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Int. J. Pharm & Ind. Res Vol - 0 1 Issue - 0 4 O ct Dec 2 0 11

ultimately provide a rational for formulation design, orsupport the need for molecular modification.Excipients9,10 are selected in formulation developmenton the basis of its compatibility and functionality withthe selected active pharmaceutical ingredient. The %compressibility was calculated because we want to

prepare tablet by direct compression method due tocost effective factor as well as easy and less time tomanufacture.Dire ctly compressed1 1 displaycompressioncharacteristics and have swelling properties that leadto a rapid formation of external layer, allowing drugrelease modification. The drug is freely soluble inwater which is good for dissolution study.

M ethod and M aterialsMetoprolol succinate USP12 obtained as a gift samplesfrom Sania Human cure pvt. Ltd, kashi nagar,

Uttaranchal (India), HPMC K4M, HPMC K15M, HPMCK100M were obtained from Colorcon AsiaPvt.Ltd.,Goa, India. Sodium stearyl fumerate, colloidalanhyd rous silica w a s p urchased f rom SD Fine Chemicals(Mumbai, India). Ethyl cellulose, microcrystallinecellulose (pharmaceutical grade) was purchased fromG.R.Traders, Hyderabad. All other chemical were ofhigh analytical gra de obta ined from Vision College ofpharmaceutical sciences & Research, Boduppal,Hyderabad. Double distilled water was usedthroughout the study .

Preparation of Calibration Curve of Metoprololsuccinate in Phosphate Buffer 6.8The UV scanning of drug sample was carried out usinga solution of drug dissolved in 6.8 pH phosphatebuffer solution12,13. The lambda max (max) wasobserved at 222nm. The graph is shown in Figure 1. The calibration curve of Metoprolol succinate wasobtained by dissolving the drug in 6.8 pH phosphatebuffer solution and the absorbance was measured at222nm by keeping 6.8 pH phosphate buffer solution

as blank. Beers law14

was obeyed in the concentrationsrange of 1- 30g/ ml in 6.8 pH p hosphate buffersolution. 100 mg of Metoprolol succinate wasaccurately weighed and taken in 100 ml volumetricflask. Drug was dissolved in 6.8 pH phosphate buffersolution and ultra sonicated for 10 min to ensurecomplete dissolving of drug, which give a concentrationof 1 00 0 g/ ml. From stock I, 10 ml is taken and

diluted to 100 ml which give a concentration of g / ml solution, this is stock II. From the a bove stsolution 0.5, 1.0, 1.5, 2.0 and 3.0 ml were withdinto 10 ml volumetric flasks and diluted up tovolume with 6.8 pH phosphate buffer solutionTheresult is shown in Tab le 1 . The g ra ph is shown in Figur

Determination of Solubility15 of M etoprolol succinateExcess of drug was placed in distilled water andsolution was occasionally stirred for 24 hours at temperature. After 24 hours sample was filtered filtrate was suitably diluted and absorbance was tat 222.0 nm against distilled water as blank on UVisible spectrophotometer (UV 3000). The resshown in table 2.

Observation: Absorbance of Metoprolol succinate

distilled w ater: 0.631 A.

Stability of Metoprolol succinate in Solvents16 Stability of Metoprolol succinate in distilled w aterStability of Metoprolol succinate in distilled watedetermined by keeping the known concentra(2 0 g/ ml), in kinetic mode of UVV ispectrophotometer (UV3000 Lab India) for 30 The da ta obta ined is shown in tab le3.

Stability of Metoprolol succinate in 0.1N HClStability of Metoprolol succinate in 0.1N HC

determined by keeping the known concentra(1 5 g/ ml), in kinetic mode of UVV ispectrophotometer (UV3000 Lab India) for 30 The da ta obta ined is shown in tab le 4 .

Stability of Metoprolol succinate in Phosphate Buffer 6.8Stability of Metoprolol succinate in Phosphate B6.8 was determined by keeping the knoconcentratio n (20g/ ml), in kinetic mode of UVV ispectrophotometer (UV3000 Lab India) for 30 The da ta obta ined is shown in tab le 5 .

