FORMULATION AND EVALUATION OF BILAYER TABLET OF ...

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Balurkar et al. World Journal of Pharmacy and Pharmaceutical Sciences

FORMULATION AND EVALUATION OF BILAYER TABLET OF

TELMISARTAN & METOPROLOL SUCCINATE

Ram Pentewar, Seema Balurkar*, R.V. Sugave, Ravi Rajurkar and S. Zingade

Channabasweshwar Pharmacy Collage, Kava Road, Latur.

ABSTRACT

The main objective of this combination therapy is to develop a stable

formulation of antihypertensive drugs of angiotensin II receptor

antagonist (ARB) as an immediate release and β1-Selective Adrenergic

Receptor Blocker (β1-SARB) as sustain release bilayer tablet and

evaluate their precompression and post-compression parameters. A

bilayer tablet comprises first layer formulated for instant release of the

angiotensin II receptor antagonist (ARB) from a dissolving tablet

matrix and a second layer formulated for sustain release β1-Selective

Adrenergic Receptor Blocker from a bilayer tablet. The formulation of

the developed work was initiated with direct compression method for

telmisartan layer and metoprolol succinate layer. In the formulation of immediate release

Micro crystalline cellulose and Croscarmellose sodium (CCS) were used as super

disintegrants and was directly compressed. Mannitol was used as diluents. Magnesium

stearate used as lubricant. The compressed bilayer tablets were evaluated for weight

variation, thickness, hardness, friability, drug content, and in-vitro drug release using USP

dissolution apparatus type 2 (paddle). The optimized formulation F-2 had 91.25% of drug

release for ARB layer and 99.38% drug release for β1-SARB layer. The IR spectrum and

DSC studies revealed that there is no disturbance in the principal peaks of pure drugs

Metoprolol succinate and Telmisartan. This further confirms the integrity of pure drugs and

no incompatibility of them with excipients. The stability studies were carried out for the

optimized batch for one months and it showed acceptable results. The present studies

concluded that bilayer tablet of Telmisartan and Metoprolol Succinate is novel approach to

prevent hypertension.

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 6.041

Volume 5, Issue 7, 1838-1855 Research Article ISSN 2278 – 4357

*Corresponding Author

Seema Balurkar

Channabasweshwar

Pharmacy Collage, Kava

Road, Latur.

Article Received on

19 May 2016,

Revised on 09 June 2016,

Accepted on 29 June 2016

DOI: 10.20959/wjpps20167-7252


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KEYWORDS: Bilayer Tablet, telmisartan, metoprolol succinate, direct compression

method.

INTRODUCTION

In the last decade, interest in developing a combination of two or more Active

Pharmaceutical Ingredients (API) in a single dosage form (bi-layer tablet) has increased in

the pharmaceutical industry. It promotes patient convenience and compliance. Bi-layer tablets

can be a primary option to avoid chemical incompatibilities between APIs by physical

separation and to enable the development of different drug release profiles (both immediate

release).[1]

Now a day’s most developed and developing countries move towards combination therapy

for treatment of various diseases and disorders requiring long term therapy such as

hypertension and diabetes. People suffering from these diseases have to take multiple drugs

and dosage, which may result in irregular intake. Combination therapies have various

advantages over monotherapy such as problem of dose dependent side effects being

minimized. A low-dose combination of two different agents reduces the dose-related risk; the

addition of one agent may counteract some deleterious effects of the other, minimizes the

clinical and metabolic effects that occur with maximal dosage of individual component of the

combined tablet and thus dosage of the single component can be produced. Development and

production of quality bi-layer tablets needs to be carried out using a purpose built tablet press

to overcome common bi-layer problems, such as layer-separation, insufficient hardness,

inaccurate individual layer weight control, cross-contamination between the layers, reduced

yield, etc.[2]

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.[3]

Telmisartan is a potent, long lasting, nonpeptide antagonist of angiotensin II (AT1) receptor

blocker, which is indicated for the treatment of hypertension. It reduces blood pressure (BP)

by interfering with the binding of angiotensin II to the angiotensin II AT1-receptor by

binding reversibly. Telmisartan is Class-II drug and has a longer half life 9- 18hrs.[4]


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Metoprolol succinate [MET] chemically is 1- (isopropyl amino)- 3- [4- (2-methoxyethyl)

penoxy] propan-2-ol. Metoprolol succinate is a beta1-selective (cardio selective) adrenergic

receptor blocking agent. Metoprolol succinate belongs to class I category in BCS

classification system, i.e. freely soluble & highly permeable. Metoprolol crosses the blood

brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous

plasma concentration.[5]

Figure.1. Chemical structures of drugs used in this method. (a)metoprolol succinate (b)

Telmisartan

MATERIALS AND METHODS

Chemicals/materials

Telmisartan and metoprolol succinate Metoprolol succinate was received from cipla from

pune and flemigo, Nanded. Hydroxypropyl methyl cellulose, Magnesium stearate, lactose

sodium lauryl sulphate, All the other chemicals were used with analytical grades.

Analytical method for estimation of telmisartan

Detection of Absorption Maxima

In order to ascertain the wavelength of maximum absorption (λ max) of the drug, different

solutions of the drugs (2,4 μg/ml, 6 μg/ml, 8 μg/ml, 10 μg/ml, 12 μg/ml) in methanol was

scanned using spectrophotometer within the wavelength region of 200–400 nm against

methanol as blank. The absorption curve showed characteristics absorption at 296 nm for

telmisartan.

