world journal of pharmaceutical research b.venkateswara et

www.wjpr.net Vol 3, Issue 4, 2014.

862

B.Venkateswara et al. World Journal of Pharmaceutical Research

DESIGN AND DEVELOPMENT OF BILAYERED TABLETS OF

AMLODIPINE BESYLATE AND METOPROLOL SUCCINATE

Dr.B.Venkateswara Reddy*1

, K.Navaneetha1,K.Venkata Ramana Reddy

2,P.Poli Reddy

3

1Department of Pharmaceutics, St.Pauls College of Pharmacy, Turkayamjal (V), Hayathnagar

(M), R.R. INDIA.

2Department of Pharmaceutics, Sree Datta College of Pharmacy, Sheriguda (V), R.R.INDIA.

3Department of Pharmacology,Swami Ramananda theerda Institute of Pharmaceutical

Sciences, Nalgonda. INDIA.

ABSTRACT

The present work aims to develop a bilayer dosage form containing

one immediate release drug amlodipine besylate and another extended

release drug metoprolol succinate. The immediate release layer was

prepared by using micro crystalline cellulose, sodium starch glycolate,

crosspovidone and dicalcium phosphate. The sustain release layer was

prepared by using HPMC K15, Sodium CMC, Carbopol. FTIR studies

for the drug and polymers shows that they are compatible. The

optimized formulations from both layers are used to prepare the bilayer

tablet. The prepared tablets are evaluated for various properties.

Release of Metoprolol Succinate from the tablets formulated by

employing Carbopol and PEO showed that the drug release was as per

within the USP limits. So formulation M7 is concluded as optimized

formulation for sustained release. Amlodipine besylate from the tablets formulated by

employing dicalcium phosphate, MCC and sodium starch glycolate showed that the drug

release was as per within the USP limits. So formulation A8 is concluded as optimized

formulation for immediate release. And for further study batch A8 and M7 were used for

tableting a bilayered formulation which is subjected to post compression and In-Vitro

dissolution studies by HPLC. The release kinetics of optimized formula (A8M7) showed non-

fickian transport and followed Higuchi model. Thus it can be concluded that the combination

therapy uses lower doses of drug to reduce the patient’s blood pressure.

World Journal of Pharmaceutical Research SJIF Impact Factor 5.045

Volume 3, Issue 4, 862-881. Research Article ISSN 2277 – 7105

Article Received on

05 April 2014,

Revised on 28 April 2014,

Accepted on 21 May 2014

*Correspondence for

Author

Dr. Basu Venkateswara

Reddy

Department of Pharmaceutics,

St.Pauls College of Pharmacy,

Turkayamjal (V), Hayathnagar

(M), R.R. India.

http://www.wjpr.net/


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KEYWORDS: Amlodipine besylate; Metoprolol succinate; Immediate release; Extended

release; Bilayered formulation; Non-fickian transport; Higuchi model.

INTRODUCTION

Drug delivery has metamorphosed from the concept of pill to molecular medicine in the past

100 years. Better appreciation and integration of pharmacokinetic and pharmacodynamic

principles in design of drug delivery system has been developed to improve the therapeutic

efficacy. Drug research has evolved and matured through several phases beginning from pill

to pharmaceutical dosage form [1, 2].

The concept of regulating drug delivery in the human body has been in existence for many

years because of major benefits such as improved patient compliance and desired side effects.

Conventional dosage forms often produce fluctuations of drug plasma level that either exceed

safe therapeutic level or quickly fall below the minimum effective level; this effect is usually

totally dependent on the particular agent’s biological half-life, frequency of administration,

and release rate. It is recognized that many patients can benefit from drugs intended for

chronic administration by maintaining plasma drug level within safe and effective range.

Many innovative methods have been developed in the last few years for obtaining modified

drug release [3].

Oral route of drug administration has wide acceptance and of the drugs administered orally in

solid dosage forms represents the preferred class of products [4]. The reasons are as follows:

Tablets and capsules represent unit dosage form in which one usual dose of drug has been

accurately placed. By comparison liquid oral dosage forms such as syrups, suspensions,

emulsions, solutions, and elixirs are usually designed to contain one dose medication in 5-30

ml. Such dosage measurements are typically error by a factor ranging from 20- 50% when the

drug is self administered by patient. Liquid oral dosage forms have other disadvantages and

limitations: They are more expensive to ship, one liquid dosage weighs 5gms or more for

average tablet, breakage or leakage is more serious problem for liquids. Liquids are less

potable and require more space in pharmacist’s shelf. Drugs are generally less stable in liquid

form than in a dry state [5].

