a three-layer guar gum matrix tablet for oral controlled delivery of highly soluble metoprolol...

International Journal of Pharmaceutics 241 (2002) 353–366

A three-layer guar gum matrix tablet for oral controlleddelivery of highly soluble metoprolol tartrate

Y.S.R. Krishnaiah *, R.S. Karthikeyan, V. SatyanarayanaDepartment of Pharmaceutical Sciences, College of Engineering, Andhra Uni�ersity, Visakhapatnam 530 003, India

Received 21 November 2001; received in revised form 25 March 2002; accepted 13 May 2002

Abstract

The objective of the study is to design oral controlled drug delivery systems for highly water-soluble drugs usingguar gum as a carrier in the form of a three-layer matrix tablet. Metoprolol tartrate was chosen as a model drugbecause of its high water solubility. Matrix tablets containing either 30 (M1), 40 (M2) or 50% (M3) of guar gum wereprepared by wet granulation technique using starch paste as a binder. Three-layer matrix tablets of metoprololtartrate were prepared by compressing on both sides of guar gum matrix tablet granules of metoprolol tartrate M1,M2 or M3 with either 50 (TL1M1, TL1M2 or TL1M3) or 75 mg (TL2M1, TL2M2 or TL2M3) of guar gum granulesas release retardant layers. Both the matrix and three-layer matrix tablets were evaluated for hardness, thickness, drugcontent uniformity, and subjected to in vitro drug release studies. The amount of metoprolol tartrate released fromthe matrix and three-layer matrix tablets at different time intervals was estimated by using a HPLC method. Matrixtablets of metoprolol tartrate were unable to provide the required drug release rate. However, the three-layer guargum matrix tablets (TL2M3) provided the required release rate on par with the theoretical release rate for metoprololtartrate formulations meant for twice daily administration. The three-layer guar gum matrix tablet (TL2M3) showedno change either in physical appearance, drug content or in dissolution pattern after storage at 40 °C/75% RH for6 months. The FT-IR study did not show any possibility of metoprolol tartrate/guar gum interaction with theformulation excipients used in the study. The results indicated that guar gum, in the form of three-layer matrixtablets, is a potential carrier in the design of oral controlled drug delivery systems for highly water-soluble drugs suchas metoprolol tartrate. © 2002 Elsevier Science B.V. All rights reserved.

Keywords: Metoprolol tartrate; Three-layer matrix tablets; Controlled drug delivery; Guar gum; Water-soluble drug; Dissolution

www.elsevier.com/locate/ijpharm

1. Introduction

Oral ingestion has long been the most conve-nient and commonly employed route of drug de-livery due to its ease of administration, highpatient compliance, least sterility constraints andflexibility in the design of the dosage form. Hy-drophilic polymers are becoming very popular in

* Corresponding author. Tel.: +91-891-530272; fax: +91-891-747969/755547.

E-mail address: [email protected] (Y.S.R. Kr-ishnaiah).

0378-5173/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved.

PII: S0 378 -5173 (02 )00273 -9

mailto:[email protected]

Y.S.R. Krishnaiah et al. / International Journal of Pharmaceutics 241 (2002) 353–366354

formulating oral controlled release tablets. Asthe dissolution medium or biological fluid pene-trates the dosage form, the polymer materialswells and drug molecules begin to move out ofthe system by diffusion at a rate determined bythe nature and composition of the polymer aswell as formulation technology. Developing oralcontrolled release tablets for highly water-solubledrugs with constant release rate has always beena challenge to the pharmaceutical technologist.Most of these highly water-soluble drugs, if notformulated properly, may readily release thedrug at a faster rate and are likely to producethe toxic concentrations, when administeredorally.

Metoprolol tartrate, widely used in the treat-ment of angina pectoris, arrhythmias and hyper-tension, was chosen as a model drug havinghigh solubility. The enhanced therapeutic effi-cacy of this drug through the provision of con-stant rate input and maintenance of steady-stateblood levels is well documented (Sandberg et al.,1988; Kendall, 1989). Early pharmacokineticstudies have established that it has a relativelyshort plasma half-life of 3–4 h and its absorp-tion is rapid as well as consistent throughout thegastrointestinal tract including the distal region(Regardh et al., 1974; Godbillon et al., 1985).As a prerequisite, a combination of both theseproperties makes metoprolol tartrate a suitablecandidate for development into a controlled re-lease formulation.

Different types of controlled release formula-tions such as matrix tablets (Eddington et al.,1998), multiple emulsions (Ghosh et al., 1996),iontophoretic application (Okabe et al., 1987),osmotic tablets (Breimer, 1983) and electrolyte-induced peripheral stiffening matrix system (Pil-lay and Fassihi, 2000) have been developed toimprove the clinical efficacy of metoprolol tar-trate.

In the recent times, multi-layer matrix tabletsare gaining importance in the design of oralcontrolled drug delivery systems. One or twolayers of release retardant polymers are appliedon both sides of a matrix tablet such that theswollen hydrophilic polymer controls the drugrelease after oral administration. These formula-

tions are designed to deliver the drugs at a con-trolled and predetermined rate, thus maintainingtheir therapeutically effective concentrations insystemic circulation for prolonged periods oftime.

The widely used polymers for sustaining thedrug delivery are HPMC, NaCMC, chitosan,HPC, MC, Eudragits, natural gums etc. In thepresent investigation, it is planned to use guargum, a naturally occurring and abundantlyavailable polysaccharide, as a release retardantcarrier in the design of three-layer matrix tabletsfor highly water-soluble drugs such as metopro-lol tartrate (model drug). A few reports appearin the literature on the use of guar gum, as acarrier, for controlled delivery of drugs (Altaf etal., 1998; Khullar et al., 1998; Jain et al., 1992).Earlier it was reported from our laboratory thatguar gum is a potential hydrophilic matrix car-rier for controlled delivery of drugs having vary-ing solubility (Krishnaiah et al., 2001). Sincemetoprolol tartrate is a highly water-solubledrug, it is planned to develop a controlled re-lease matrix formulation using guar gum as acarrier.

