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DESIGN AND EVALUATION OF BILAYER TABLETS OF CAPECITABINE AND ONDANSETRON

DESIGN AND EVALUATION OF BILAYER TABLETS OF CAPECITABINE AND ONDANSETRON

Register number: 261311006

DEPARTMENT OF PHARMACEUTICS Under the guidance of CHERRAANS COLLEGE OF PHARMACY Dr. N. THIRUMOORTHY, COIMBATORE-641039 M. PHARM, PH.D.,

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.

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

1. AIM OF PRESENT WORK

2. BILAYER TABLET

Bi-layer tablet which is made up of two Distinct layers. compressed together with the individual layers lying one on top of Another.

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.

3. LITERATURE REVIEW

ResearcherResearch Title

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.

4. PLAN OF WORK

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.

4.DRUG PROFILE

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

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

EXCIPIENTS

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

5.PREFORMULATION & FORMULATIONS STUDY

.PREFORMULATION STUDY:Organoleptic propertiesSolubilityDensityCarrs compressibility index & 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.

a) First layer fill ; b) First layer tamping; c) Upper punch withdrawal; d) second layer fill; e) main compression; f) Ejection;

IngredientsF1F2F3F4F5F6F7F8F9F10Capacetabine (mg)150150150150150150150150150150HPMC K4M(%)10----------5------HPMC K100M(%)--10----152015151520HPMC E15(%)----10--------5----EC(%)------10--------55PVP K30 (%)5555555555Talc (%)2.52.52.52.52.52.52.52.52.52.5Magnesium stearate(%)2.52.52.52.52.52.52.52.52.52.5MCC(mg)Q.SQ.SQ.SQ.SQ.SQ.SQ.SQ.SQ.SQ.STotal weight (mg)400400400400400400400400400400

COMPOSITION OF SUSTAINED RELEASE LAYERTable no 1 formulation table for sustained release layer

5.PREFORMULATION & FORMULATIONS STUDYDIRECT COMPRESSION FOR IMMEDIATE LAYER

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

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(%)2.52.52.52.52.52.52.52.52.5Talc (%)2.52.52.52.52.52.52.52.52.5SLS(%)------------0.511.5Total weight150150150150150150150150150

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

TABLE NO 3 : ACCEPTANCE CRITERIA OF FLOW PROPERTIES

Flow propertiesAngle of repose()Compressibility Index (%)Hausner ratioExcellent25-30 66>38>1.6

EVALUATIONS PARAMETERS

AppearanceWeight variation testThickness testHardness testFriability testDevelopment of analytical methods In-vitro studiesSwelling indexDrug content(assay of tablet)Release of kineticsStability study

6. RESULT & DISCUSSION Pre-compression parameters:Preformulation studies: Capacetabine(API)

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

6. RESULT & DISCUSSIONPreparation of standard calibration curve of Ondansetron: in 0.1N HCl calibration curve of Ondansetron in 0.1N HCl

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

COMPATIBILITY STUDIES

(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

Fig no 2: FTIR spectra of Ondansetron pure drug

Fig no 3: FTIR spectra of bilayered tablet

EVALUATION OF PRE COMPRESSION PARAMETERS FOR SUSTAINED RELAESE LAYER OF CAPACETABINE

FormulationsAngle of Repose ()Loose BulkDensity (g/ml)Tapped BulkDensity (g/ml) %CompressibilityHausners ratio

INVITRO DISSOLUTION STUDIES FOR SR TABLETS -DISSOLUTION STUDY ( SR TABLETS) :

Acidic Stage: Medium : 0.1N HCLType of apparatus: USP - II (paddle type)RPM : 50Volume : 900mlTemperature : 37C 0.5Time : 2hrs Buffer Stag