Spectral Analysis of Additives at 222nm todetermine any interference with DrugThe highest concentration of the additives that wbe present in 500 ml of dilution media was estimon the basis of amount present in per tablet different batches and the same quantities of diffeadditives were taken in 100ml volumetric flasks

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up volume with water and shaken thoroughly andfiltration was done, filtrate taken for spectral scan at222.0nm in UVVisible spectrophotometer (UV3000,Lab India).

Determination of interference of additives in the

estima tion of M etoprolol succinateThe highest concentration of the additives that wouldbe present in 500 ml of dilution media was estimatedon the basis of amount present in per tablet ofdifferent batches and the same quantities of differentadditives were taken in 10 ml volumetric flaskscontaining 10 ml of 20g/ ml concentration ofMetoprolol succinate solution. The flasks were kept for24 hours with occasional shaking and filtration wasdone. The absorbance of filtrate were measured at222 nm on UVVisible spectrophotometer (UV3000)

and compared with the absorbance of control drugsample of 20g/ ml concentration without a dd itives.O bservations are shown in tab le 6 .

Determination of % Compressibility14 I = Dt - Db * 100

DtBulk Density (Db) = 0.32 7 (Calculated )Tap ped Bulk Density (Dt) = 0.38 (Calcula ted)I = (0 .38 0 .327 / 0 .38) * 10 0 = 13 .94

DrugExcipient Compatibility Studies17

A small amount of drug substance with excipients thatis, physical mixture of the drug and excipients (in 1:1ratio were prepared to have maximum likelihoodinteraction between them) was placed in a vial, andrubber stopper was placed on the vial and sealedproperly. A storage period study was done for 1st,2nd , 3rd month at 4 0C/ 75 %RH. After storag e thesample were observed physically for liquefaction,caking, odour or gas formation, discoloration. Thecompatibility study is also carried out by IR

Spectroscopy curves are shown below. The overallobservations are recorded in table 7.

IR Spectroscopic Studies18 IR Spectra of pure Metoprolol Succinate and incombination with tablet excipients (physical mixture)were recorded between 4000-450cm-1. The chemical

structure of Metoprolol Succinate shown in figure 7spectra are shown in figure 8.

Figure 01: Scan Spectrum curve ofMetoprolol succinate show ed at 222 nm

Table 01: Absorbance Vs concentration at 222 nmConcentration

( g/ml)Absorbance

Set 1 Set 2 Set 3 Av erage SD0 0.000 0.000 0.000 0.0005 0 .185 0 .188 0 .191 0 .188 0 .003

10 0 .356 0 .360 0 .352 0 .356 0 .00415 0 .487 0 .480 0 .484 0 .484 0 .00320 0 .646 0 .649 0 .652 0 .649 0 .00330 0 .981 0 .987 0 .993 0 .987 0 .006

Figure 02: Cal ibration curve of M etoprolol succinateUSP in Phosphate buffer (pH 6 .8) a t 222 nm

Table 02: Solubility of Metoprolol succinate inDistilled Water

Solvent Solubility InterferenceDistilled water 9 5 8 9 6g / ml Freely soluble

Concentration mcg / ml

y = 0.0323x + 0.0136R2 = 0.999

0

0.2

0.4

0.6

0.8

1

1.2

0 5 10 15 20 25 30 35

cocentration((g/ml)

A b s o r

b a n c e

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Figure 03: M etoprolol succinate in Distilled w ater inkinetic mode for 1800 seconds

Table 03: Stability of M etoprolol succinate in

Distilled Water in Kinetic Mode of UV- VisibleSpectrophotometer at max 222.0 nm(A bsorbance of 20 g/ ml drug solution is 0.6 58 )

Time(seconds)

Absorbance dA

0 0.658 0.000200 0 .668 0 .010400 0 .659 0 .011600 0 .657 0 .009800 0 .658 0 .000

1000 0 .662 0 .0041200 0 .662 0 .0041400 0 .661 0 .003

1600 0 .663 0 .0051800 0 .663 0 .005

Figure 04: Metoprolol succinate in 0.1N HCl inkinetic mode for 1800 seconds

Table 04: Stability of M etoprolol succinate in0.1N HCl in Kinetic Mode of UV - VisibleSpectrophotometer at max 222.0 nm