In the recent times, multi-layer matrix tablets are gaining importance in the design of oral

controlled drug delivery systems. Bi-layer tablets are novel drug delivery systems where

combination of two or more drugs in a single unit [6]. They are preferred for the following



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reasons: to co-administer two different drugs in the same dosage form, to minimize physical

and chemical incompatibilities, for staged drug release, IR and SR in the same tablet, for

chronic condition requiring repeated dosing [7].

In the present study a combination drug therapy is recommended for treatment of

hypertension to allow medications of different mechanism of action to complement each

other and together effectively lower blood pressure at lower than maximum doses of each.

The rational for combination therapy is to encourage the use of lower doses of drug to reduce

the patient’s blood pressure, minimize dose dependent side effects and adverse reactions.

This is novel type of dosage form for oral administration in which one layer contain extended

release metoprolol succinate and another layer contains immediate releasing drug amlodipine

besylate. Therapy with metoprolol alone and the combination of metoprolol and amlodipine

was well tolerated in patients with mild to severe heart failure, as evidenced by a lack of

adverse effects on hemodynamic improvement with long-term treatment [8].

The present work aims to develop a stable and optimized bilayer dosage form containing one

immediate release drug amlodipine besylate and another extended release drug metoprolol

succinate as extended release dosage form [9]. The main purpose of this formulation is to

lowers the risk of hypertension in people which may lead to higher complications. The

rational for combination therapy is to encourage the use of lower doses of drug to reduce the

patient’s blood pressure, minimize dose dependent side effects and adverse reactions.

MATERIALS AND METHODS

Materials

Metoprolol succinate was obtained as a gift sample from Paras Impex, Ahmedabad and

Amlodipine was obtained as a gift sample from Siflon drugs, Hyderabad. Microcrystalline

cellulose was obtained from FMC biopolymers, Mumbai. Lactose and Crospovidone was

obtained from Himedia laboratories.Pvt.Ltd, Mumbai. Dicalcium phosphate was obtained

from All India drug supply.co, Mumbai. HPMC K4M, HPMC K15 was obtained from

Colorcon Asia Pvt. Ltd, Goa. Sodium starch glycolate was obtained from Bioplus Pvt. Ltd,

Banglore. Carboxy methyl cellulose sodium was obtained from Simla industries, Mumbai.

Carbopol was obtained from Jayman chemicals, Mumbai. Poly ethylene oxide was obtained

from Rimproindia, Ahmedabad. Aerosil and Magnesium stearate was obtained from S.D.Fine

chemicals, Mumbai.



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Drug – Excipient compatibility studies [10]

In the present study FTIR spectra of the Metoprolol succinate pure drug, Amlodipine besylate

pure drug, and with combination of different excipients of both layers and optimized bilayer

formulation were recorded using a Fourier transform infrared spectrophotometer. Samples

were prepared as KBr disks using a hydraulic pellet press and scanned from 4000 to 400 cm1.

Formulation Of Dosage Forms

Formulation of Amlodipine besylate immediate release tablets

Amlodipine besylate immediate release tablets were prepared by using direct compression

method. The microcrystalline cellulose, Dicalcium phosphate, sodium starch glycolate and

the active ingredient were passed through sieve no. 30 and mixed homogenously. Magnesium

stearate and Aerosil were passed through sieve no.60 and added as a lubricant to the above

dry mix and mixed well for 5 minutes. Finally the colorant Iron oxide was sieved through

sieve no.100 mesh and then mixed with the dry mix homogenously to get uniform blend.

Then the blend is directed to compression.

Formulation of Metoprolol succinate sustained release tablets:

Metoprolol Succinate sustained release tablets were prepared by direct compression method.

The hydroxyl propyl methyl cellulose (HPMC K15 & HPMC K4M), Carbopol, sodium

CMC, microcrystalline cellulose, polyethylene oxide, and Metoprolol succinate were passed

through sieve no.30 and mixed homogenously. Magnesium stearate and Aerosil were passed

through sieve no.60 and added as a lubricant to the above dry mix and mixed well for 5

minutes to get uniform blend directed to compression.