Guar gum is a natural non-ionic polysaccha-ride derived from the seeds of Cyamopsis te-tragonolobus (Family-Leguminosae). Inpharmaceuticals, guar gum is used in soliddosage forms as a binder and disintegrant, andin liquid oral and topical products as a suspend-ing, thickening and stabilizing agent. Therapeuti-cally guar gum is used as part of the diet of thepatients suffering from diabetes mellitus. Guargum on exposure to dissolution fluids gets hy-drated and forms a viscous gel layer that slowsdown further seeping-in of dissolution fluids to-wards the core of the matrix tablet (RamaPrasad et al., 1998; Krishnaiah et al., 1998a,b,1999). The strength of the viscous gel layeraround the core of the matrix tablets generallydepends on several factors such as particle size,force of compression, presence of other excipi-ents, viscosity of the polymer, solubility of thedrug etc. This paper describes the developmentand evaluation of oral controlled drug deliverysystems for metoprolol tartrate using guar gumas a carrier in the form of a three-layer matrixtablet.

Y.S.R. Krishnaiah et al. / International Journal of Pharmaceutics 241 (2002) 353–366 355

2. Materials and methods

2.1. Materials

Metoprolol tartrate (98–101% purity) and rofe-coxib (98.6–101.4% purity) were gift samplesfrom M/s Astra-IDL Ltd., Bangalore, India andM/s. Torrent Laboratories, Ahmedabad, India,respectively. Guar gum (viscosity of 1% aqueousdispersion is 3725 cps; particle size �75 �m) wasobtained from M/s. Dabur Research Foundation,India and was of pharmacopoeia quality (USP/NF). Acetonitrile (HPLC grade) and methanol(HPLC grade) were obtained from M/s. QualigensFine Chemicals, Mumbai, India. Other materialsused in the study such as hydroxypropylmethyl-cellulose (HPMC, 15 cps), talc, magnesiumstearate and starch were of pharmacopoeia qual-ity (USP/NF).

2.2. Preparation of metoprolol tartrate matrixtablets

Matrix tablets of metoprolol tartrate were pre-pared by wet granulation method. A mixture oftalc and magnesium stearate (2:1 ratio) was usedas lubricant and HPMC was used as diluent.Guar gum was included in the formulation invarious proportions. Three matrix formulationswere prepared with 30, 40 or 50% of guar gumand were coded as M1, M2 or M3, respectively.The composition of formulations used in thestudy containing 150 mg of metoprolol tartrate ineach case is shown in Table 1. In all the formula-tions, guar gum was sieved (�250 �m) separatelyand mixed (planetary mixer, R&D model, Kar-nawati Engineering Ltd., India) with metoprololtartrate (�150 �m) and HPMC (�250 �m). Thepowder mix was granulated with 10% w/w starchpaste in the same planetary mixer. The wet masswas passed through a mesh (1680 �m; Multimill,Pharma Fab Industries, India) and the granuleswere dried at 50 °C for 2 h in a tray drier (HiconLaboratory Equipment, India). The dried gran-ules were passed through a mesh (1190 �m; Drygranulator, R&D model, Karnawati EngineeringLtd., India) and these granules were lubricatedwith a mixture of talc and magnesium stearate

(2:1) using a cone blender (R&D model, CadmachMachinery Co. Pvt. Ltd., India). The lubricatedgranules were compressed at a compression forceof 4500–5500 kg using 11 mm round, flat andplain punches on a single station tabletting ma-chine (M/s. Cadmach Machinery Co. Pvt. Ltd.,India). Matrix tablets of each composition weretested for their drug content and release charac-teristics with a suitable number of tablets for eachtest. The hardness of the matrix tablets was deter-mined by using Monsanto Hardness Tester.

2.3. Preparation of three-layer matrix tablets

Three-layer matrix tablets were prepared bycompressing 50 mg of granules containing 87% ofguar gum on both sides of matrix granules con-taining either 30, 40 or 50% of guar gum (codedas TL1M1, TL1M2 or TL1M3, respectively). Theother three-layer tablets were prepared by com-pressing 75 mg of granules containing 87% ofguar gum on both sides of matrix granules con-taining either 30, 40 or 50% of guar gum (codedas TL2M1, TL2M2 or TL2M3, respectively). Thepreparation of three-layer matrix tablets involvedthe following steps:1. Preparation of granules for the matrix tablets.2. Preparation of guar gum granules for layering.3. Compression of a layer of either 50 or 75 mg

of guar gum granules on both sides of thematrix tablet granules.

Table 1Composition of metoprolol tartrate matrix tablets containingeither 30 (M1), 40 (M2) or 50% (M3) of guar gum

Ingredients Quantity (mg) present in matrixtablet

M3M2M1

150150 150Metoprolol tartrate135Guar gum 225180

4545Starch 45106.5HPMC 61.5 16.59.0 9.0Talc 9.0

4.54.5Magnesium stearate 4.5450Total weight (mg) 450 450


Table 2Composition of guar gum granules for three-layer tablets of metoprolol tartrate

Quantity (mg) present in guar gum release retardant layer formulationIngredients

TL1M1 TL1M2 TL1M3 TL2M1 TL2M2 TL2M3

43.5 43.5Guar gum 65.2543.5 65.25 65.255Starch as paste 5 5 7.5 7.5 7.5

1.0 1.0 1.51.0 1.5Talc 1.50.5 0.5 0.75 0.75 0.75Magnesium stearate 0.550 50 75 75 7550Weight of guar gum granules

Three-layer matrix tablets (TL1M1) containing 50mg of guar gum granules as release controllinglayer on both sides of 30% matrix granules wasprepared as follows. Granules of the matrix for-mulation containing 30% of guar gum (M1) wereprepared as described above.