(A bsorbance of 15 g/ ml drug solution is 0.439 )Time

(seconds) Absorbance dA

0 0.439 0.000200 0.445 -0.004400 0 .440 0 .001600 0 .439 0 .000800 0.437 -0.002

1000 0 .437 -0 .0021200 0 .439 0 .0001400 0 .442 0 .0031600 0 .439 0 .0001800 0 .437 -0 .002

Figure 05: M etoprolol succinate in Phospha te Buffer 6 .in kinetic mode for 1800 seconds

Table 5 : Stability of M etoprolol succinate inPhosphate Buffer 6.8 in Kinetic Mode of UV- Visibl

Spectrophotometer at max 222.0 nm(A bsorbance of 20 g/ ml drug solution is 0.646 )

Time(seconds)

Absorbance dA

0 0.646 0.000200 0 .649 0 .003400 0 .646 0 .000

600 0.641 -0.005800 0 .646 0 .0001000 0 .646 0 .0001200 0 .648 0 .0021400 0 .644 -0 .0021600 0 .645 -0 .0011800 0 .643 -0 .003

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Figure 06 : Spectral A naly sis of A dditives and Drug

Table 06 : Interference of A dditives in the Estima tion ofM etoprolol succinate in Distilled w ater at 222 .0 nm

(A bsorbance of plain drug solution (20 g/ ml): 0.658 A)S.No. Additiv es Absorban ce Interference

1 Hpmc K4M 0.654 Nil



4 Ethyl Cellulose 0.65 0 Nil

5 Micro crystalline cellulose 0.66 0 Nil

6 Colloida l Anhydrous silica 0.65 6 Nil

7 Sodium steary l fumerate 0.654 Nil

Figure 07: Chemical structure ofMetoprolol Succinate USP

Figure 08: IR Spectra of Metoprolol succinate USP

Table 07: Drug-Excipient Compatibility ObservationsAdditives( 50 mg each)

w ith drugObservations at 400C/75% RH

for 1st monthObservations at 400C/75% RH

for 2nd monthObservations at 400C/75% RH

for 3rd month Remark

Drug(Metoprolol succinate) No Change No Change No Change Accept

Drug+ Hpmc K4M No Change No Change No Change AcceDrug+ Hpmc K15 M No Change No Change No Change AcceDrug+ Hpmc K10 0M No Change No Change No Change AcceDrug+ Ethyl Cellulose No Change No Change No Change AccDrug+ Micro crystallinecellulose No Change No Change No Change Accept

Drug+ ColloidalAnhydrous silica No Change No Change No Change Accept

Drug+ Sodium steary lfumerate No Change No Change No Change Accept

Results and Discussion There was no significant change in the absorbancevalue of Metoprolol succinate up to 30 minute, whichindicates that Metoprolol succinate is stable in distilled

water as well as in Phosphate Buffer pH 6.8. calibra tion curve shows a linear relation betwconcentration (0 3 0 g / ml) and a bsorbancshows that Beer Lambert law is obeyed in

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concentration range of 5 30 g / ml. There wa s nosignificant change of absorbance was observed betweenadditives and drug sample solutions. This indicates therewas no interference with Metoprolol succinate duringanalysis by UV spectrophotometer. Spectral Analysis ofAdditives at 222.0 nm had shown no interference withDrug. Calculated value of % compressibility (13.94)indicate s that Metop rolo l succinate is suitab le for dir ectcompression as well as having good flow property soalmost negligible chances of weight variation duringfilling of dye by the blend. Compatibility studiesperformed on the physical mix of Metoprolol succinateand different tablet excipients at temperature4 00C/ 75 % RH no physical changes observed. Thecharacteristics spectral bands of Metoprolol succinatewere not significantly affected in the physical mixture ofdrug and excipients. All the characteristics bands of thedrug were retained at their respective positions in the IR

spectra of drug-excipient physical mixtures. This indicatesthat during the formulation the components have notundergone any chemical reaction during any stage oftablet formulation. No significant shift in the position ofthe characteristics bands observed this shows that therewa s no intera ction betw een M etop rolol succinate a nd theselected tablet excipients in the physical mixtures.