Table 1: Batch composition of Amlodipine besylate

Working

Ingredients A1 A2 A3 A4 A5 A6 A7 A8 A9 A10

Amlodipine besylate 5 5 5 5 5 5 5 5 5 5

Microcrystalline

cellulose 100 100 0 100 100 100 100 25 50 75

Sodium starch

glycolate 0 10 10 0 10 10 10 10 10 10

Dicalcium phosphate 100 0 100 100 75 50 25 100 100 100

Magnesium stearate 1 1 1 1 1 1 1 1 1 1

Aerosil 2 2 2 2 2 2 2 2 2 2

Iron oxide 0.16 0.16 0.16 0.16 0.16 0.16 0.16 0.16 0.16 0.16

PVP K30 5 5 5 0 0 0 0 0 0 0

Cross povidone 10 10 10 0 0 0 0 0 0 0



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Table 2: Batch composition of Metoprolol succinate

Working

Ingredients M1 M2 M3 M4 M5 M6 M7 M8 M9 M10

Metoprolol succinate 100 100 100 100 100 100 100 100 100 100

HPMC K4M 50 75 100 0 0 0 0 0 0 0

Lactose 20 25 0 25 0 0 0 0 0 0

Microcrystalline

cellulose 78 25 0 25 0 0 0 0 0 0

HPMC K15 0 0 0 50 100 100 100 125 150 150

Sodium CMC 0 0 0 0 25 50 0 0 0 0

Carbopol 0 0 50 0 0 0 0 0 0 0

Poly ethylene oxide 0 0 0 0 0 0 50 50 50 25

Magnesium stearate 1 1 1 1 1 1 1 1 1 1

Aerosil 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5

Formulation of optimized bilayered tablets of Amlodipine besylate and Metoprolol

succinate

Out of all the formulations of Metoprolol succinate sustained release tablets and Amlodipine

besylate immediate release tablets, one formulation is selected from each on the basis of in

vitro drug release studies. The selected combination of Metoprolol succinate sustained and

Amlodipine besylate immediate release blends were used for formulation of bilayer tablet.

The blends are compressed using Cadmach high speed double rotary tablet press (CPD IIA-

37). The formulated bilayered tablet formulation composition is as shown in the table 3.

Table 3: Batch composition of Optimized formulation

S.NO WORKING INGREDIENTS M7 WORKING INGREDIENTS A8

1 Metoprolol succinate 100 Amlodipine besylate 5

2 HPMC K15 100 Microcrystalline cellulose 25

3 Poly ethylene oxide 50 Sodium starch glycolate 10

4 Magnesium stearate 1 Dicalcium phosphate 100

5 Aerosil 2.5 Magnesium stearate 1

6 Aerosil 2

7 Iron oxide 0.16

TABLET WEIGHT (mg) 253.5 143.16

TOTAL TABLET WEIGHT (mg) 253.5+143.16 396.66

EVALUATION OF DOSAGE FORMS

Precompression studies [11, 12]

The powder blend is evaluated for various precompression parameters such as bulk density,

tapped density, angle of repose, hausner’s ratio, compressibility index to determine the flow

properties of the powdered blend.



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Post compression studies [11, 12]

Thickness

Ten tablets from each formulation were taken randomly and their thickness was measured

with a screw gauge micrometer.

Hardness test

The tablet crushing strength, which is the force required to break the tablet by compression in

the diametric direction was measured in triplicate using Monsanto tablet hardness tester. The

tablet was held between the edges of the fixed and movable part of the instrument. The scale

was adjusted by sliding, so that the zero on the scale coincides with the pointer. The

adjustable knob was moved slowly till the tablet breaks. The hardness was measured in

kg/cm2.

Weight variation test

Twenty tablets were selected randomly, weighed individually and average weight was

calculated. Not more than two of the individual weights should deviate from the average

weight by more than the percentage as per the specifications and none should deviate by

more than twice that percentage.

