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<p>DESIGN AND EVALUATION OF BILAYER TABLETS OF CAPECITABINE AND ONDANSETRON</p> <p>DESIGN AND EVALUATION OF BILAYER TABLETS OF CAPECITABINE AND ONDANSETRON</p> <p>Register number: 261311006</p> <p> DEPARTMENT OF PHARMACEUTICS Under the guidance of CHERRAANS COLLEGE OF PHARMACY Dr. N. THIRUMOORTHY, COIMBATORE-641039 M. PHARM, PH.D.,</p> <p> It comprises of two layers, one of which is sustained release of Capacetabine and another one is immediate release of Ondansetron. Hence, it uses Dual Release Drug Absorption System(DUREDAS) technology.</p> <p>To provide once a day dosage form for the treatment of nausea and vomiting .As Capacetabine having shorter half life, bilayer tablet provide extended release of Capacetabine .Hence reduce dose frequency. Also, Ondansetron formulated as an immediate release part provides initial relief as is the case with loading dose in an extended release formulation.Give additive effect of used both the drugs.Hence reduce dose dependent side -effects. Also, Ondansetron is able to overcome the some side effects of Capacetabine.The process involves reduced manufacturing steps and manufacturing time and finally makes a cost effective formulation</p> <p>1. AIM OF PRESENT WORK</p> <p>2. BILAYER TABLET</p> <p>Bi-layer tablet which is made up of two Distinct layers. compressed together with the individual layers lying one on top of Another. </p> <p>The administration of sustained release preparation as one layer with the immediate release preparation as the second layer is possible. The separation of two incompatible substances with addition of any barrier layer between them is possible.DUal RElease Drug Absorption System(DUREDAS technology) is a bilayer tablet which can provide immediate or sustained release of two drugs or different release rates of the same drug in one dosage form.</p> <p>3. LITERATURE REVIEW</p> <p>ResearcherResearch Title</p> <p>M.Sowmya, M.SarithaHas developed and optimized bilayered sustained release matrix tablets of Valsartan. Pandey Hdeveloped sustained release bilayer tablet of domperidone using hydrophilic matrix material such as HPMC, carbapol and poly-ethylene oxide.Shirwaikar A.formulated sustained release of Diltiazem hydrochloride tablets by utilizing the bilayer concept using matrix material rosin and ethyl cellulose.Bhavesh Shiyani et al.The aim of this study was to prepare bi-layer tablet of Metoclopramide Hydrochloride (MTH) and Ibuprofen (IB) for the effective treatment of migraine. Jayabalan Nirmal et alformulated bilayer tablets consisting of atorvastatin calcium (AT) as an immediate release layer and nicotinic acid (NA) as an extended release layer. </p> <p>4. PLAN OF WORK</p> <p>Pre-formulation studies Calibration curve. Flow properties. Drug excipient compatibilities.Preparation Of Tablets By Direct Compression Method ( IR tablets).Preparation Of Tablets By Direct Compression Method (SR tablets).Evaluation of the prepared tablets for various physico-chemical parameters such as.Appearance.Hardness. Weight variation.Friability.Thickness.In vitro drug release.Kinetic studies.