visible spectrophotometer. The inhouse formulations were taken for comparative study with market formulation to observe the dissolution characteristics of inhouse formulationswithmarketformulation. Table3:SolubilityandIrbesartancontentofallsoliddispersions Formulationcode PM1 PM2 PM3 PM4 PM5 PM6 PM7 PM8 PM9 PM10 PM11 PM12 SE1 SE2 SE3 SE4 SE5 SE6 SE7 SE8 SE9 SE10 SE11 SE12 Solubility(mg/ml) 0.0017 0.003 0.0041 0.002 0.0038 0.0072 0.0058 0.0115 0.0147 0.0094 0.024 0.0287 0.0018 0.0027 0.0035 0.004 0.007 0.0098 0.0112 0.0124 0.026 0.0178 0.0264 0.0356 Table4:PreFormulationStudiesofIrbesartanaloneanditsSolidDispersions System Anglesofrepose() Irbesartan 31 SE3 28.4 SE6 25.34 SE9 26.21 SE12 25.8 Indicatesmeanofthreereadings. Table5:Evaluationoftablets Tabletformulation F1 F2 F3 F4 F5 Hardness(kg/sq.cm) 4.50.43 4.30.67 4.00.68 4.10.69 3.90.01 Disintegrationtime(sec) 1300.88 1200.80 1170.86 1090.78 940.89 Table6:DissolutionparametersofIrbesartantablets Formulations F1 F2 F3 F4 F5 IrbesartanMP Dissolutionparameters %Drugdissolvedin10min 6.67 38.65 40.48 45.99 53.52 46.49 T50(min) 55 15 14 15 8 15 DE30% 12.3 40.29 41.93 40.43 52.23 40.66 K1(min) 0.0161 0.0484 0.0553 0.0345 0.0991 0.0345 R2value 0.9930 0.9900 0.9723 0.9896 0.9936 0.9524 Friability(%) 0.380.22 0.340.12 0.290.15 0.300.67 0.220.81 Drugcontent(%) 99.78 99.87 98.40 99.09 99.51 Bulkdensity 0.52 0.61 0.63 0.63 0.57 Tappeddensity 0.64 0.72 0.74 0.62 0.61 Carrsindex 18.75 18.03 17.46 16.98 17.01 Hausnersratio 1.23 1.18 1.17 1.16 1.07 %Drugcontent 98.700.32 96.640.87 95.120.36 95.870.54 96.350.65 98.230.23 94.740.86 97.760.45 96.670.65 95.830.34 96.290.24 99.100.18 96.440.78 98.800.35 97.560.79 95.370.34 97.650.23 98.740.73 98.340.63 94.760.37 99.360.26 96.320.65 97.980.77 98.610.90 Drugexcipientcompatibilitystudies FTIR studies were performed for pure drug alone and in combinationwithexcipients.

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Kumaretal. AsianJPharmClinRes,Vol4,Issue2,2011,3640

120 100 % Drug dissolved F1 80 60 40 20 0 0 10 20 30 40 50 60 Tim e (m in) F2 F3 F4 F5 Irbesartan MP