Friability

Friability is the measure of tablet strength. About 10 tablets were carefully dedusted and

weighed. The tablets were placed in friability test apparatus and rotated 100 times at 25±1

rpm for 4mins. The tablets were removed, dedusted and weighed. The percent friability was

calculated using the formula,

Initial wt. of Tablets – Final wt. of Tablets

Friability (%) =

X 100

Initial wt. of Tablets

Disintegration test

The disintegration test for all amlodipine formulations was carried out using tablet

disintegration test apparatus. Six tablets were placed individually in each tube of

disintegration test apparatus and discs were placed. The phosphate buffer pH 6.8 was

maintained at a temperature of 37°±2°C and time taken for the entire tablet to disintegrate

completely was noted.



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In-Vitro drug release study for Amlodipine formulations [13]

In-Vitro dissolution studies of the immediate release tablets of Amlodipine Besylate

formulations were performed according to USP Type-II dissolution apparatus employing a

paddle stirrer at 50 rpm using 900 ml of pH 6.8 phosphate buffer solution as dissolution

medium at 37 ± 0.5°C. One tablet was used in each test. Aliquots of the dissolution medium

(5 ml) were withdrawn at specific time intervals and replaced immediately with equal volume

of fresh medium. The samples were filtered through membrane filter disc and analyzed for

drug content by measuring area with HPLC. Drug concentration was calculated from the

standard curve and expressed as cumulative percent drug release.

In-Vitro drug release study for metoprolol formulations [13]

In-Vitro release studies of prepared Metoprolol succinate formulations were carried out in

0.1N hydrochloric acid pH 1.2 medium for first 2 hours, which was then replaced with the

same volume of a phosphate buffer solution pH 6.8 kept at 37˚C ± 0.5˚C and stirred at 50

rpm, using USP dissolution apparatus type 2. A 5-mL sample was withdrawn through

membrane filter discs and replaced with another 5 ml of a suitable fresh dissolution medium

at preselected intervals up to 20 hours. The samples are analyzed for drug content by HPLC.

Invitro drug release of bilayer tablet [13]

In-Vitro release studies of manufactured bilayered tablets of Amlodipine besylate and

Metoprolol succinate were carried out in 900 ml of (pH 1.2) 0.1N hydrochloric acid medium

for first 2 hours, which was then replaced with the same volume of a phosphate buffer

solution pH 6.8 kept at 37˚C ± 0.5˚C and stirred at 50 rpm, USP Type-II dissolution

apparatus. A 5mL sample was withdrawn at preselected intervals up to 20 hours and replaced

with another 5 ml of a suitable fresh dissolution medium. The samples were filtered through

membrane filter disc and analyzed for drug content by measuring area with HPLC. Drug

concentration was calculated from the standard curve and expressed as percent drug release.

Drug release kinetics of metoprolol succinate formulations [14]

The dissolution profile of all the batches was fitted to Zero order, First order and Higuchi to

ascertain the kinetic modeling of the drug release.

The results obtained from in vitro release studies were plotted in four kinetics models of data

treatment as follows:

Cumulative percentage drug release Vs. Time (zero order rate kinetics)



869


Log cumulative percentage drug retained Vs. Time (first order rate kinetics)

Cumulative percentage drug release Vs. √T (Higuchi’s classical diffusion equation)

Log of cumulative percentage drug release Vs. log Time (Peppa’s exponential equation).

RESULTS AND DISCUSSION

Drug – Excipient compatibility studies

Chemical interaction between Metoprolol Succinate and Amlodipine Besylate with various

combinations of polymers and excipients was studied by using FTIR. There is no interaction

between drugs and excipients. FTIR study revealed that combinations are showing all

characteristic peaks of both the drugs i.e., 1613, 1374, 1107, 1374, 3275, 3426, 777, 1232,

722, 1050cm-1

are observed and there is no shift of the peaks. The FTIR spectrums are shown

in fig 1 to 13 .