</p> <p>4.DRUG PROFILE</p> <p>NameCapacetabineBrand namesXelodaCategoriesAntineoplastic AntimetabolitesIndicationFor the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen.Plasma Half lifeCapacetabine having shorter half life, 45-60 minutesand its metabolites.Mechanism of actionFolate cofactor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2'-deaxyuridylate.AbsorptionReadily absorbed through the GI tract (~70%).Properties:Statemelting pointSolid110-121 C polarizability35.81Dosage formsTablet oral</p> <p>4.DRUG PROFILENameOndansetronDescriptionA competitive serotonin type 3 receptor antagonist. It is effective in the treatment of nausea and vomiting caused by cytotoxic chemotherapy drugs.Category AntiemeticsIndicationFor the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy, postoperation, and radiation. Mechanism of actionOndansetron is a selective serotonin 5-HT3receptor antagonist. The antiemetic activity of the drug is brought about through the inhibition of 5-HT3receptors present both centrally (medullary chemoreceptor zone) and peripherally (GI tract). AbsorptionOndansetron is well absorbed after oral administration and undergoes limited first-pass metabolism.Protein binding70%-76% (Plasma protein binding)Half life5.7 hoursStatesolid</p> <p>EXCIPIENTS</p> <p>POVIDONEEnhancer; tablet Disintegrant; dissolution binder.MAGNESIUM STEARATETablet and capsule lubricant .CROSS POVIDONE (CP)Tablet disintegrant. and dissolution agent.SODIUM STARCH GLYCOLATE (SSG)Tablet and capsule disintegrant.Microcrystalline cellulose (MCC)Adsorbent; suspending agent; tablet and capsule diluent; tablet disintegrant.Hydroxy Propyl Methyl Cellelose (HPMC)Minimize interaction problems when used in acidic, basic,Polyvinyle pyrrolydine (PVP)Binder in wet granulationEthyl Cellelose (EC)Coating agent,Sodium Lauryl Sulphate (SLS)Excipient in dissolvable dosage forms.TalcLubricant</p> <p>5.PREFORMULATION &amp; FORMULATIONS STUDY</p> <p> .PREFORMULATION STUDY:Organoleptic propertiesSolubilityDensityCarrs compressibility index &amp; Hausners ratioAngle of repose()Compatibility studiesF.T.I.RFORMULATIONSThe bilayer tablet was prepared by direct compression method. As shown in Table powder mixtures of Capacetabine, microcrystalline cellulose, polymers and binder were dry blended for 20 min followed by addition of Magnesium Stearate and Talc. The mixtures were then further blended for 10 min., 400mg of resultant powder blend was manually compressed using KBr hydraulic press at a pressure of 1 ton, with a 12mm punch and die to obtain the tablet.</p> <p>a) First layer fill ; b) First layer tamping; c) Upper punch withdrawal; d) second layer fill; e) main compression; f) Ejection;</p> <p>IngredientsF1F2F3F4F5F6F7F8F9F10Capacetabine (mg)150150150150150150150150150150HPMC K4M(%)10----------5------HPMC K100M(%)--10----152015151520HPMC E15(%)----10--------5----EC(%)------10--------55PVP K30 (%)5555555555Talc (%) stearate(%) weight (mg)400400400400400400400400400400</p> <p>COMPOSITION OF SUSTAINED RELEASE LAYERTable no 1 formulation table for sustained release layer</p> <p>5.PREFORMULATION &amp; FORMULATIONS STUDYDIRECT COMPRESSION FOR IMMEDIATE LAYER</p> <p>All the ingredients were passed through sieve and mixed in a motor and pestle for 30min for uniform mixing. The addition of ingredients was done in a geometrical manner. Then the ondansetron layer was compressed using 8mm round punch.COMPOSITION OF IMMEDIATE RELEASE LAYER</p> <p>Table no2: formulation table for immediate release layerIngredients (mg)F1F2F3F4F5F6F7F8F9Ondansetron888888888HPC (%)555555555SSG(%)5----------------CCS(%)--5--7.51012.5101010CP(%)----5------------Lactose monohydrateQ.SQ.SQ.SQ.SQ.SQ.SQ.SQ.SQ.SMagnesium stearate(%) (%) weight150150150150150150150150150</p> <p>BILAYERED TABLET PUNCHAfter the batch was optimized in both immediate release layer ( F8) and sustained release layer (F7).The optimized batch in both was compressed by using same ingredientsFlow PropertiesAngle of ReposeBulk density:Tapped density Compressibility index and Hausner ratio</p> <p>TABLE NO 3 : ACCEPTANCE