ConclusionIn the light of this research work, it may be concluded thattab lets of M etopr olol succinate can be mad e by dir ectcompression method by using K4M, HPMC K15M, HPMCK100M, Sodium stearyl fumerate, colloidal anhydroussilica, Ethyl cellulose, microcrystalline cellulose as suitableexcipients as all they showed the compatibility with theMetoprolol succinate.

References1 . Ansel,H.C., Allen, L.V., and Pop vich, N.G .,

Pharmaceutical Dosage Forms and Drug Deliverysystems, Seventh Edi tion(19 9 9), Lip p incott W illia msand w ilkins, Philad elphia, USA, 17 9-2 28 .

2 . ww w.drugs.com/ cdi/ metoprolol-succinate-ex tended -

release-tablets.html3 . www .rxlist.com/ toprol_xl-drug.4 . Khan,K.A., and Rhodes, C.T., The Production of

Tablets by Direct Compression, Can. J. Pharm,Sci.,197 3, 8: 1-5.

5 . Shangraw, R.F., Compressed Tablets by DirectCompression Granulation Pharmaceutical Dosage

Forms: Tablets, Vol.-1, Marcel Dekkar, USA, SecEdition, (19 89 ), 19 5-2 46 .

6 . Ray mond C Row e, Pa ul J Sheskey a nd Sian C O wHandbook of Pharmaceutical Excipients, Fifth Ed(2006), Ph. Press, Royal Pharmaceutical societyG reat Britain, AphA, W ashington DC, 188 -19 1,282 ,346-349 ,430-433 ,705-707 .

7 . Lordi NG. Sustained release dosage forms. Lachman L, Liberman HA, Joseph LK. The TheoryPractice of Industrial Pharmacy, 3rd ed. VarghesePublishing House, Bomba y, 19 86 , 430 -4 56 .

8 . www.tapi.com9 . Lachman,L., Liberman, H.A., and Kanig, J.L.,

Theory and Practice of Industrial Pharmacy, LeFebiger, Philadelphia, 1986,171-195.

1 0 . 10. Armstrong, N.A., Selection of Excipients for DCompression Tablet Formulation, Pharm.Technol. 1997 , 9 : 24-30 .

1 1 . Antonio Moronim, A Novel Copovidone BindDry Granulation and Direct Compression TablePharm. Technol., 19 86 , 24 : 8 12 .

1 2 . www.usp.org1 3 . USP34 -NF29, edision 20 07 , pg no:2695 -26 96 .1 4 . Backett, A.H., and Stenlake, J.B., Practi

Pha rmaceutical Chemistry , First Ed ition, Repr int, 2CBS Publishers and Distributors, New Delhi, 23 2 5 .

1 5 . Carstensen, J.T., Pharmaceutical Preformulati1998, Technomic Publishing Company, Inc., NHolland Avenue, Lancaster, Pennysylvania, USA, 24 , 41 48 , 259 274 .

1 6 . M.M.Gupta, T.R.saini, Preformulation paramcharacterization to design,development aformulation of vancomycin hydrochloride tabletpsud omembr a nous colitis, IJPRD/ 20 09 / PUARTI/ VO L-1/ ISSUE-9/ NO V/ 002

1 7 . www .ikev.org/ ICH Q 1A(R2) G uideline/ StaTesting of Ne w Drug Substances and Prod ucts.

1 8 . Vogals Textbook of Quantitative Chemical AnaFifth Edition, reprint, 1996, English Language Society, London, 64 55 1, 7 52 55 .

1 9 . Jhon coates, coates consulting, Newtown,UInterpretation of infrared spectra, A practAp pr oach,infrare d.als.lbl.go v/ BLM anual/ IR.Inter-etation. Pdf

2 0 . Pavia , D.L., Lamp man, G .M., and Kriz, GIntroduction to Spectroscopy, Third Edition, 2Harcourt College Publishers, Orlando, Florida, pp . 36-107 ,353 35 9 .

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