Fig 1: FTIR of Amlodipine Besylate

Fig 2: FTIR of Metoprolol Succinate



870


Fig 3: FTIR of Amlodipine Besylate + MCC

Fig 4: FTIR of Amlodipine Besylate + DCP

Fig 5: FTIR of Amlodipine Besylate + SSG



871


Fig 6: FTIR of Amlodipine Besylate + PVP K30

Fig 7: FTIR of Amlodipine Besylate + Iron oxide

Fig 8: FTIR of Amlodipine Besylate + Crospovidone



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Fig 9: FTIR of Metoprolol Succinate + HPMC K4M

Fig 10: FTIR of Metoprolol Succinate + HPMC K15

Fig 11: FTIR of Metoprolol Succinate + Carbopol



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Fig 12: FTIR of Metoprolol Succinate + PEO

Fig 13: FTIR of Placebo (mixture)

Evaluation of Amlodipine immediate release layer

Pre compression

For each formulation blend of Amlodipine Besylate drug and excipients were prepared and

evaluated for various pre compression parameters like angle of repose, bulk density, tapped

density, Carr’s index and Hausner’s ratio. The results of precompression parameters are given

in the table-4.



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Table 4: Pre compression parameters for the powder blend of Amlodipine Besylate

Formul

ation

Angle of

repose

Avg±sd

Bulk density

gm/ml Avg±sd

Tapped

density

gm/ml Avg±sd

Carr’s index

(%) Avg±sd

Hausner’s

ratio

Avg±sd

A1 31˚.251'±0.742 0.517±0.022 0.612±0.011 15.52±1.231 1.184±0.021

A2 30˚.754'±0.881 0.514±0.014 0.611±0.031 15.88±1.343 1.189±0.035

A3 32˚.125'±1.240 0.524±0.028 0.621±0.026 15.62±1.262 1.185±0.031

A4 31˚.075'±0.951 0.531±0.031 0.631±0.022 15.45±1.316 1.183±0.032

A5 33˚.141'±0.980 0.519±0.024 0.619±0.018 16.16±1.241 1.193±0.024

A6 30˚.663'±0.815 0.523±0.020 0.603±0.014 15.41±1.256 1.175±0.022

A7 30˚.298'±0.765 0.511±0.017 0.618±0.011 16.62±1.134 1.187±0.021

A8 30˚.367'±0.569 0.502±0.021 0.621±0.028 15.44±1.230 1.191±0.023

A9 30˚.530'± 0.77 0.521±0.018 0.611±0.016 15.43±1.342 1.185±0.025

A10 30˚.187'± 0.812 0.518±0.016 0.621±0.012 15.72±1.201 1.187±0.024

The good flow ability of blend was made evident with angle of repose values which are in a

range of 30˚.187' to 33˚.141' indicating passable flow ability. The Carr’s index was found to

be in a range of 15.41% to 16.16% indicating good flow ability. The powder blend of all the

Amlodipine Besylate formulations had Hausner’s ratio in range of 1.175 to 1.193 indicating

good flow ability. Since the powder material was free flowing, tablets were prepared by

direct compression technique.

Post compression

For each formulations of Amlodipine Besylate (A1 – A10) prepared were evaluated for

various post compression parameters like weight variation, friability, disintegration time,

hardness, thickness and in vitro dissolution. The results obtained are represented in table 5.

The thickness values of the all formulations ranged from 2.26 to 2.89 mm. The hardness of

all the formulations A1 to A10 ranged from 2.6 to 3.0 kg/cm2 with good mechanical strength.

The weight variation of the tablets was in the range of 2.011% to 2.371% which is an

acceptable range. Friability values of 0.53% to 0.68% showed that the formulations are

physically stable to mechanical shocks during handling and transportation. All tablets

disintegrated rapidly in the USP disintegration test. The disintegration time was dependent on

the concentration and type of disintegrant used and as the disintegration is rapid they are

considered suitable for immediate release.



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Table 5: Post compression parameters for the Amlodipine Besylate IR layer

Formul

ation

Hardness(kg/c

m2) Avg ± SD

Thickness(m

m) Avg ± SD

Weight

variation (%)

Avg ± SD

Friability

(%)

Avg ± SD

Disintegration

time(sec)