CRITERIA OF FLOW PROPERTIES </p> <p>Flow propertiesAngle of repose()Compressibility Index (%)Hausner ratioExcellent25-30 66&gt;38&gt;1.6</p> <p>EVALUATIONS PARAMETERS</p> <p>AppearanceWeight variation testThickness testHardness testFriability testDevelopment of analytical methods In-vitro studiesSwelling indexDrug content(assay of tablet)Release of kineticsStability study</p> <p>6. RESULT &amp; DISCUSSION Pre-compression parameters:Preformulation studies: Capacetabine(API)</p> <p> Physical characterization: physical characterization of Capacetabine was studied.Density and flow properties of drug: the drug having the excellent flow properties.Evaluation of Formulated blend: Bulk density, Tapped density, Carrs compressibility index , Hausners ratio and Angle of repose are studied .the values are within the limits. And the Formulation blend was good flow property</p> <p>6. RESULT &amp; DISCUSSIONPreparation of standard calibration curve of Ondansetron: in 0.1N HCl calibration curve of Ondansetron in 0.1N HCl</p> <p>Standard Graph of Capacetabine (0.1 N Hcl): calibration curve for Capacetabine in 0.1N HCl at 303nm Standard Graph of Capacetabine in 6.8pH phosphate buffer : calibration curve for capacetabine in 6.8pH phosphate buffer at 304nm</p> <p>COMPATIBILITY STUDIES</p> <p>(FTIR) was used for infrared analysis of samples to intercept the interactions of drug with polymers and other ingredients. The powder sample along with KBr was used for FTIR studies. The samples were analyzed between the wave numbers 4000 and 400 cm2.Fig no 1: FTIR spectra of Capecitabine pure drug</p> <p>Fig no 2: FTIR spectra of Ondansetron pure drug</p> <p>Fig no 3: FTIR spectra of bilayered tablet</p> <p>EVALUATION OF PRE COMPRESSION PARAMETERS FOR SUSTAINED RELAESE LAYER OF CAPACETABINE</p> <p>FormulationsAngle of Repose ()Loose BulkDensity (g/ml)Tapped BulkDensity (g/ml) %CompressibilityHausners ratio</p> <p>INVITRO DISSOLUTION STUDIES FOR SR TABLETS -DISSOLUTION STUDY ( SR TABLETS) :</p> <p>Acidic Stage: Medium : 0.1N HCLType of apparatus: USP - II (paddle type)RPM : 50Volume : 900mlTemperature : 37C 0.5Time : 2hrs Buffer Stage: Medium : 6.8pH phosphate bufferType of apparatus : USP - II (paddle type)RPM : 50Volume : 900mlTime : 24hrs</p> <p>In vitro dissolution for SR tablets were done initially in 0.1N HCL for 2hrs and next in 6.8 phosphate buffer for 12hrs</p> <p>In-Vitro Drug Release Studies for SR tablets:Table no 4. Cumulative Percentage Drug Release of Sustained Layer</p> <p>Time(hrs)F1F2F3F4F5F6F7F8F9F10Dissolution medium 0.1N HCL138.545.980.432.425.519.625.534.535.626.3245.772.295.645.539.924.339.242.14033.26.8pH phosphate buffer353.880.7--67.443.431.446.552.749.740.1470.492.4--72.659.445.955.260.353.945.6584.9----85.478.257.368.572.463.855.2693.6----95.894.280.775.978.370.463.88----------94.981.380.175.873.612------------96.5--84.980.4</p> <p>Dissolution Medium for SR tabletsTable no 5: Dissolution profile of bilayered tablet</p> <p>S.NOSampling timePercentage drug released (%)ONDANSETRANCAPACETABINE115mins80.74.2230 mins99.86.631hr--20.642hr--37.753hr--45.464hr--53.875hr--69.786hr--77.998hr--89.01012hr--97.3</p> <p> Discussion for in-vitro release of Capacetabine layer SR From the table, it was confirmed that the F1, F2, F3, F4, F5, F6 and F8 of SR layer does not fulfill the sustained release theory up to 12 hrs. And also from the table, it was also confirmed that the formulation made with combination of HPMC K100 and HPMC K4M (F7) showed maximum drug release up to 12hrs.