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2. CONTENTS1.Aim of Present Work2.Introduction to Bilayer Tablet3.Drug Profile4.Literature Review of Dosage Form5.Literature Review of API6.List of Materials7.List of Equipments8.Experimental Work9.Summary10.ReferencesMohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP2/44 3. 1. Aim of Present WorkIt comprises of two layers, one of which is sustained release ofmetoprolol and another one is immediate release ofhydrochlorothiazide. Hence,it uses Dual Release Drug AbsorptionSystem(DUREDAS) technology.To provide once a day dosage form for the treatment ofhypertension. As metoprolol having shorter half life, bilayer tabletprovide extended release of metoprolol. Hence reduce dosefrequency. Also, Hydrochlorothiazide formulated as an immediaterelease part provides initial relief as is the case with loading dose inan extended release formulation.Give additive effect of used both the drugs. Hence reduce dosedependent side-effects. Also, Hydrochlorothiazide is able toovercome the some side effects of Metoprolol.The process involves reduced manufacturing steps andmanufacturing time and finally makes a cost effective formulation.Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP3/44 4. 2.Bilayer TabletSustainreleaseImmediatereleaseBilayertabletBi-layer tablet which is made up of twodistinct layers . compressed together withthe individual layers lying one on top ofanother.The administration of sustained releasepreparation as one layer with theimmediate release preparation as thesecond layer is possible.The separation of two incompatiblesubstances with addition of any barrierlayer between them is possible.DUal RElease Drug Absorption System(DUREDAS technology) is a bilayer tabletwhich can provide immediate or sustainedrelease of two drugs or different releaserates of the same drug in one dosage form.Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP4/44 5. 3. Drug Profile (MetoprololSuccinate)Category :1 - adrenergic blockerMol. Mass : 267.36 g/molBCS Class : IBioavailability : ~50%Half life : 3-4 hrsSolubility : Freely soluble in water, sparingly solublein alcohol. max : 275nm in 0.1NHClMohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP5/44 6. PKa : 9.6Protein Binding : 11-12 %Mechanism of action :It competes with adrenergicneurotransmitters such as catecholamines for binding at 1adrenergic receptors in the heart and vascular smoothmuscle. 1 receptor blockade results in a decrease in heartrate, cardiac output, and blood pressure..Indication : Treatment of hypertension, anginaand cardiac arrhythmiaDose : Usually 25 to 100 mg daily as singledose.Excretion : Metoprolol Succinate and itsmetabolites are excreted in urine mainly via glomerularfiltration.Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP6/44 7. Drug Profile (Hydrochlorothiazide)Category :Thiazide class of diureticMol. Mass : 297.7 g/molBCS Class : IllBioavailability : ~70%Half life : 13-15 hrsSolubility : soluble in water, sparingly soluble in alcohol. max : 273nm in 0.1M NaOHMohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP7/44 8. PKa : 7.9Protein Binding : 40-60 %Mechanism of action :It is low-ceiling diuretic, acting on loop of henle.It increases bicarbonate, phosphate, magnesium, sodium, chloride andpotassium excretion also gives volume depleting effect so it reducevascular peripheral resistance.Indication :It is indicated as adjunctive therapy in edemaassociated with congestive heart failure, hepatic cirrhosis, andcorticosteroid and estrogen therapy.Dose : Usually 12.5 to 50mg daily as single dose ordivided dose.Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP8/44Excretion :As it is a weak acid, raising urinepH will increase excretion. 9. 