Avg ± SD

A1 3.0±0.194 2.89±0.01 2.011±0.219 0.66±0.021 21.52±0.67

A2 2.8±0.120 2.31±0.01 2.266±0.328 0.56±0.020 20.94±0.51

A3 2.6±0.114 2.29±0.02 2.310±0.429 0.52±0.016 17.64±0.24

A4 3.0±0.213 2.65±0.01 2.118±0.231 0.68±0.021 13.73±0.62

A5 2.8±0.172 2.43±0.01 2.197±0.310 0.54±0.038 11.69±0.63

A6 2.9±0.160 2.36±0.02 2.291±0.330 0.58±0.021 21.19±0.60

A7 3.0±0.193 2.28±0.01 2.301±0.117 0.53±0.010 20.66±0.39

A8 2.6±0.054 2.26±0.01 2.071±0.291 0.59±0.015 15.53±0.51

A9 2.8±0.151 2.36±0.02 2.108±0.102 0.63±0.022 16.11±0.33

A10 3.0±0.182 2.44±0.01 2.371±0.017 0.62±0.028 18.33±0.75

In-vitro dissolution studies were performed for all the formulated tablets using USP-II tablet

dissolution apparatus employing rotating paddle method at 50 rpm using 900 ml of pH 6.8

phosphate buffer solution as dissolution medium and the temperature of dissolution medium

was maintained at 37±0.5°C. The results of In-Vitro drug release data are given in table 6.

Table 6: In-Vitro dissolution profile for Amlodipine formulations

Time

in

min

Cumulative percentage Drug Release

A1 A2 A3 A4 A5 A6 A7 A8 A9 A10

5 46.080 48.217 79.489 45.044 64.427 62.101 59.452 66.197 48.264 46.342

10 51.060 56.379 83.148 49.001 69.188 66.367 63.205 72.164 57.085 51.209

20 57.252 63.278 87.399 55.303 73.143 71.120 68.029 79.300 62.285 58.266

30 63.291 70.036 91.475 61.535 80.003 77.112 74.253 86.203 71.225 65.078

45 71.147 78.516 96.244 70.198 87.087 82.481 81.202 93.067 83.500 73.0044

60 76.302 85.219 100 75.120 92.144 87.176 46.079 100 89.322 79.033

As per the results of dissolution studies, the formulations from A1 to A10 showed that the

drug release was satisfactory but whereas the formulation A8 is considered, the drug release

is reflecting the USP specification of NLT 85% by 30th

min and NLT 90% by 45th

min.



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Evaluation of Metoprolol sustained release layer:

Pre compression

For each formulation blend of Metoprolol Succinate drug and excipients were prepared and

evaluated for various pre compression parameters like angle of repose, bulk density, tapped

density, Carr’s index and Hausner’s ratio. The results of precompression parameters are given

in the table-7.

The good flow ability of blend was made evident with angle of repose values which are in a

range of 19˚.093' to 27˚.613' indicating excellent flow ability. The Carr’s index was found to

be in a range of 5.240% to 6.403% indicating excellent flow ability. The powder blend of all

the Metoprolol Succinate formulations had Hausner’s ratio in range of 1.055 to 1.068

indicating excellent flow ability. Since the powder material was free flowing, tablets were

prepared by direct compression technique.

Table 7: Pre compression parameters for the powder blend of Metoprolol Succinate

Formul

ation

Angle of

repose

Avg±sd

Bulk density

gm/ml Avg±sd

Tapped

density

gm/ml Avg±sd

Carr’s index

(%) Avg±sd

Hausner’s

ratio

Avg±sd

M1 23˚.699'±0.013 0.497±0.011 0.531±0.010 6.403±0.021 1.068±0.041

M2 24 .139 ±0.022 0.477±0.021 0.508±0.011 5.731±0.032 1.061±0.012

M3 24 .546 ±0.011 0.458±0.042 0.486±0.021 5.761±0.041 1.061±0.011

M4 25 .371 ±0.023 0.466±0.051 0.494±0.031 5.668±0.040 1.060±0.013

M5 26 .331 ±0.024 0.446±0.043 0.471±0.036 5.307±0.012 1.056±0.048

M6 27 .613 ±0.030 0.469±0.041 0.497±0.062 5.633±0.011 1.059±0.054

M7 19 .093 ±0.020 0.458±0.013 0.485±0.053 5.567±0.010 1.059±0.062

M8 23 .734 ±0.014 0.465±0.014 0.492±0.047 5.488±0.016 1.058±0.051

M9 24 .764 ±0.010 0.442±0.032 0.467±0.028 5.353±0.027 1.056±0.034

M10 26 .552 ±0.013 0.434±0.034 0.458±0.018 5.240±0.029 1.055±0.041

Post compression

For each formulations of Metoprolol Succinate (M1–M10) prepared were evaluated for

various post compression parameters like weight variation, friability, hardness, thickness and

in vitro dissolution. The results obtained are represented in table 8. The thickness values of

the all formulations ranged from 4.66 to 4.72 mm. The hardness of all the formulations M1 to