</p> <p>KINETIC RELEASE MODELS:Drug release kinetics and mechanism: </p> <p>To analyze the mechanism of drug releasefrom the formulation, the dissolution profile of all the batches were fitted to zero order, first order, Higuchi and Peppas models to ascertain the kinetic modeling of drug release.</p> <p> Zero Order: Q = K0 t First order: Log Qt = Log Qo+ K1t / 2.303 Peppas model: Mt/M = ktn Higuichi model: Q = K2 t1/2</p> <p>Fig no 5 - kinetic release graph for F7 sustained release formulation</p> <p>Table no 6:EVALUATION PARAMETERS FOR IMMEDIATE RELEASE LAYER OF ONDANSETRANPRE COMPRESSION PARAMETERS</p> <p>FormulationsAngle of Repose ()Loose BulkDensity (g/ml)Tapped BulkDensity (g/ml)%CompressibilityHausners ratioF123.900.30.3514.291.17F224.200.380.4515.561.18F327.200.530.6214.521.17F425.500.570.6816.181.19F523.800.430.4912.241.14F624.100.370.4517.781.22F729.400.430.514.001.16F822.1000.440.5113.731.16F926.400.40.4714.891.18</p> <p>From the above pre-compression parameters it was clear evidence that drug and excipients has good flow properties and suitable for direct compression.</p> <p>Post-compression parameters:</p> <p>Post compression evaluation parameters for immediate release formulation</p> <p>The results of the uniformity of weight, hardness, thickness and friability of the tablets are given in Table. All the tablets of different batches complied with the official requirements of uniformity of weight as their weights varied between 147 to 152mg. The hardness of the tablets ranged from 3.1 to 3.6kg/cm2 and the friability values were less than 0.5% indicating that the matrix tablets were compact and hard. The thickness of the tablets ranged from to 2.1 to 2.5mm. Thus all the physical attributes of the prepared tablets were found be practically within control.</p> <p> Table no 7. Post compression parameters for immediate release tabletsFormulationsAverage weight (mg)HardnessKg/cm2Thickness (mm)Friability (%)F11493.42.10.29F21473.52.30.25F31503.12.50.30F41523.32.20.41F51503.62.40.52F61503.22.20.49F71483.12.50.44F81493.42.40.43F91503.32.30.42</p> <p>Table No 8. Dissolution for immediate release tablet of Ondansetran</p> <p>Time in minsF1F2F3F4F5F6F7F8F952522142236314065481037382642575967706315454940566565798480305056546372728696944548726378888694----60628075899395------</p> <p>BILAYERED TABLET COMPRESSION</p> <p>After the batch was optimized in both immediate release layer (F8) and sustained release layer (F7).The optimized batch in both was compressed by using same ingredients.DISSOLUTION STUDY (BILAYERED TABLETS) :Dissolution Medium for IR tabletsAcidic Stage: Medium : 0.1N HCLType of apparatus : USP - II (paddle type)RPM : 50Volume : 900mlTemperature : 37C 0.5Time : 30min In vitro dissolution for IR tablets were done in 0.1N HCL for 30 minutes.</p> <p>Dissolution Medium for SR tabletsAcidic Stage: Medium : 0.1N HCLType of apparatus: USP - II (paddle type)RPM : 50Volume : 900mlTemperature : 37C 0.5Time : 2hrs In vitro dissolution for SR tablets were done in 6.8 pH for 12hrs.</p> <p>Table no 9 : Dissolution profile of bilayered tablet</p> <p>S.NOSampling timePercentage drug released (%)ONDANSETRANCAPACETABINE115mins80.74.2230 mins99.86.651hr--20.662hr--37.773hr--45.484hr--53.895hr--69.7106hr--77.9118hr--89.01212hr--97.3</p> <p>Stability Studies</p> <p>Stability of a drug has been defined as the ability of a particular formulation, in a specific container, to remain within its physical, chemical, therapeutic and toxicological specifications.</p> <p> The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time underthe influence of a variety of environmental factors such as temperature, humidity, light, and enables recommendedstorage condition...</p>