Formulation And Evaluation Of Sustained Release Matrix .
RIranian Journal of Pharmaceutical SciencesAutumn 2009: 5(4): 205-214ijps.sums.ac.irOriginal ArticleFormulation and Evaluation of Sustained ReleaseMatrix Tablets of GlipizideP.R. Radhikaa,*, T.K. Pala, T. SivakumarbaBioequivalenceStudy Centre, Department of Pharmaceutical Technology,Jadavpur University, Kolkata, IndiabNandha College of Pharmacy and Research Institute, Koorapalayam "Pirivu", Erode,Tamilnadu, IndiaAbstractThe purpose of this study was to develop a new monolithic matrix tablet to completelydeliver glipizide in a zero order manner over a sustained period. Two approaches wereexamined using drug in a formulation that contain polymer like hydroxylpropyl methylcellulose K 100 (HPMCK) and Eudragit L 100. The granules were prepared by wetgranulation method and thereby formulated as F-1, F-2. F-3 and F-4 by using the above bringup polymers with other ingredients. The granules of different formulations were evaluatedfor angle of repose, loose bulk density and tapped density, compressibility index, total porosity,and drug content. The angle of repose and compressibility index (%) ranged from 25.0 0.8to 28.0 1.1 and 12.92 0.02 to 13.08 0.03, respectively. The results of angle of repose ( 30)indicate good flow properties of the granules. This was further supported by lower compressibility index values. The granules showed satisfactory flow properties, compressibilityand drug content. All of the formulations showed uniform thickness (C.V 0.5%), uniformweight with little significance difference were observed with varying formulation composition.In the weight variation test, the pharmacopoeial limit for the percentage of deviation fortablets of more than 130 mg to 324 mg is 7.5 % difference. Technological characterizations(thickness, diameter, weight variation test, drug content, hardness, and friability) wereconceded with the formulated matrix tablet and in vitro drug release was measured by meansof dissolution apparatus. Of the various formulation distinguished, out of which, theformulation (F3) were preferred to be full of 30 mg of HPMCK and 35 mg of Eudragit L100was subjected to stability were accomplished studies for three months at 4 C. The roomtemperature (25 C) and (45 C) with relative humidity 75 5% were maintained and itsstability with respect to release pattern. The kinetic release treatment showed that therelease of drug follows zero order kinetic (r2 0. 9959), Koresmeyer equation gave valueof r2 0.9853 which was close to one indicating that the drug was released by zero orderkinetic. According to Koresmeyer equation, the formulation F-1, F-2, and F-4 showed theregression values of 0.9823, 0.9785, and 0.9742, respectively. The identical plot for (logcumulative percentage drug release vs time) for Koresmeyer-Peppas equation indicated agood linearity for the commercially available sustained release tablet and formulation F3 with regression values of 0.9619 and 0.9959, respectively. Scanning electron microscopeconfirmed both diffusion and erosion mechanism for the optimized batch of matrix tabletF-3. Results suggest that the formulated tablet F-3 of glipizide could perform therapeutically better than the reachable marketed drug leading to improve better efficacy.Keywords: Eudragit L 100; Glipizide; HPMC K 100; Matrix tablet; Sustained release.Received: July 29, 2008; Accepted: June 21, 2009.*Corresponding author: P.R. Radhika, Bioequivalence Study Centre,Department of Pharmaceutical Technology, Jadavpur University,Kolkata, India-700032E-mail: radhi kannan 2005@yahoo.co.in