M10 ranged from 4.0 to 5.0 kg/cm2 with good mechanical strength. The weight variation of

the tablets was in the range of 2.161% to 4.159% which is an acceptable range. Friability



877


values of 0.55% to 0.88% showed that the formulations are physically stable to mechanical

shocks during handling and transportation.

Table 8: Post compression parameters for the SR layer of Metoprolol Succinate

Formulat

ion

Hardness(kg/cm2

) Avg ± SD

Thickness(mm)

Avg ± SD

Weight

variation (%)

Avg ± SD

Friability

(%)

Avg ± SD

M1 4.4 ±0.156 4.71±0.01 2.161±0.045 0.75±0.011

M2 4.6 ±0.114 4.70±0.02 2.951±0.173 0.88±0.021

M3 4.1 ±0.245 4.66±0.02 3.527±0.416 0.82±0.032

M4 4.3 ±0.112 4.72±0.02 3.367±0.174 0.85±0.010

M5 4.0 ±0.158 4.70±0.03 2.758±0.192 0.76±0.022

M6 4.7 ±0.312 4.67±0.03 4.159±0.057 0.72±0.033

M7 4.2 ±0.158 4.72±0.03 2.469±0.127 0.71±0.021

M8 5.0 ±0.315 4.71±0.02 2.494±0.066 0.68±0.024

M9 4.9 ±0.214 4.69±0.01 3.095±0.071 0.55±0.025

M10 4.2 ±0.132 4.72±0.02 2.585±0.053 0.81±0.028

In-Vitro dissolution studies were performed for all the formulated tablets using USP-II tablet

dissolution apparatus employing rotating paddle method at 50 rpm using 900 ml of pH 1.2

(0.1N HCl) solution as dissolution medium for first 2hours followed by 900 ml of pH 6.8

phosphate buffer solution as dissolution medium up to 20 hours and the temperature of

dissolution medium was maintained at 37±0.5°C. The results of In-Vitro drug release data are

given in table 9.

Table 9: In-Vitro dissolution profile for metoprolol formulations

As per the results of dissolution studies, the formulations from M1 to M10 showed the drug

release was not so satisfactory but whereas the formulation M7 is considered, the drug release

is reflecting the USP specification of NMT 20% by 1hour, 20-40% by 4th

hour, 40-60% by 8th

hour and NLT 80% by 20th

hour.

Time

in

hours

Cumulative percentage Drug Release

M1 M2 M3 M4 M5 M6 M7 M8 M9 M10

1 21.3315 30.066 14.249 19.239 30.068 12.362 20.026 19.455 16.348 26.024

4 50.2273 42.213 32.092 46.089 61.043 44.146 39.172 31.148 28.261 51.394

8 69.1654 58.188 55.176 67.262 91.147 58.130 58.426 49.348 46.078 73.080

20 92.2073 96.442 89.045 94.182 100 95.292 96.501 79.016 75.034 98.018



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Evaluation of bilayered tablets (Optimized formulation):

Post compression

The optimized formulation prepared was evaluated for various post compression parameters

like weight variation, friability, hardness, thickness and in vitro dissolution. The results

obtained are represented in table 10.The weight variation of the tablets was in the range of

2.869 ± 0.134% which is an acceptable range. Friability values of 0.62 ± 0.015% showed that

the formulations are physically stable to mechanical shocks during handling and

transportation. The hardness of the formulation was 4.0 ± 0.158 kg/cm2 with good

mechanical strength. The thickness values of the formulation were from 5.72 ± 0.02mm.

Table 10: optimized formulation post compression evaluation studies

Formulation OPTIMIZED FORMULATION POST COMPRESSION EVALUATION

Thickness(mm) Hardness (kg/cm2) Friability (%) Weight variation (%)

A8M7 5.72±0.02 4.0 ±0.158 0.62±0.015 2.869±0.134

As per the results of optimized formulation dissolution studies as mentioned in table 11, the

drug release is reflecting the USP specification of NMT 20% by 1hour, 20-40% by 4th

hour,

40-60% by 8th

hour and NLT 80% by 20th

hour.