Guar gum granules containing 87% of guargum for layering were prepared by wet granula-tion method using 10% w/w of starch as paste.The guar gum and starch paste was mixed well(Planetary mixer, R&D model, Karnawati Engi-neering Ltd., India) and the resulting wet masswas passed through a mesh (1680 �m; Multimill,Pharma Fab Industries, India) and the granuleswere dried at 50 °C for 2 h in a tray drier (HiconLaboratory Equipment, India). The dried gran-ules were passed through a mesh (1190 �m; drygranulator, R&D model, Karnawati EngineeringLtd., India) and these granules were lubricatedwith a mixture of talc and magnesium stearate(2:1) using a cone blender (R&D model, CadmachMachinery Co. Pvt. Ltd., India). The compositionof guar gum granules used in the study for layer-ing in three-layer matrix tablets is given in Table2.

Initially the volume of the die cavity (11 mmround, flat and plain) was adjusted equivalent tothe weight of three-layer matrix tablets (550 or600 mg). Then preweighed amount of guar gumgranules equivalent to bottom layer (50 or 75 mg)was taken and placed in die cavity and slightlycompressed for uniform spreading. The upperpunch was lifted up, and granules of the matrixformulation (M1) were placed over the bottomlayer of guar gum granules in the die cavity andagain slightly compressed for uniform spreading.

The remaining volume of the die cavity was filledwith the preweighed amount of guar gum gran-ules equivalent to top layer (50 or 75 mg) andcompressed with a maximum force of compres-sion on single station tabletting machine to obtainthree-layer matrix tablets. Thus the top and bot-tom layers of the three-layer matrix tablet con-sisted of release retardant guar gum and themiddle layer consisted of guar gum matrix layeralong with metoprolol tartrate.

2.4. HPLC analysis of metoprolol tartrate inmatrix tablets, three-layer matrix tablets anddissolution fluids

The quantitative determination of metoprololtartrate in guar gum matrix tablets, three-layermatrix tablets and dissolution fluids was per-formed by a reversed phase high performanceliquid chromatography (HPLC). A ShimadzuHPLC system (Shimadzu, Japan) with two LC-10AT VP pumps, a SPD-10A VP variable wave-length UV/Vis detector, a CTO-10AS VP columnoven, a SCL-10A VP system controller (Shi-madzu) and a RP C-18 column (250×4.6 mm2

I.D.; particle size 5 �m; YMC, Inc., Wilmington,NC 28403, USA) was used. The HPLC systemwas equipped with the software ‘Class-VP seriesversion 5.03 (Shimadzu)’.

The mobile phase used was a mixture of 0.01 Mpotassium dihydrogen phosphate, acetonitrile andmethanol in the ratio of 55:22.5:22.5. The filteredmobile phase components were pumped at a flowrate of 1.2 ml min−1. The column temperaturewas maintained at 40 °C. The eluent was detectedby UV detector at 274 nm and the data were


acquired, stored and analyzed with the software‘Class-VP series version 5.03 (Shimadzu)’. A stan-dard curve was constructed for metoprolol tar-trate in the range of 0.1–40 �g ml−1 usingrofecoxib (100 �g) as internal standard. A goodlinear relationship was observed between the con-centration of metoprolol tartrate and the ratio ofthe peak area of metoprolol tartrate to that ofrofecoxib (internal standard) with a high correla-tion coefficient (r=0.9999). The required studieswere carried out to estimate the precision andaccuracy of this HPLC method of analysis ofmetoprolol tartrate. The standard curve con-structed as described above was used for estimat-ing metoprolol tartrate either in the matrixtablets, three-layer matrix tablets or in dissolutionfluids.

2.5. Determination of drug content

The metoprolol tartrate guar gum matrixtablets and three-layer matrix tablets were testedfor their drug contents. Ten tablets were finelypowdered; 100 mg of the powder was accuratelyweighed and transferred to 100-ml volumetricflask. Initially about 50 ml of triple distilled water(TD water) were added to the volumetric flaskand allowed to stand for 6 h with intermittentsonication to ensure complete solubility of thedrug. Then the volume was made up with TDwater and the mixture was centrifuged. Onemilliliter of the supernatant liquid was added with100 �g of rofecoxib (internal standard), the vol-ume made upto 10 ml with TD water, filteredthrough 0.2-�m membrane filter and analyzed formetoprolol tartrate by HPLC as describedpreviously.

2.6. In �itro drug release studies

Metoprolol tartrate matrix tablets and three-layer matrix tablets were subjected to in vitrodrug release studies in simulated gastric and intes-tinal fluids to assess their ability in providing thedesired controlled drug delivery. Drug releasestudies were carried out using USP dissolutionrate test apparatus (apparatus 1, 100 rpm, 37�0.5 °C) for 2 h in pH 1.2 buffer (900 ml) as the

average gastric emptying time is about 2 h. Thenthe dissolution medium was replaced with pH 7.4phosphate buffer (900 ml) and the experiment wascontinued for another 10 h. At different timeintervals, 1 ml of the sample was withdrawn andreplaced with 1 ml of pH 7.4 phosphate buffer.One milliliter of dissolution sample was addedwith 100 �g of rofecoxib (internal standard), thevolume made upto 10 ml with TD water, cen-trifuged, the supernatant liquid was filteredthrough 0.2-�m membrane filter and analyzed formetoprolol tartrate by HPLC as described previ-ously. During the drug release studies, all theformulations were observed for physical integrity.

2.7. Drug release studies in rat caecal contentmedium

Earlier reports indicate the susceptibility ofguar gum to the action of colonic bacterial en-zymes (Rama Prasad et al., 1998; Krishnaiah etal., 1998a,b, 1999). In this context, it is essentialto study the influence of colonic bacterial enzymeson the release of metoprolol tartrate from theguar gum formulations. This was assessed byconducting in vitro drug release studies in ratcaecal content medium as reported earlier (RamaPrasad et al., 1998). The rat caecal content wasprepared as described previously (Rama Prasad etal., 1998). The care of the rats was in accordancewith the institutional guidelines, which were basedon Canadian Council on Animal Care (1984).