PR Radhika et al / IJPS Summer 2009; 5(3): 205-2141. IntroductionIncreased complications and expenseinvolved in marketing of new drug entities hasfocused greater attention on development ofsustained release (SR) or controlled release(CR) drug delivery systems [1].Sustained orcontrolled release delivery systems canachieve predictable and reproducible releaserates, extended duration of activity for shorthalf - life drugs, decreased toxicity, andreduction of required dose, optimized therapyand better patient compliance [2, 3]. Matrixtype sustained delivery systems are popularbecause of their ease of manufactures. Itexcludes complex production procedure suchas coating and pellitization duringmanufacturing and drug release from thedosage form. It is controlled mainly by thetype and proportion of the polymers used inthe preparation. Hydrophilic polymer matrixis widely used for formulating a sustainedrelease dosage form [4, 5].The hydrophilic polymer selected for thepresent study was hydroxylpropyl methylcellulose K 100 (HPMC K 100). Hydrophilicpolymer matrix system are widely used fordesigning oral sustained release deliverysystems because of their flexibility to providea desirable drug release profile, costeffectiveness, and broad regulatoryacceptance. HPMC K 100 forms transparenttough and flexible films from aqueoussolution. The films dissolve completely inthe gastrointestinal tract at any biological pHand provide good bioavailability of the activeingredient. However, the use of hydrophilicmatrix alone for extending drug release forhighly water soluble drugs is restricted due torapid diffusion of the dissolved drug throughthe hydrophilic matrix. For such drugs itbecomes essential to include hydrophobicpolymers in the matrix system as Eudragit L100. Among the several polymers available aspossible matrix forming materials, methacrylicresins (Eudragit) appear particularly attractive[8], due to their high chemical stability, goodcompatibility properties and large variety ofproducts with different physicochemical characteristics present on the market.Glipizide is an oral hypoglycemic agent,which is a commonly prescribed drug for thetreatment of patients with type II diabetes[7]. It is used adjunct to diet to themanagement of type II (non-insulindependent) diabetes mellitus in patients whosehyperglycemia cannot be controlled by dietand exercise alone. Glipizide stimulatesinsulin secretion from the β cells of pancreaticislets tissue, increases the concentration ofinsulin in the pancreatic vein and may increasethe number of insulin receptors. Glipizide isa weak acid (pKa 5.9) practically insolublein water and acidic environment and highlypermeable (class II) drugs according to theBiopharmaceutical Classification System(BCS) [9]. The oral absorption is uniform,rapid and complete with a bioavailability ofnearly 100% and an elimination half-life of 24 hours [9]. Glipizide is reported to have ashort biological half-life (3.4 0.7 h) requiringit to be administered in 2 to 3 doses of 2.5 to10 mg per day [10]. SR formulations thatwould maintain plasma levels of drug for 8 to12 hrs might be sufficient for once a daydosing for glipizide. SR products are neededfor glipizide to prolong its duration of actionand to improve patient compliance [11].2. Materials and methods2.1. MaterialsGlipizide, HPMC K-100, Eudragit L-100,were received as gift samples from AravindRemedies (AR), Chennai. Lactose, povidone,iso propyl alcohol (IPA), aerosil, magnesiumstearate, was of AR Grade.2.2. Methods2.2.1. Preparation of matrix tabletsDifferent tablet formulations were preparedby wet granulation technique (Table 1). All thepowders were passed through sieve number80. Required quantities of drug and polymer206
Sustained release matrix tablets of glipizideTable 1. Composition of sustained release matrix tablets of glipizide.S. e (mg)HPMC-K100 (mg)Lactose (mgEudragit 100 (mg)Povidone (mg)Iso propyl alcohol (IPA) (ml)Aerosil (mg)Magnesium Stearate 27.55500.51were mixed thoroughly and a sufficientvolume of granulating agent was addedpovidone in isopropyl alcohol, slowly. Afterenough cohesiveness was obtained the masswas sieved through sieve number 22. Thegranules were dried at 55 5 C for one hour.Once dried the granules retained on sievenumber 44 were mixed with magnesiumstearate and aerosil for 2 min. The practicalweight of tablets, were calculated based on thedrug content of the granulations and the tabletswere compressed using double punchtableting