4. Literature Review of Dosage FormResearcher Research Title JournalCh. NiranjanPatra et alDesign and evaluation of sustained releasebilayer tablets of propranololhydrochloride.Acta Pharm, 57(2007), 479-489.Z. Rahman et al Design and evaluation of bilayer floatingtablets of captopril.Acta Pharm., 56,2009Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP4957Jayabalan Nirmalet alFormulation and evaluation of bilayertablets of atorvastatin calcium andnicotinic Acid.Chemical & Pharmaceutical Bulletin.,56(10),2008, 14551458Dhake et al Formulated and evaluated the delayedrelease bilayer tablets of diclofenacsodium and misoprostol.Controlled ReleaseSociety-IndianChapter Book ofAbstracts, NinthEdition,2008,117-118.9/44 10. Researcher Research Title JournalGhadge et al Developed and evaluated thebuccoadhesive bilayered tablets asdrug delivery system for nicotinebitartrate dehydrate micro spheresControlled Release Society-Indian Chapter Book ofAbstracts, NinthEdition,2008,9-11.Girish et al Developed and evaluated a bilayerand floating bioadhesive drugdelivery system using rosiglitazonemaleate .Asian journal ofpharmaceuticalsciences,2007,2(4),161-169.Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP10/44Jadhav P et al Floating Bilayer Tablet ofClarithromycin For prolongedGastric Residence time.Controlled Release Society-Indian Chapter Book ofAbstracts,NinthEdition,2008,121-122.Sale V et al Development andcharacterization of bilayercontrolled release tablet ofTramadol HydrochlorideJournal of Control.Release,40,2006, 31- 36 11. 5. Literature Review of APIResearcher Research Title JournalAtram SC et al Formulation of bilayer tablet containingmetoprolol succinate and amlodipinebesylate as a model drug forantihypertensive therapy .Journal of PharmacyResearch, 2(8), 2009,1335-1347Rathi et al Formulation and Evaluation ofBuccoadhesive Bilayer Tablet of MetoprololTartrateControlled ReleaseSociety-Indian ChapterBook of Abstracts, NinthEdition, 2008, 12-15.Friedl et al Bilayer tablet comprising telmisartan andhydrochlorothiazide.European patent EP1467712,www.freepatentsonline.com.Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP11/44 12. Jha A.K. et al Studied formulation and invitro evaluationof sustained release matrix tablet ofmetoprolol succinate using hydrophilicpolymers.12/44International Journal ofPharmaTech Research,Dec-2009, 1(4),972-977Rahman M. et al Evaluate various grades ofhydroxypropylmethylcellulose matrixsystems as oral sustained release drugdelivery systems.Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCPJournal ofPharmaceutical Sciencesand Research, 2011,3(1), 930-938VenkatachalamT. et alDeveloped and validated for quantitationof Metoprolol succinate andHydrochlorthiazide in tablet dosage formbased on the simultaneous estimation ofdrugs by using their absorptivity values atwavelength maxima, viz., 222 nm and 272nm.Asian Journal ofResearch in Chemistry,2010, 3(2) 13. 6. List of Materials1. Metoprolol Succinate 2. Hydrochlorothiazide3. HPMC K100M 4. HPMC K15M5. HPMC K4M 6. PVP7. Sodium StarchGlycolate8. Cross-Povidone9. Cross-carmellosesodium10. Microcrystallinecellulose11. Magnesium stearate 12. Brilliant blue13. Talc 14. StarchMohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP13/44 14. 7. List of EquipmentsDigital Weighing Balance Hot air ovenSingle punch tablet machine FriabilatorTablet crushing strengthtesterBulk Density apparatusSchleuniger hardness tester Dissolution apparatusFourier Transform InfraredSpectrophotometerUV-VisibleSpectrophotometerFluidized bed drier Rapid mixer granulatorMohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP14/44 15. 8. Experimental WorkCalibration CurvesMohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP15/44Sr. no. Concentration(g/ml)Absorbance(max = 222)(n=3)1. 