The drug release studies were carried out usingUSP dissolution rate test apparatus (apparatus 1,100 rpm, 37 °C) with slight modifications. Abeaker (capacity 150 ml) containing 100 ml of ratcaecal content medium was immersed in the watermaintained in the 1000 ml vessel, which, in turn,was in the water bath of the apparatus. Theswollen matrix tablets contained in the baskets ofthe apparatus, after completing the dissolutionstudy in 0.1 M HCl (2 h) and pH 7.4 phosphatebuffer (3 h) were immersed in the rat caecalcontent medium. As the caecum is naturallyanaerobic, the experiment was carried out withcontinuous CO2 supply into the beakers.

At different time intervals, 1 ml of dissolutionsample was withdrawn and replaced with 1 ml of


fresh PBS bubbled with CO2, and the experimentwas continued upto 19 h. After the addition of100 �g of rofecoxib (the internal standard), thevolume of the dissolution sample was made upto10 ml with PBS and centrifuged; the supernatantwas filtered through 0.2-�m membrane filter andanalyzed for metoprolol tartrate content byHPLC method as described above. Drug releasestudies were also conducted on metoprolol tar-trate matrix tablets after completing in vitro dis-solution study in 0.1 M HCl (2 h) and pH 7.4phosphate buffer (3 h) without rat caecal contentsin PBS (control study). The drug content re-mained either in the mass of the formulation or inswollen formulation was also determined byHPLC to account for the total amount of drugpresent in the formulation. This ensures the esti-mation of all the finely suspended drug particlesthat may be released from the guar gum matrixformulation on erosion by colonic bacteria.

2.8. Kinetics of drug release

The cumulative amount of metoprolol tartratereleased from matrix tablets and three-layer ma-trix tablets at different time intervals was fitted tozero order kinetics using Least-Squares Methodof analysis to find out whether the drug releasefrom the formulations is providing a constantdrug release. The correlation coefficient betweenthe time and the cumulative amount of drugreleased was also calculated to find the fitness ofthe data to zero order kinetics. The fitness of thedata to first order kinetics was assessed by deter-mining the correlation coefficient between thetime and the amount of drug to be released fromthe formulations.

The data were also fitted to the model devel-oped by Korsmeyer et al. (1983) in order to findout the drug release mechanism from the formula-tions. The cumulative percent of drug releasedfrom the formulations was plotted against time onlog– log scale, and analyzed for linearity usingLeast-Squares Method. Calculating correlationcoefficients between time and the cumulative per-cent of drug released on log– log scale, tested thefitness of the data.

2.9. Statistical analysis

The cumulative percent of metoprolol tartratereleased from guar gum matrix tablets (n=3) inthe dissolution medium at 24 h with and withoutrat caecal contents was compared, and the statisti-cal significance was tested by using Student’s t-test. A value of P�0.05 was consideredstatistically significant.

2.10. Stability studies

Stability studies were conducted on metoprololtartrate three-layer matrix tablets containing vari-ous proportions of guar gum to assess their stabil-ity with respect to their physical appearance, drugcontent and release characteristics after storing at40 °C/75% RH for 6 months (Mathews, 1999).

2.11. Fourier Transform Infrared Studies (FT-IR)

The FT-IR spectra of metoprolol tartrate, guargum, powdered sample of middle layer of thethree-layer matrix tablet coated with 75 mg ofguar gum (before storage) or powdered sample ofmiddle layer of the three-layer matrix tabletcoated with 75 mg of guar gum (after storage)were obtained (Shimadzu FT-IR system, Japan)after making potassium bromide discs with thesample to detect drug–excipients interaction, ifany.

3. Results and discussion

The present study was carried out to developoral controlled release tablet dosage form forhighly water-soluble drug such as metoprolol tar-trate. For management of hypertension, the usualeffective dose of metoprolol tartrate is 100–300mg daily in two divided doses. For managementof angina pectoris, the usual dose is 100–400 mgin two divided doses. In the present study, 150 mgof metoprolol tartrate was incorporated in theformulations. The required first order release rateconstant (kr1) of metoprolol tartrate from thetablet formulation, for twice daily oral adminis-tration, was calculated using the following equa-tion (Lordi, 1989).


kr1=ke(exp(−ke×Ti),

where ke is the elimination rate constant (0.2165h−1) and Ti, crossing time at which the bloodlevel profiles produced by administration of sepa-rate loading and maintenance doses intersect. Thevalue of ‘Ti’ was in turn calculated using therelationship Ti=h−Tp (where ‘h ’ is the durationof therapy, i.e. 12 h in the present study and Tp isthe time taken for maximum plasma concentra-tion, i.e. 1.68 h). Thus, the required first orderrelease rate constant based on the mean pharma-cokinetic parameters of the drug in humans (Perryet al., 1996) was found to be 0.0232 h−1. Theguar gum formulations developed in the studywere subjected to in vitro drug release studies andwere optimized till the required first order releaserate of metoprolol was obtained.

3.1. In-�itro drug release studies on matrixtablets

In the present study, guar gum was used, as ahydrophilic matrix carrier, in the design of oralcontrolled drug delivery systems for highly water-soluble drug such as metoprolol tartrate. Guargum was found to have poor flow properties andlow compressibility, and since it is to be incorpo-rated in the matrix tablets in a larger proportion,metoprolol tartrate tablets were prepared by wetgranulation technique using starch paste as abinder to impart good flow as well ascompressibility.

Good flow of powders/granules is essential intabletting. The present investigation involves thepreparation of three-layer matrix tablets contain-ing high proportion of guar gum and the excipi-ents. Thus, the compressibility and flow propertiesof the drug and guar gum are likely to influencethe compression process in the preparation ofthree-layer matrix tablets. In view of this, thethree-layer matrix tablets were prepared by wetgranulation technique using starch paste as abinder. The flow property of pure drug, guar gumand the resulting granules was evaluated by deter-mining angle of repose and Carr’s Index.

Angle of repose was determined by the fixedfunnel method (Craik, 1958; Train, 1958). A fun-

nel with the end of the stem cut perpendicular tothe axis of symmetry was secured with its tip at agiven height (H) above a graph paper placed on aflat horizontal surface. The material was carefullypoured through the funnel until the apex of theconical pile so formed just touches the tip of thefunnel. The mean diameter (2R) of the base of thepowder cone was determined and the tangent ofthe angle of repose is given by tan �=H/R, where� is the angle of repose.