machine, equipped with beveledflat faced punch of size 8 mm of diameter(Cadmach Machinery Company, Ahmedabad,India). Each tablet contained 10 mg ofglipizide and other pharmaceutical ingredientsas listed in Table 1. Prior to the compressionthe granules were evaluated for several tests.The angle of repose of granules wasdetermined by the funnel method. Thegranules were allowed to flow through thefunnel freely onto the surface. The diameterof the powder cone was measured and angleof repose was calculated using the followingequation [11].Tan θ h/rWhere ‘h’ and ‘r’ are the height and radius ofthe powder cone, respectively.2.3. Evaluation of granules2.3.1. Angle of reposeLBD Weight of the powder/ Volume of the packing2.3.2. Bulk densityBoth loose Bulk density (LBD) and tappeddensity (TBD) were determined. A calculatedquantity of 2 g of powder from each formulawas introduced into a measuring cylinder andtapped for certain time until no further changein volume was noted. LBD and TBD werecalculated using the following formula.TBD Weight of the powder/ Tapped Volume of the packingFigure 1. Percentage of drug release from the marketed tablet and formulated tablets (n 4, mean SE).207
PR Radhika et al / IJPS Summer 2009; 5(3): 205-2142.3.3. Compressibility indexThe compressibility Index of the granuleswas determined by Carr's compressibilityindex (Equation 1) [12].Carr's Index (%) (TBD-LBD) 100 / TBDvalues were calculated.2.4.2. Weight variation testTo study the weight variation, 20 tablets ofeach formulation were selected at randomand determine their average weight [14]. Notmore than 2 of the individual weights maydeviate from the average weight by morethan the % deviation and none should deviateby more than twice that percentage (Limitfor not more than 130 to 324 mg is 7.5 %.).(Equation 1)2.3.4. Total porosityTotal Porosity was determined bymeasuring the volume occupied by a selectedweight of a powder (V bulk) and the truevolume of the granules V the space occupiedby the powder exclusive of spaces greaterthan the intermolecular space) (Equation 2)[13].Porosity (%) [V bulk-V/ V Bulk] 1002.4.3. Drug contentTwenty Tablets were weighed individuallyand the drug was extracted in water. The drugcontent was determined by filtering thesolution through 0.45 μm. The drug contentwas analyzed after suitable dilution by spectrophotometrically at 276 nm.(Equation 2)2.3.5. Drug contentAn accurately weighed amount ofpowdered glipizide granules (15 mg)equivalent of glipizide was extracted withwater and the solution was filtered through0.45 μ membrane. The absorbance wasmeasured spectrophotometrically at 276 nmafter suitable dilution.2.4.4. Hardness and friabilityFor each formulation, the hardness andfriability of 20 tablets each were determinedusing the Monsanto Hardness Tester andRoche Friabilator (Cadmach, Ahmedabad,India), respectively.2.4. Evaluations of tablets2.4.1. ThicknessThe thickness of the tablets weredetermined using a Digital Caliper (Mitutoyo,Digimatic Caliper, New Delhi, India) 20tablets from each batch were used and average2.5. In vitro release studiesThe in vitro dissolution studies wereperformed using USP -22 type I dissolution(Electro Lab, TDT -08 L, Mumbai, India)Figure 2. Percentage of drug release from the marketed tablet and formulated tablet, (n 4, mean SE).208
Sustained release matrix tablets of glipizideapparatus 37 5 C, at 50 rpm. Using 900 mlof 0.1 N HCl for first 2 hr and phosphatebuffer of pH 6.8 from 2-12 hr. An aliquot (5ml) of the sample solution was withdrawn atpredetermined time intervals , filtered througha 0.45 μm membrane filter, diluted suitablyand analyzed spectrophotometrically at 276nm (Shimadzu Model 1601). An equal amountof fresh dissolution medium was replacedimmediately after withdrawal of the testsample. The release studies were conductedin triplicate.The optimum formulation was selectedon the above equation so that it could attaincomplete and controlled drug release upon"trading off" various response variables; thefollowing maximizing criteria were