Fig.1:DissolutionprofilecomparisonofIrbesartantabletswith marketedproduct

Fig.2:FirstorderplotscomparisonofIrbesartantabletswith marketedproduct

a)IRBESARTANPUREDRUG

Fig.3:FTIRspectrumofIrbesartanpuredrugandFormulationsF2F5

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Kumaretal. AsianJPharmClinRes,Vol4,Issue2,2011,3640 RESULTSANDDISCUSSION PreparationofIrbesartanSolidDispersions Solid dispersions of Irbesartan were prepared by physical mixing and solvent evaporation method. The carriers like microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate and crosspovidone were used in the preparation of solid dispersions. Variousratiosofdrugandcarriersuchas1:1,1:2and1:4wereused inthepreparation.Allthesoliddispersionspreparedwerefoundto befinefreeflowingpowders. Drugcontentandsolubility Thepercentdrugcontentandsolubilitydataofallsoliddispersions are given in table 3. Low standard deviation in the percent drug contentvaluesindicateduniformityofdrugcontentineachbatchof soliddispersions. Itwasobservedthatastheconcentrationofcarrierisincreasedthe solubility was increased and it was also noticed that at the same concentrationofcarrier,thesoliddispersionspreparedwithsolvent evaporation method displayed greater solubility than that of physicalmixingmethod. PreFormulationStudies Angle of repose, bulk density, tapped density, carrs index and Hasusnersratiowerecalculatedandwerefoundtobeintherange of 25.831, 0.520.63, 0.610.74, 16.9818.75 and 1.071.23 respectively and is shown in table 4. From the preformulation studies of the Irbesartan solid dispersions, it is clear that all the Irbesartan solid dispersions fulfilled the official requirements for compressionoftabletsthroughdirectcompressionmethod. Evaluationoftablets Hardness was found to be in the range of 44.5 kg/sq.cm with standarddeviationnotmorethan0.7.Disintegrationtimewasfound tobe130,120,117,109and94secondsforformulationF1,F2,F3, F4andF5respectively,theresultsofthedisintegrationtestrevealed that F5 has faster disintegration and it disintegrates within two minutes (94sec).Friability was found toin between0.220.38 with standarddeviationnotmorethan0.81. Drug content was above 99% in all the formulations. All the parameters evaluated are shown in table 5. From the physico mechanical parameters of the formulated tablets, it is clear that all the tablets fulfilled the official requirements of the compressed tablets. InvitrodissolutionstudiesofIrbesartantablets Dissolution studies showed enhanced dissolution of Irbesartan whencomparedtopuredrugandisshowninfig.1.Dissolutiondata ofIrbesartanfollowedfirstorderkineticsandisshownisfig.2.First orderdissolutionrateconstant(K1)werecalculatedfromtheslopes of the linear regressions are given in table 6. T50, T90 and DE30% values for optimized formulations were calculated from the dissolutiondataandprofilesaregivenintable6. Formulation F2 showed 3.01 and 3.27 fold increase in the dissolutionrate(K1)andDE30%respectivelywhileF3displayed3.43 and 3.41 fold increase in the dissolution rate (K 1) and DE30% respectively.2.14and3.28foldincreaseinthedissolutionrate(K1) and DE30% respectively was observed with formulation F4. It was observedthatF5showedmaximumdissolution,a4.25and6.15fold increase in DE30% and dissolution rate (K1) respectively were observed. From this, it is clear that instead of the pure drug Irbesartan, Irbe: CP (1:4) solid dispersion prepared by solvent evaporationmethodcan beused toformulatetablets,sothatthere willbemaximumdissolutionofthedrugfromtheformulationandin turn,itincreasesthebioavailabilityofthedrug.Fromthedissolution profiles and dissolution parameters, it is clear that among all in houseformulationsF5showedmaximumdissolution DrugExcipientcompatibilitystudies Infraredspectroscopy Infrared spectra were recorded on a Fourier transform Infrared (FTIR) spectrophotometer using KBr dispersion method14. All sampleswererecordedintherangeof4000400cm 1.IRspectraof Irbesartan, carriers, solid dispersions prepared by solvent evaporation(1:4)methodareillustratedinFig.3. CharacteristicpeaksofIrbesartanat3436.51cm1 (NHstretching), 2960.52 cm1 (CH stretching), 1733.30 cm1 (C=O stretching), 1485.77cm1 (C=Cstretching)and1614.83cm1 (NHbending)were observed. All Physical mixtures and solid dispersions prepared by solvent evaporationmethodshowedcharacteristicpeaksofIrbesartandrug and carriers. These results indicated that there is no chemical interaction between drug and carrier when formed as solid dispersion. CONCLUSION The enhancement of dissolution rate and oral bioavailability of poorlysolubledrugsremainsoneofthemostchallengingaspectsof drug development. Among the various methods of enhancement of the dissolution rate and oral bioavailability, solid dispersion technologies were found to be more successful with a number of drugs. In the present investigation, studies were carried out on enhancement of dissolution rate of Irbesartan by solid dispersion technology employing various water dispersible carriers. A new class of tablet excipients called super disintegrants was evaluated as carriers for solid dispersions and for enhancing the dissolution rate of poorly soluble drugs. Among the super disintegrants tested CP gave highest enhancement of dissolution rate and efficiency of Irbesartan. In each case the dissolution rate (K1) and DE30% were increased as the concentration of carriers in the solid dispersions wasincreased.Theorderofincreaseindissolutionratewithvarious superdisintegrantsisCP>SSG>CCS>MCC. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. RaymondCRowe,PaulJSheskeyandSiaaneOwen, Handbook ofPharmaceuticalExcipients,Page.No:132,188,213,214,449, 701and764. Bharmankar,D.M. and Sunil B. Jaiswal., Biopharmaceutics and Pharmacokinetics,2004,Page.No:1,296. Remington: The science and practice of pharmacy, 20th edition volume1,Page.No:858863. P.SrinivasaBabuandT.P.Rao,PharmaBuzz,Volume3/Issue 8,Aug2008,Page.No:1418. Leon Lachman et.al; The Theory and Practice of Industrial Pharmacy,3rdedition,Page.No:293345. M.E.Aulton,Pharmaceutics Thescience ofdosageformdesign, 2ndedition,PageNo:360461. 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