Carr’s Index relates the poured density of thematerial to the tapped density and was calculatedby using the following relationship:

Carr’s Index

=tapped density−poured density×100

tapped density.

Carr’s Index values for pure drug, guar gumand granules were determined by measuring theinitial volume (Vp) and final volume (Vt) of aknown weight (W) of material after subjecting to100 tappings in a graduated measuring cylinder.From these volumes, the poured density (W/Vp)and the tapped density (W/Vt) values were calcu-lated and were substituted in the above equationto determine Carr’s Index.

The angle of repose for pure drugs and guargum samples could not be obtained since they didnot flow at all through the funnel indicating verypoor flow properties. The Carr’s index of puremetoprolol tartrate and guar gum was found tobe 33.71�0.11 and 23.98�0.77, respectivelyconfirming that both the drug and guar gum havepoor flow properties. The results of the studywarrants the granulation of the drug/gum powdermix for compression into a matrix tablet to giveuniform dose. Metoprolol tartrate guar gum ma-trix granules were prepared by wet granulationmethod using 10% w/w starch paste as binder.

The improvement in the flow property of thegranules has been evaluated by determining angleof repose and Carr’s Index as described above. Alldried granules were found to be free flowing withan angle of repose ranging from 18 to 25° andCarr’s index ranging from 11.21�0.01 to 14.10�0.02 indicating that the desired flow propertieswere achieved after granulation with starch paste.


Metoprolol tartrate matrix tablets containingdifferent proportions of guar gum along withother additives were prepared by wet granulationmethod and subjected to various tests such ashardness, thickness, drug content (Table 3) and invitro drug release studies. The mean values forhardness of the matrix tablets of metoprolol tar-trate were in the range of 4.94�0.11–5.11�0.12kg. The HPLC method used in the study wasfound to be highly precise (�1.4% CV) andaccurate (99.8–101.1% recovery). All the matrixtablets satisfied the drug content uniformity asthey contained between 98.44�0.83 and101.44�0.53% of metoprolol tartrate when as-sayed by HPLC method as described above. Ma-trix tablets prepared with different proportion ofguar gum were subjected to in vitro drug releasestudies in pH 1.2 buffer for the first 2 h and in pH7.4 buffer for another 10 h. When the amount ofdrug released at different time intervals was fittedto zero and first order kinetics, a better correla-tion (r=0.9537�0.02–0.9946�0.01) was ob-served for first order kinetics when compared tozero order kinetics (Table 4). The first order re-lease rate constants obtained from M1, M2 andM3 formulations were 0.0750�0.01, 0.0680�0.01 and 0.0560�0.02 h−1, respectively. Thougha controlled release was observed (Fig. 1), meto-prolol matrix tablets could not provide the re-quired release rate (0.0232 h−1). Moreover, thedrug release in pH 1.2 buffer was significantlyhigh indicating the need for further control. Inorder to provide the required control of drug

release, it is planned to coat a layer of guar gumas a release retardant polymer on both sides ofthe guar gum matrix formulations so as to pre-pare three-layer matrix tablets.

3.2. In-�itro drug release studies on three-layerguar gum matrix tablets

Metoprolol tartrate three-layer matrix tabletswith either 50 or 75 mg of guar gum as releaseretardant layer were formulated and prepared.Guar gum granules containing 87% of guar gumwere prepared by wet granulation technique usingstarch paste as binder. Thus, the three-layer guargum matrix tablets of metoprolol tartrate con-tained a middle layer of guar gum and metoprololwith only guar gum in the top and bottom layers.These formulations were tested for hardness anddrug content (Table 3), and were subjected to invitro drug release studies. The mean values forhardness of the three-layer matrix tablets of meto-prolol tartrate were in the range of 5.02�0.14–5.63�0.15 kg. All the three-layer matrix tabletssatisfied the drug content as they contained98.23�0.67–102.44�0.23% of drug indicatinguniform mixing of the guar gum, drug and otherformulation excipients.

All the formulations were found swollen andretained their physical integrity till the end of the12-h dissolution study except that the edges of theswollen formulations were rounded off due toslight erosion of swollen gum. The mean correla-tion coefficients obtained with all three-layer for-

Table 3Characteristics of metoprolol tartrate guar gum matrix tablets and guar gum three-layer matrix tablets (n=3)

Hardness (kg)Tablet formulation Thickness of tablet (mm) Drug content (%)

4.94�0.11 3.80�0.01M1 98.44�0.83M2 101.44�0.533.81�0.015.08�0.1

5.11�0.12M3 3.81�0.01 100.23�0.675.02�0.14TL1M1 4.52�0.01 99.30�0.355.13�0.17TL1M2 5.03�0.01 102.44�0.235.24�0.16 98.23�0.674.53�0.01TL1M35.56�0.15TL2M1 5.04�0.01 98.73�1.07

TL2M2 5.63�0.12 4.53�0.01 101.30�0.35TL2M3 5.59�0.15 5.04�0.01 100.99�0.18

Values shown in the table are mean�S.D.