adopted.2.7. Kinetic release profileTo study the release kinetics, data obtainedfrom in vitro drug release studies were plottedin various kinetic models, zero order(Equation 4) as cumulative amount of drugreleased vs time, first order (Equation 5) as logcumulative percentage of drug remaining vs.time, and Higuchi's model (Equation 6) ascumulative percentage of drug released vs.square root o f time.2.6. Optimum release profileOptimum release profile for once dailySR formulation was calculated by theEquation 3 using available pharmacokineticdata [15].Dt Dose (1 0.693 t / t ½)Q Ko.t(Equation 4)Where ‘Ko’ is the zero -order rate constantexpressed in units of concentration / time andt is the time in hours. A graph of concentrationvs. time would yield a straight line with aslope equal to Ko and intercept the origin ofthe axes [16].(Equation 3)Where Dt is total dose of drug, dose is doseof the immediate release part, t is time duringwhich the sustained release is desired (24 h)and t ½ is half -life of the drug (3 h).Figure 3. Scanning electron photographs of the matrix tablet formulation F3 taken at different time intervals after thedissolution experiment. A, B, C and D revealing the dissolution studies at the time of 0, 2, 8, 12 h, respectively.209
PR Radhika et al / IJPS Summer 2009; 5(3): 205-214Table 2. Characterisation of granules and formulated glipizide tablets.Formulation Angle ofrepose ( )Bulkdensity (g/ml)Tap Density(g/ml)F128 1.10.43F225 0.80.37F327 0.90.36F426 0.60.39All values are expressed as mean S.D. (n 3).Log C Log Co- kt/ 2.3030.530.520.500.53Carr'sindex (%)13.08 0.0298 3.612.95 0.0399 3.912.92 0.02 99.5 3.712.95 0.03 99 4.1(Equation 6)Where ‘K’ is the constant, reflecting thedesign variables of the system and t is the timein hours. These models fail to explain drugrelease mechanisms due to the swelling (uponhydration) along with gradual erosion of thematrix. Therefore the dissolution data wasalso fitted to the well known Koresmeyerequation (Equation 7) which is often used todescribe the drug release behavior frompolymer systems.Log (Mt/Mα) log K n LogtDrugcontent (%)98.3 4.399.2 4.099.5 3.098.7 4.0Friability(%) 0.31 0.31 0.32 0.29Hardness(Kg/cm2)6.3 0.26.1 0.26.0 0.16.2 0.1Weightvariation(%)0.2500.2500.2500.2502.8. Accelerated stability studiesTablets from optimized formulated batchF3 was packed in an air tight high densitypolythene bottles and kept at 45 C with75 5% RH for 3 months as per InternationalCongress on Harmonization states (ICH)guidelines. Samples were withdrawn at 0,30, 60 and 90 days of storage and evaluatedfor appearance, hardness and drug content.(Equation 5)Where ‘Co’ is the initial concentration ofdrug, ‘k’ is the first order constant, and t is thetime [17].Q ketTotal drugcontent (%)2.9. Scanning electron microscopyThe optimized tablet samples wereremoved from the dissolution apparatus atpredetermined time intervals and sectionedthrough an undisturbed portion of the sampleholder so as to present a cross section of thetablet to the microscope. Samples were coatedwith gold and visualized under scanningelectron microscope (SEM).(Equation 7)Where ‘Mt’ is the amount of the drug releaseat time ‘t’, ‘Mα’ is the amount of drug releaseafter infinite time and ‘K’ is a release rateconstant incorporating structural andgeometric characteristic of the tablet and ‘n’is the diffusion exponent indications of themechanism of drug release. To clarify therelease exponent for different batches ofmatrix tablet the log value of percentage ofdrug dissolved was plotted against log time foreach batch according to the equation. A valueof n 0.45 indicates Fickian (case -I) release: 0.45 but 0.89 for non-Fickian (Anomalous)release and 0.89 indicates super case II typeof release. Case II generally refers to theerosion of the polymeric chain and anomaloustransport (non-Fickian) refers to acombination of both erosion and diffusioncontrolled drug release [17].3. Results and discussion3.1. Evaluation of granulesGranulation is the key process in theproduction of tablet dosage