Drug release kinetics of metoprolol succinate formulations

The drug release kinetics was performed for all the Metoprolol Succinate formulations and

optimized formulation, in that only M2, M5, and M10 formulations showed Fickian type of

diffusion and remaining 7formulations (i.e., M1, M3, M4, M6, M7, M8, M9) showed Non-

fickian type of diffusion. The release kinetics of the optimized formula followed Higuchi

model and non-fickian transport. The results of the both were shown in table 12 and 13.

Table 11: In-Vitro dissolution profile of optimized formulation

Time Optimized Formulation Invitro Drug Release

Amlodipine % Dr Metoprolol % Dr

5Min 66.1869 5.7853

10Min 72.1586 9.6083

20Min 79.2903 12.7020

30Min 86.1980 15.8607

45Min 93.0569 17.4726

1 Hour 100 20.005

4 Hour 99.9843 30.0947

8 Hours 99.9776 58.1728

20 Hours 99.9706 96.2667



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Table 12: In-Vitro drug release kinetics of the Metoprolol formulations

Formul

ation

code

Zero order First order Higuchi’s Krosmeyer- peppas Drug

release

mechanism R

2 slope R

2 slope R

2 slope R

2

Diffusion

exponent(n)

M1 0.822 4.112 0.993 -0.053 0.979 21.21 0.976 0.495 Non-fickian

diffusion

M2 0.898 4.162 0.968 -0.070 0.987 20.62 0.957 0.384 fickian

diffusion

M3 0.942 4.206 0.996 -0.047 0.990 20.38 0.996 0.621 Non-fickian

diffusion

M4 0.863 4.288 0.999 -0.060 0.990 21.70 0.985 0.538 Non-fickian

diffusion

M5 0.705 4.333 0.982 -0.100 0.921 23.40 0.942 0.420 fickian

diffusion

M6 0.911 4.461 0.985 -0.065 0.988 21.96 0.968 0.678 Non-fickian

diffusion

M7 0.932 4.410 0.975 -0.072 0.997 21.56 0.998 0.525 Non-fickian

diffusion

M8 0.923 3.563 0.993 -0.032 0.994 17.48 0.980 0.472 Non-fickian

diffusion

M9 0.935 3.438 0.994 -0.029 0.994 16.75 0.986 0.514 Non-fickian

diffusion

M10 0.829 4.317 0.993 -0.083 0.984 22.23 0.991 0.450 fickian

diffusion

Table 13: In-Vitro drug release kinetics of the Optimized formulations

Zero order First order Higuchi Korsmeyer-peppas

Diffusion

exponent (n) mechanism

r2 Slope r

2 Slope r

2 Slope r

2

0.955 0.075 0.969 -0.001 0.981 2.864 0.980 0.477

Non-fickian

diffusion

CONCLUSION

The present investigation showed that desired bilayered tablet formulation was prepared with

expected drug release and can be obtained by decreasing the tablet weight. Drug-excipient

compatibility studies were confirmed by using FTIR. Direct compression method is used for

preparing the tablets. The formulated tablets are subjected to all official and unofficial tests

for the evaluation studies. Release of Metoprolol Succinate from the tablets formulated by

employing Carbopol and PEO showed that the drug release was as per within the USP limits.

So formulation M7 is concluded as optimized formulation for sustained release. Release of

Amlodipine besylate from the tablets formulated by employing dicalcium phosphate, MCC



880


and sodium starch glycolate showed that the drug release was as per within the USP limits.

So formulation A8 is concluded as optimized formulation for immediate release. And for

further study batch A8 and M7 were used for tableting a bilayered formulation which is

subjected to post compression and In-Vitro dissolution studies by HPLC. The In-Vitro

dissolution study results of optimized formulation reflected the drug release was as per the

USP limits. So A8M7 is concluded as optimized formulation. The release kinetics of all

Metoprolol formulations (M1- M10) showed that the drug release following either fickian or

non-fickian transport. The release kinetics of optimized formula (A8M7) showed non-fickian

transport and followed Higuchi model.

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