Table 4In vitro dissolution kinetics of metoprolol tartrate guar gum matrix tablets and guar gum three-layer matrix tablets (n=3)

Zero order release rate Diffusional exponentFirst order rate constant Kinetic constant (k)Tabletformulation (mg h−1) (n)(h−1)

6.277�0.01 1.566�0.030.0750�0.01M1 0.45�0.02(r=0.9904�0.012)(r=0.9618�0.04) (r=0.9898�0.24)

1.523�0.010.0680�0.016.181�0.02M2 0.49�0.03(r=0.9946�0.01)(r=0.8849�0.20) (r=0.9925�0.13)0.0560�0.02 0.48�0.016.137�0.03 1.500�0.02M3

(r=0.8698�0.01) (r=0.9537�0.02) (r=0.9924�0.01)6.013�0.02TL1M1 0.0510�0.01 0.53�0.011.491�0.03

(r=0.9919�0.09)(r=0.9907�0.01)(r=0.9714�0.01)5.350�0.17TL1M2 0.0386�0.02 0.40�0.021.472�0.01

(r=0.9991�0.04)(r=0.9723�0.11)(r=0.9694�0.02)TL1M3 0.0323�0.024.929�0.34 1.416�0.02 0.38�0.01

(r=0.9985�0.05)(r=0.9857�0.02) (r=0.9878�0.01)6.005�0.01TL2M1 0.0473�0.03 0.42�0.011.372�0.01

(r=0.9960�0.01)(r=0.9955�0.02)(r=0.9715�0.04)TL2M2 0.0351�0.01 1.255�0.025.151�0.03 0.57�0.03

(r=0.9884�0.02) (r=0.9984�0.01) (r=0.9950�0.02)TL2M3 0.0302�0.024.782�0.01 0.788�0.03 0.58�0.02

(r=0.9816�0.01)(r=0.9847�0.02) (r=0.9866�0.04)


mulations for first order release kinetics werefound slightly higher (r=0.9537�0.02–0.9984�0.01) when compared to those of zero order kinet-ics (r=0.8698�0.01–0.9884�0.02) indicatingthat the drug release from all the formulationsfollowed first order kinetics (Table 4). A better-controlled drug release was observed when a re-lease retardant layer was applied on both sides ofthe matrix formulations (Figs. 2 and 3). When 50mg of guar gum was layered on the matrix formu-lations M1, M2 and M3, the first order releaserate constants obtained from TL1M1, TL1M2and TL1M3 formulations were 0.0510�0.01,0.0386�0.02 and 0.0323�0.02 h−1, respectively.On further increasing the amount of guar gumlayer from 50 to 75 mg on both sides of themiddle matrix layer (M1, M2 or M3), the firstorder release rate constants further reduced to0.0473�0.03, 0.0351�0.01 and 0.0302�0.02h−1, respectively in case of TL2M1, TL2M2 andTL2M3 formulations (Table 4). It is evident fromthese data that the three-layered tablet formula-tion TL2M3 is providing a release rate constantof 0.0302�0.02 h−1 which is nearer to the re-quired release rate constant of 0.0232 h−1.

When the percent of metoprolol tartrate re-leased was plotted against time on log– log scale,the diffusional exponent values (n) ranged from0.38�0.01 to 0.58�0.02 indicating that meto-prolol tartrate release from guar gum matricesfollowed Fickian diffusion (Table 4). When thehydrophilic guar gum tablets come in contact withthe dissolution medium, they take up water andswell forming a viscous gel barrier. In case of guargum matrix tablets, the initial swelling of the gummay aid dissolution of the freely soluble drugs,and the dissolved drug diffuses out of the swollengel barrier into the dissolution medium. Unlessthe swollen gel barrier erodes, further seeping-inof the dissolution medium does not occur. Thus,the release rate of the drug depends on thestrength of the gel barrier i.e. the proportion ofthe hydrophilic guar gum in the matrix tablet, itsrate of hydration and viscosity. Guar gum being ahydrophilic polymer was incorporated in the ma-trix tablets in different proportions to optimizethe amount of guar gum needed to provide re-quired release rate. Metoprolol tartrate matrixformulation (M3), in spite of containing higher(50%) proportion of guar gum, could not provide


the required rate of drug release. This might bebecause of the rapid release of the highly solublemetoprolol tartrate from the surface of the matrixtablet within first 2 h.

Three-layer matrix tablets are based on the ideathat the restriction of the matrix area exposed tothe dissolution medium may lead to a dual con-trol in the system performance. This is possiblefor two reasons: (a) matrix hydration rate andconsequent swelling are lowered; and (b) the sur-face through which the drug can be delivered isreduced. These effects, possibly more effective inthe initial phase of the dissolution process and lesspronounced as swelling proceeds, lead to a lin-earization of release profile. The drug releasemechanism from the three-layer matrix tabletsinvolves the following sequence. In the initialphase, barriers applied to the core are able todelay the interaction of the core with the dissolu-tion medium by reducing the surface available fordrug release and by limiting the solvent penetra-tion rate. Thus, in this system the burst effect canbe controlled and the area available for drugrelease can be maintained at a relatively constant

Fig. 2. Mean (�S.D.) percent of metoprolol tartrate releasedfrom three-layer matrix tablets (n=3) containing 50 mg ofguar gum as release controlling layer on both sides of thematrix tablet containing 30 (TL1M1), 40 (TL1M2) or 50%(TL1M3) of guar gum in the dissolution study.

level during the swelling/erosion processes. Dur-ing dissolution, barrier layers are progressivelyeroded and the surface available for the drugrelease increases. In this way the decrease of thedelivery rate due to an increase of the diffusionpath length is compensated by the concurrentincrease of the area for drug release. After thismain release phase, in the last portion of thedissolution process, water can finally reach thecore even under the layer, and the matrix canfreely swell or dissolve.

3.3. In-�itro drug release studies in rat caecalcontents

The In-vivo performance of a controlled releasedosage form, especially a hydrophilic matrixtablet, depends on its biodegradability in GI tract.The present study involved the use of guar gum,as a carrier for oral controlled drug delivery, inthe form of three-layer matrix tablets. Earlierreports indicate the susceptibility of guar gum tothe action of colonic bacterial enzymes (Rama

Fig. 1. Mean (�S.D.) percent of metoprolol tartrate releasedfrom matrix tablets (n=3) containing either 30 (M1), 40 (M2)or 50% (M3) of guar gum in the dissolution study.


Prasad et al., 1998; Krishnaiah et al., 1998a,b,1999). In this context, it is essential to study theinfluence of colonic bacterial enzymes on meto-prolol tartrate release characteristics from theguar gum three-layered matrix tablets. This wasassessed by conducting in vitro drug release stud-ies in rat caecal content medium as per the proce-dure described by Rama Prasad et al. (1998).