form involving thesustained release of a drug from coated tomatrix type particles. A granule is theaggregation of constituent particles that isheld together by the presence of bonds ofrestricted strength. Physical properties ofgranules such as specific surface area, shape,hardness, surface characteristics, and size cansignificantly affect the rate of dissolution ofdrugs contained in the heterogeneousformulation. The granules of differentformulations were evaluated for angle ofrepose, LBD, TBD, compressibility index,total porosity, and drug content (Table 2).The angle of repose and compressibility index(%) ranged from 25.0 0.8 to 28.0 1.1 and12.92 0.02 to 13.08 0.03, respectively. The210
Sustained release matrix tablets of glipizideTable 3. Correlation coefficients according to different kinetic equations used for describing glipizide release behavior.FormulationF1F2F3F4Commerciallyavailable tabletZero Order0.99320.98790.99590.98670.9619First Orderr2-0.8923-0.9124-0.9505-0.8123-0.6109results of angle of repose ( 30) indicate goodflow properties of the granules [18]. This wasfurther supported by lower compressibilityindex values (Table 2). Generally, compressibility index values up to 15% result inexcellent flow properties. The results of LBDand TBD ranged from 0.36 to 0.43 and 0.50to 0.53, respectively. The percentage porosityvalues of the granules ranged from 26.92 to37.61%, indicating that the packing of thegranules may range from close to loosepacking and also further confirming that theparticles are not of greatly different sizes.Generally, a percentage porosity value below26% shows that the particles in the powdersare of greatly different sizes and a valuegreater than 48% shows that particles in thepowder are in the form of aggregates orflocculates [19]. The drug content in theweighed amount of granules of allformulations was found to be uniform.Higuchi model0.97270.97070.96950.95100.9922Korsmeyer 0.98530.97420.9957of all tablet formulations was found to bewithin the said limit, and hence allformulations passed the test for uniformity ofweight as per official requirements [20]. Drugcontent was found to be uniform amongdifferent batches of the tablets (n 20) andranged from 98.3 0.4 to 99.5 0.3. Thehardness of the tablets (n 10) ranged from6.0 0.1 to 6.3 0.2 kg / cm2. The percentagefriability of the tablets (n 10) ranged from0.079 0.310 to 0.088 0.12 %. The percentagefriability for all the formulations were below1% indicating that the friability is within theprescribed limits [22]. All the tabletformulationsshowedacceptablepharmacopoeial properties and complied withthe in house specifications for weightvariation, drug content, hardness, andfriability.3.3. Dissolution studiesIdeally, an extended release tablet shouldrelease the required quantity of drug withpredetermined kinetics in order to maintain aneffective drug plasma concentration. Toachieve this, the tablet should be formulatedso that it releases the drug in a predeterminedand reproducible manner. By considering thedrugs biopharmaceutic and pharmacokineticprofile, one can determine the required releasefrom the tablet [23]. Figures 1 and 2 shows thein vitro drug release profile of glipizide SRmatrix tablets. Visual observation of the tabletsduring dissolution testing revealed thatswelling was dominant during the testprocedure. According to the theoretical releasepattern, once daily glipizide SR formulation3.2. Technological characteristics of glipizidematrix tablet and drug contentThe tablets of different formulations weresubjected to various evaluation tests, such asthickness, diameter, and
Formulation and Evaluation of Sustained Release Matrix Tablets of Glipizide P.R. Radhikaa,*, T.K. Pal a, T. Sivakumar b aBioequivalence Study Centre, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India bNandha College of Pharmacy and Research Institute, Koorapalayam "Pirivu", Erode, Tamilnadu, India Abstract The purpose of this study was to develop a new monolithic .
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