5 0.1382. 10 0.2283. 15 0.4784. 20 0.6655. 25 0.7956. 30 0.970Calibration curve of Metoprolol succinate in pH 6.8 phosphate buffer at 222nm.Absorbance of Metoprlol Succinate in 6.8Phosphate buffer at 222nm 16. Calibration curve of Metoprolol succinate in pH 6.8 Phosphate buffer at 222nmMohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP16/44y = 0.031x + 0.016R = 0.998Absobance0.80.60.40.200 5 10 15 20 25 30Concentration(g/ml) 17. Calibration curve for simultaneous determination ofmetoprolol succinate and hydrochlorothiazideMohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP17/44Sr. no. Concentration(g/ml)Absorbanceat max = 222Absorbanceat max = 2721. 5 0.187 0.0252. 10 0.321 0.0473. 15 0.487 0.0734. 20 0.597 0.0845. 25 0.761 0.104Calibration curve of Metoprolol Succinate in0.1NHCl (at max = 222 nm and max = 272) 18. Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP18/44Sr.no.Concentration(g/ml)Absorbance(max = 222) Absorbance(max = 272)1. 2.5 0.488 0.2822. 5.0 0.656 0.3473. 7.5 0.915 0.4954. 10 1.181 0.6445. 12.5 1.481 0.813Calibration curve of Hydrochlorothiazide in 0.1 NHCl (at max = 222 nm and max = 272nm) 19. Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP19/44Sr. no. Concentration(HCTZ+MS)(g/ml)Absorbance(max = 222)(n=3)Absorbance(max=272)(n=3)1. 2.5+5 0.475 0.1972. 5+10 0.867 0.3653. 7.5+15 1.461 0.5464. 10+20 1.755 0.7305. 12.5+25 2.186 1.026Calibration curve of synthetic Mixture in 0.1 NHCl (max = 222 nm and max = 272 nm ) 20. Absorbance10.8 y = 0.028x + 0.038R = 0.9980.60.40.200 5 10 15 20 25 30Concentration(g/ml)Calibration curve of Metoprolol succinate in 0.1N HCL at222nmCalibration curve of Hydrochlorothiazide in 0.1N HCL at272nm.8 y = 0.0607x + 0.0445R = 0.9991.7.6.5.4.3.2.10 2 4 6 8 10 12ConcentrationAbsorbanceMohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP20/44 21. PRELIMINARY STUDIESPreliminary studies were carried out i) to optimize a suitable polymer34 system for extended releaselayer of metoprolol succinate, so that the drug is able to release uptill 22hrs, also to select particulargrade of HPMC from various grades viz. K4M, K15M and K100M ii) to optimize a suitablesuperdisintegrant for immediate release layer of hydrochlorothiazide, so that the drug is able torelease as per the criteria.SELECTION OF SUPERDISINTEGRANTIngredients A1 A2 A3 A4 A5 A6 A7 A8 A9Hydrochlorothiazide 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5MicrocrystallineCellulose54 55.4 53 54 50.4 46.7 54 53 51.8Starch 54 54 54 54 54 54 54 54 54Sodium StarchGlycolate2.7 1.3 3.8 - - - - - -Cross-carmelloseSodium- - - 2.7 6.3 10 - - -Crosspovidone - - - - - - 2.7 3.8 5Magnesium stearate 1.25 1.25 1.25 1.25 1.25 1.25 1.25 1.25 1.25Talc 1.25 1.25 1.25 1.25 1.25 1.25 1.25 1.25 1.25Brilliant Blue 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3Disintegrationtime(sec)88 108 88 110 94 93 101 98 9321/44The Tablet with sodium starchglycolate shows betterdisintegration time in lowerconcentration as compare to othersuperdisintegrant viz. Cross-carmelloseMohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCPsodium andcrosspovidone.So, taking consideration the aspectof disintegration time,sodiumstarch glycolate is selected as asuperdisintegrant. 22. SELECTION OF PARTICULAR HPMC GRADEIngredient A1 A2 A3Metoprololsuccinate25 25 25HPMC K4M 100 - -HPMC K15M - 100 -HPMC K100M - - 100PVP 20 20 20MicrocrystallieCellulose51 51 51Magnesiumstearate2 2 2Talc 2 2 2Total 200mg 200mg 200mgBatches %Drug Release3hrs 6hrs 10hrs 22hrsA1 35.22 59.56 98.25 -A2 24.65 46.76 90.88 97.25A3 19.15 37.33 58.22 94.33Formulation batch A1and A2 showed burstrelease of drug in the initial hours which isprobably due to faster dissolution ofhighly water soluble drug and its diffusionout of the matrix forming the pores for theentry of solvent molecules. A suitablesustained release formulation shouldrelease the required amount in the initialhours followed by slow release. Hence,HPMC K100M is selected as hydrophilicpolymer for sustained release matrixsystem of Metoprolol succinate.Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP22/44 23. COMPATIBILITY STUDIES1) DIFFERENTIAL SCANNING CALORIMETRY OF METOPROLOL SUCCINATEDSC of METOPROLOL SUCCINATE DSC of a mixture of METOPROLOLSUCCINATE and EXCIPIENTSThe results of DSC thermograms indicate that there was no interaction betweenMetoprolol succinate - excipients and confirmed the drug-excipient compatibilityMohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP23/44 24. 2 )DIFFERENTIAL SCANNING CALORIMETRY OF HYDROCHLOROTHIAZIDEDSC of HYDROCHLOROTHIAZIDE DSC of a mixture ofHYDROCHLOROTHIAZIDE andEXCIPIENTSThe results of DSC thermograms indicate that there was no interaction betweenHydrochlorothiazide and excipients and confirmed the drug-excipientcompatibility.Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP24/44 25. OPTIMIZATION OF ANTI-HYPERTENSIVE BILAYER TABLET OFMETOPROLOL SUCCINATE AND HYDROCHLOROTHIAZIDE USING 32 FULLFACTORIAL DESIGN.METOPROLOL SUCCINATE EXTENDED RELEASE LAYERIngredientQuantity in mgF1 F2 F3 F4 F5 F6 F7 F8 F9MetoprololSuccinate25 25 25 25 25 25 25 25 25HPMC K100M 60 60 60 80 80 80 100 100 100PVP 20 40 60 20 40 60 20 40 60MicrocrystallieCellulose90 70 50 70 50 30 50 30 10MagnesiumStearate3 3 3 3 3 3 3 3 3Talc 2 2 2 2 2 2 2 2 2Total 200 200 200 200 200 200 200 200 200HYDROCHLOROTHIAZIDE IMMEDIATE RELEASE LAYERIngredient Quantity in mgHydrochlorothiazide 12.5Microcrystalline cellulose 54Starch 54Sodium starch glycolate 2.6Magnesium stearate 1.25Talc 1.25Brilliant blue 0.4Total 126Total weight of Bilayer tablet 326mgMohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP25/44 26. EVALUATION OF TABLETS1) PHYSICAL PARAMETERSBatchWeightvariation(mg) (n=20)Thickness(mm) (n=10)Hardness(kg/cm2)(n=10)Friability (%)(n=2)F1 322 4.3 6.6 0.92F2 319 4.25 6.5 0.95F3 324 4.3 6.3 0.94F4 322 4.3 7.4 0.95F5 320 4.28 7.1 0.80F6 321 4.35 6.7 0.91F7 322 4.3 6.3 0.93F8 323 4.2 6.8 0.96F9 321 4.3 6.5 0.94Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP26/44 27. 2) DISINTEGRATION TESTDisintegration time(second) (n =5)869089899491898688BatchF1F2F3F4F5F6F7F8F9Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP27/44 28. 3) ASSAY OF BILAYER TABLETBatch% Metoprololsuccinate(n =3)% Hydrochlorothiazide(n= 3)F1 101.3 99.71F2 98.5 98.45F3 103.1 99.32F4 102.3 98.33F5 98.4 99.33F6 97.3 99.33F7 103.4 98.88F8 98.3 98.66F9 97.4 98.98Simultaneous equation method was used to calculate the drug content within tablet. Drugcontent of metoprololsuccinate for all batches was found within Pharmacopoeial limit(90%-110%). Similarly, drug content for Hydrochlorothiazide for all batches was found withinPharmacopoeial limit (98%-102%).Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP28/44 29. 4) In vitro release study% cumulative release of hydrochlorothiazide in pH 1.2Time(in hr)F1 F 2 F3 F4 F5 F6 F7 F8 F91 87.5 88.52 86.8 85.45 86.55 85.25 86.85 89.25 87.652 99.56 99.25 98.25 101.25 99.25 99.88 101.66 99.25 99.88% cumulative release of Metoprolol succinate pH 6.8 phosphate buffer3 28.25 24.25 23.25 22.25 21.21 21.1 19.15 18.25 16.984 33.56 31.22 30.33 31.22 30.22 28.22 25.22 26.33 22.656 48.85 45.33 43.33 44.33 42.22 40.33 37.33 36.84 32.338 57.36 55.22 53.22 55.25 55.73 52.33 50.33 46.25 43.3310 68.65 66.22 63.33 64.33 64.1 61.31 58.22 54.78 52.6512 75.33 74.33 70.98 72.22 71.52 68.78 64.25 63.12 61.3314 80.54 78.33 77.33 78.33 75.1 74.42 72.85 71.36 69.3318 91.22 89.22 85.22 87.22 84.25 81.33 84.62 82.65 79.3322 99.25 98.25 