Three-layer matrix formulation of metoprololtartrate containing 75 mg of guar gum as ratecontrolling layer on both sides of matrix formula-tion (TL2M3) was found to provide the requiredrelease rate in presence of simulated GI fluids.Hence the three-layer matrix tablets (TL2M3) wassubjected to in vitro drug release studies in ratcaecal content medium to study the influence ofcolonic bacterial enzymes on the release pattern ofTL2M3 formulation. In the presence of rat caecalcontents, the three-layer matrix tablets (TL2M3)were found intact upto 8 h and the guar gumformulation started degrading slowly. At the endof 24 h of the study, the three-layer matrix tabletswere found disintegrated into a thick mass and

Fig. 4. Mean (�S.D.) percent of metoprolol tartrate releasedfrom three-layer matrix tablets (n=3) containing 75 mg ofguar gum as release controlling layer on both sides of thematrix tablet containing 50% of guar gum (TL2M3) in thedissolution study with and without rat caecal contents.

released almost the remaining quantity of meto-prolol tartrate in the rat caecal content medium(simulated colonic conditions). At the end of 12 hof dissolution testing, three-layer tablet (TL2M3)released 63.17�0.50% of metoprolol tartrate inrat caecal content medium and 59.28�0.36% insimulated gastrointestinal fluids (Fig. 4). It is clearthat about 40% of the drug is still left over in theformulation after reaching the physiological envi-ronment of colon. Since metoprolol tartrate isreported having good permeability through colon(Kinget et al., 1998), the formulation TL2M3 islikely to provide the same extent of first orderrelease rate because of the high colonic residencetime thereby providing a slow release of metopro-lol tartrate. Thus, guar gum being a colon-specificdrug carrier appears to provide oral controlleddrug delivery.

3.4. Stability studies

Based on the results of the in vitro drug releasestudies, three-layer guar gum matrix tablets ofmetoprolol tartrate are found to provide the re-

Fig. 3. Mean (�S.D.) percent of metoprolol tartrate releasedfrom three-layer matrix tablets (n=3) containing 75 mg ofguar gum as release controlling layer on both sides of thematrix tablet containing 30 (TL2M1), 40 (TL2M2) or 50%(TL2M3) of guar gum in the dissolution study.


quired oral controlled drug delivery. Hence, sta-bility studies were carried out by storing the for-mulation at 40 °C/75% RH for 6 months(climatic zone IV conditions for accelerated test-ing) to assess their long-term (2 years) stability.The protocol of the stability studies was in con-formation with the recommendation in WHOdocument for stability testing of products in-tended for global market (Mathews, 1999). At theend of the storage period, studies were conductedon metoprolol tartrate three-layer matrix tabletsto assess their stability with respect to their physi-cal appearance, drug content and release charac-teristics. The three-layer tablets after storing at40 °C/75% RH for 6 months (Mathews, 1999)showed no change either in physical appearance,drug content or in dissolution pattern (Table 5).The results of the stability studies indicate that theformulations could provide a minimum shelf lifeof 2 years (Mathews, 1999).

3.5. FT-IR studies

The FT-IR spectrum of guar gum, metoprololtartrate, powdered sample of middle layer of thethree-layer matrix tablet coated with 75 mg ofguar gum (before storage) and powdered sample

Fig. 5. The FT-IR spectra of guar gum (A), metoprololtartrate (B), powdered sample of middle layer of the three-layer matrix tablet coated with 75 mg of guar gum beforestorage (C) or powdered sample of middle layer of the three-layer matrix tablet coated with 75 mg of guar gum afterstorage (D).

Table 5Percent of metoprolol tartrate released from guar gum three-layer matrix tablets (n=3) layered with 75 mg of guar gumgranules (TL2M3) in 0.1 M HCl (2 h) and pH 7.4 Sorenson’sphosphate buffer (10 h) before and after storage at 40 °C/75%RH for 6 months

Percent of metoprolol tartrate released fromTime (h)TL2M3

Before storage After storage

0 0 04.24�0.64.25�0.60.5

1 7.17�1.17.19�1.32 10.96�1.0511.03�1.3

17.53�1.417.57�2.034 22.53�1.3 22.49�1.46 35.38�1.535.40�1.7

43.97�2.0 43.94�1.7851.65�1.410 51.61�1.2

12 54.58�2.3 54.52�2.1


of middle layer of the three-layer matrix tabletcoated with 75 mg of guar gum (after storage) isshown in Fig. 5. The slight difference in peakheight at 1592 cm−1 may be due to the tartratemolecule that has no influence on the metoprololstructure. Based on the spectra obtained withFT-IR spectroscopy, there appears to be no possi-bility of interaction between metoprolol tartrateand guar gum/other excipients used in the matrixtablets.

4. Conclusions

The present study was carried out to developoral controlled delivery systems for metoprolol


tartrate using guar gum as a carrier. Guar gummatrix tablets containing various proportions ofguar gum were prepared and subjected to in vitrodrug release studies. Matrix formulations couldnot provide the required release of metoprololtartrate. The first order release rate constantsobtained from matrix tablets containing 30, 40and 50% of guar gum were found to be 0.0750�0.01, 0.0680�0.01 and 0.0560�0.02 h−1, respec-tively, which were far above the required releaserate constant. Hence, guar gum three-layer matrixtablets with either 50 or 75 mg of guar gum layerson both sides of the metoprolol tartrate guar gummatrix containing various proportions of guargum were prepared and subjected to in vitro drugrelease studies. The three-layer matrix tablet with75 mg of guar gum layers on both sides of themetoprolol tartrate matrix formulation containing50% of guar gum was found to provide the re-quired release rate matching with the theoreticalrelease rate constants calculated on the basis ofpharmacokinetic properties of the drug, for meto-prolol tartrate tablet formulations meant for twicedaily administration. This three-layer guar gummatrix tablet after storing at 40 °C/75% RH for 6months showed no change either in physical ap-pearance, drug content or in dissolution pattern.Based on the FT-IR studies, there appears to beno possibility of interaction between metoprololtartrate and guar gum/other excipients used in thetablets. The results clearly indicate that guar gumin the form of three-layer matrix tablet is a poten-tial hydrophilic carrier in the design of oral con-trolled drug delivery systems for highly solubledrugs. Bioavailability studies are in progress toassess the usefulness of three-layer matrix tablet(TL2M3) in comparison with conventional imme-diate release metoprolol tartrate tablets.

Acknowledgements

The authors acknowledge the financial supportreceived from Government of India, Departmentof Science and Technology (DST). The authorsgreatly acknowledge M/s Astra-IDL Ltd., Banga-lore India, M/s. Torrent Laboratories, Ahmeda-bad, India and M/s. Dabur Research Foundation,

New Delhi, India for the gift samples of metopro-lol tartrate, rofecoxib and guar gum, respectively.The authors greatly acknowledge M/s Sipra LabsPvt. Ltd., Hyderabad, India for FT-IR study.

References

Altaf, S.A., Yu, K., Parasrampuria, J., Friend, D.R., 1998.Guar gum based sustained release diltiazem. Pharm. Res.15, 1196–1201.

Breimer, D.D., 1983. Gastrointestinal drug delivery systems.Pharm. Tech. 7, 18–23.

Craik, D.J., 1958. The flow properties of starch powders andmixtures. J. Pharm. Pharmacol. 10, 73.

Eddington, N.D., Marroum, P., Uppoor, R., Hussain, A.,1998. Development and internal validation of an in vitro–in vivo correlation for a hydrophilic metoprolol tartrateextended-release tablet formulation. Pharm. Res. 15, 466–473.

Ghosh, L.K., Sairam, P., Gupta, B.K., 1996. Developmentand evaluation of an oral controlled release multiple emul-sion drug delivery system of a specific beta blocker meto-prolol tartrate. Bulletino Chemico Farmaceutico 135,468–471.

Godbillon, J., Evard, D., Vidon, N., Duval, M., Schoeller,J.P., Bernier, J.J., Hirtz, J., 1985. Investigation of drugabsorption from gastrointestinal tract of man. III. Meto-prolol in the colon. Br. J. Clin. Pharmacol. 19, 113S–118S.

Jain, N.K., Kulkarni, K., Talwar, N., 1992. Controlled-releasetablet formulation of Isoniazid. Pharmazie 47, 277–278.

Kendall, M.J., 1989. Metoprolol-controlled release, zero orderkinetics. J. Clin. Pharm. Ther. 24, 159–179.

Khullar, P., Khar, R.K., Agarwal, S.P., 1998. Guar gum as ahydrophilic matrix for preparation of theophylline con-trolled-release dosage form. Drug Dev. Ind. Pharm. 24,1095–1099.

Kinget, R., Kalala, W., Vervoort, L., Van den Mooter, G.,1998. Colonic drug targeting. J. Drug Target. 6, 129–149.

Korsmeyer, R.W., Gurny, R., Doelker, E., Buri, P., Peppas,N.A., 1983. Mechanisms of solute release from poroushydrophilic polymers. Int. J. Pharm. 15, 25.

Krishnaiah, Y.S.R., Satyanarayana, S., Rama Prasad, Y.V.,Narasimha Rao, S., 1998a. Gamma scintigraphic studieson guar gum matrix tablets for colon-specific drug deliveryin healthy subjects. J. Controlled Release 55, 245–252.

Krishnaiah, Y.S.R., Satyanarayana, S., Rama Prasad, Y.V.,Narasimha Rao, S., 1998b. Evaluation of guar gum as acompression coat for drug targeting to colon. Int. J.Pharm. 171, 137–146.

Krishnaiah, Y.S.R., Satyanarayana, S., Rama Prasad, Y.V.,1999. Studies on guar gum compression coated 5-aminosalicylic acid tablets for colon-specific drug delivery. DrugDev. Ind. Pharm. 25, 651–657.

Krishnaiah, Y.S.R., Rama Rao, T., Ushasree, M., Satya-narayana, S., 2001. A study on the in-vitro evaluation of


guar gum as a carrier for oral controlled drug delivery. SaudiPharm. J. 9, 98.

Lordi, N.G., 1989. Sustained release dosage forms. In: Lach-man, L., Liberman, H.A., Kanig, J.L. (Eds.), The Theoryand Practice of Industrial Pharmacy, 2nd ed. Lea & Febiger,Philadelphia, pp. 430–456.

Mathews, B.R., 1999. Regulatory aspects of stability testing inEurope. Drug Dev. Ind. Pharm. 25, 831–856.

Okabe, K., Yamoguchi, H., Kawai, Y., 1987. New iontophoretictransdermal administration of the beta-blocker-metoprolol.J. Controlled Release 4, 79–85.

Perry, B.M., Raymond, W.R., 1996. Pharmacokinetic Data. In:Goodman & Gilman’s The Pharmacological Basis of Ther-apeutics, IX ed. p. 1760.

Pillay, V., Fassihi, R., 2000. A novel approach for constant rate

delivery of highly soluble bioactives from a simple mono-lithic system. J. Controlled Release 67, 67–78.

Rama Prasad, Y.V., Krishnaiah, Y.S.R., Satyanarayana, S.,1998. In vitro evaluation of guar gum as a carrier for colon-specific drug delivery. J. Controlled Release 51, 281–287.

Regardh, C.-G., Borg, K.O., Johnsson, R., Johnsson, G.,Palmer, L., 1974. Pharmacokinetic studies on the selective�1-receptor antagonist metoprolol in man. J. Pharma-cokinet. Biopharm. 2, 347–364.

Sandberg, A., Ragnarsson, G., Jonsson, U.E., Sjogren, J., 1988.Design of a new multiple unit controlled release formulationof metoprolol–metoprolol CR. Eur. J. Clin. Pharmacol. 33,S3–S7.

Train, D., 1958. Some aspects of the property of angle of reposeof powders. J. Pharm. Pharmacol. 10, 127T–135T.

a three-layer guar gum matrix tablet for oral controlled delivery of highly soluble metoprolol...

Documents