98.33 97.66 96.35 95.25 94.33 93.22 90.35Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP29/44 30. In vitro drug release of Metoprolol succinate extendedrelease%Cumulativerelease100908070504030201000 2 4 6 8 10 12 14 16 18 20 22 24Time in hrsF1 F2 F3 F4 F5 F6 F7 F8 F960Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP30/44 31. Contour plot and Response surface plot1) Contour plot and Response surface plot for Q3Df SS MS F p valueANOVA for Q3Regression 5 83.98 16.80 51.38 0.0041Residual 3 0.98 0.33 - -Total 8 84.96 - - -Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP31/44 32. 2) Contour plot and Response surface plot for Q6Df SS MS F p valueANOVA for Q6Regression 5 112.31 22.46 33.39 0.0078Residual 3 2.02 0.67 - -Total 8 114.33 - - -Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP32/44 33. 3) Contour plot and Respose surface plot for Q10Df SS MS F p valueANOVA for Q10Regression 5 227.97 45.59 85.85 0.002Residual 3 1.59 0.53 - -Total 8 229.57 - - -Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP33/44 34. 4) Contour plot and Response surface plot for Q22Df SS MS F p valueANOVA for Q22Regression 5 258.40 51.68 130.07 0.0011Residual 3 1.19 0.40 - -Total 8 259.59 - - -Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP34/44 35. 5) Desirability plot & overlay plotDesirability plot and overlay plot showed that prediction is 0.920 when 85.84 mg HPMCK100M and 60 mg of PVP are used.Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP35/44 36. Fomulation of Check Point BatchEXCIPIENTS BATCH CODEF10Metoprolol Succinate layerMetoprolol Succinatemg25HPMC K100M 85.84PVP 60MCC 24.16Mg stearate 3Talc 2Total wt of layer 200Hydrochlorothiazide layerHydrochlorothiazidemg12.5MCC 54Starch 54Sodium StarchGlycolate2.6Magnesium Stearate 1.25Talc 1.25Brilliant Blue 0.4Total wt of layer 126Total wt of Bilayer326TabletMohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP36/44 37. Evaluation of checkpoint batch F10Weight Variation test(mg) 323Thickness(mm) 4.3Hardness(kg/cm2) 6.6Friability(%) 0.92Disintegration time(sec) 88Time (in hrs) %Drug Release (ofHydrochlorothiazide in first2hrs and after that MetoprololSuccinate)1 84.262 99.103 22.456 38.9510 58.2222 95.35Experimental values gavealmost same values as perthe specified limits. Here,by optimization study it wasconfirmed that factors likeconcentration of HPMCK100M and concentrationof PVP are significant forthe zero order release ofdrug.Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP37/44 38. Kinetic study and Mechanism of drug releaseModel SSR F-value R-square Slope InterceptZero order 298.4781 37.3098 0.9635 0.0712 9.2097First order 818.9722 102.3715 0.9522 -0.0020 4.8339Higuchi 283.1220 35.3903 0.9654 2.7943 -10.6506Hixon-Crowell 43.0748 5.3844 0.9937 0.0021 -0.0756Korsmeyer 129.0641 18.4377 0.9867 0.8067 -2.5044Weibull 32.6929 4.6704 0.9920 1.2565 -3.5323Shows that Weibullmodel shows bestfit for release ofMetoprololSuccinate fromdosage formbecause it showsminimum F value(4.6704) andminimum SSRvalue (32.6929).Mohanish/102280802002/M.PHARM SEM-IV/2011-12/LMCP38/44 39. STABILITY STUDY OF OPTIMIZED BATCHTest Initial 1 MonthAppearanceWhite and blue colourlayer,bilayer TabletNo Change inappearanceHardness 6.6 6.7Friability 0.92% 0.93%Assay forHydrochlorothiazide 98.5 99.25Assay for Metoprololsucinate 98.45 95.45In vitro drug release study of bilayer tabletMedium Initial 1 Month%cumulativerelease of Hydrochlorothiazidein pH 1.284.26% 86.35%99.10% 99.25%%cumulativerelease of Metoprololsuccinate in pH 6.8phaosphate buffer22.45% 19.25%38.95% 38.25%58.22% 57.32%95.35% 95.22%t-Test: Paired Two Sample forMeansVariable 1 Variable 2Mean 50.939 50.352Variance 3020.4 2954.9Observations 4 4HypothesizedMeanDifference 0Df 6t Stat 0.0151P(T