Calibration curve for estimation of telmisartan in methanol

In this method, the drug was dissolved in little amount of distilled water to get a clear

solution, volume was adjusted with distilled water. Then the maximum absorbance was

measured at 296 nm. Beer’s law obeyed in concentration range of 2-12 mcg/ml.


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Analytical method for estimation of metoprolol succinate

Detection of Absorption Maxima

In order to ascertain the wavelength of maximum absorption (λ max) of the drug, different

solutions of the drugs (2,4 μg/ml, 6 μg/ml, 8 μg/ml, 10 μg/ml, 12 μg/ml) in distilled water

was scanned using spectrophotometer within the wavelength region of 200–400 nm against

distilled water as blank. The absorption curve showed characteristics absorption at 222 nm

for metoprolol succinate.

Calibration curve for estimation of metoprolol succinate in distilled water

In this method, the drug was dissolved in little amount of distilled water to get a clear

solution, volume was adjusted with distilled water. Then the maximum absorbance was

measured at 222 nm. Beer’s law obeyed in concentration range of 2-12 mcg/ml.

Formulation of tablets

1. Preparation of telmisartan immediate release layer

Fast dissolving tablets of telmisartan were prepared by direct compression method after

incorporating different superdisintegrants such as, croscarmellose sodium (Ac-Di-Sol),

Crospovidone and sodium starch glycolate, Fenugreek seeds in different concentrations. The

above ingredients was weighed and mixed in geometric progression in a dry and clean

mortar. Then the ingredients were passed through mesh #60.

Magnesium stearate as lubricant and mannitol as diluents were added in a final step and

mixed, this blend was subjected to analysis of pre-compression parameters which included

Angle of repose, Bulk density, Tap density, Carr’s index and Hausner’s ratio.

The Blend was compressed on 12 mm (diameter) fat punches on a ‘Rimek mini press rotary

compression machine. Five formulations of telmisartan were prepared. Each tablets weighing

170 mg, were obtained.

2. Preparation of Metoprolol succinate sustained release layer

The Metoprolol layer was prepared by using direct compression method. All the ingredients

except magnesium Stearate and Aerosil were passed through sieve No: 40 weighed and

mixed for 15 mints and finally blended well in ascending order of their weights. Magnesium

Stearate and Aerosil were passed through sieve No: 60 and mixed it to the above blend.


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Finally colorant was added and blended uniformly and compressed in a 16 station automatic

punching machine with a punch size of 12 mm. Each tablets weighing 460mg, were obtained.

3. Tablet compression

The bilayer tablet compression was made using 12 mm punch in a 27 station rotary tablet

machine with double feed. In this, sustained release metoprolol succinate powder were

introduced first in to the die cavity and a slight Precompression was made so that the layer

was uniformly distributed. After that immediate release telmisartan power were added

through the other feed and a final compression was made.

Table 1: Formulation of immediate release layer of telmisartan (in mg)

Table 2: Formulation of sustained release layer of Metoprolol succinate (in mg)

Sr.no INGREDIENS F1 F2 F3 F4 F5

1 Telmisartan 10 10 10 10 10

2 Microcrystalline cellulose 50 50 50 50 50

3 Croscarmellose sodium 3 6 - - -

4 Crosspovidone - - 4 - -

5 Fenugreek seeds - - - 4 -

6 Sodium starch glycolate - - - - 4

7 Sodium lauryl sulphate 1 1 1 1 1

8 Menthol 2 2 2 2 2

9 Mg. stearate 3 3 3 3 3

10 Mannitol 100 100 100 100 100

11 Wight of ARB(mg) 170 170 170 170 170

SR.No. INGRADIENTS F1 F2 F3 F4 F5

1 Metoprolol succinate 100 100 100 100 100

2 Guar gum - 37.5 - - -

3 Xanthum gum - - 37.5 37.5 -

4 Eudragit Rs 100 37.5 37.5 - 37.5 -

5 HPMC K100M 37.5 - - - 37.5

6 HPMC K15M - - 37.5 - -

7 Carbapol - - - - 37.5

8 Aerosil 1 1 1 1 1

9 Mg. stearate 4.5 4.5 4.5 4.5 4.5

10 Microcrystalline cellulose 100 100 100 100 100

11 Lactose 178 178 178 178 178

12 Amaranth q.s q.s q.s q.s q.s

13 Wight of β1-SARB (mg) 460 460 460 460 460


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Precompression parameter study

Pre compression parameters

The power of telmisartan and metoprolol succinate were evaluated for its bulk density, tapped

density, carr’s index, hausner’s ratio and angle of repose were evaluated.

a) Bulk Density

Bulk density is the ratio of mass of the powder to the bulk volume it occupies. Bulk density

largely depends on particle shape, as the particles become more spherical in shape, bulk

density increases. In addition as granules size increase, bulk density decreases. It is expressed

in gm/ml.

Bulk density is determined by measuring the volume of a known mass of powder sample that

has been passed through a screen into a graduated cylinder or through a volumetric measuring

apparatus into a cup.

A known quantity of powder was poured into the measuring cylinder carefully level the

powder without compacting, if necessary and read the unsettled apparent volume, Vo, to the

nearest graduated unit. Calculate the bulk density, in gm per ml, by the formula,

Bulk density = Bulk of Mass/ Bulk of Volume

ρb =W/Vb

Where,

ρb = Bulk density

W = Mass of blend

Vb = Untapped Volume

b) Tapped Density

10 grams of granules was taken into graduated cylinder occupied by granules was noted

down. Then cylinder was subjected to 500 taps in tapped density tester. (Electrolab USP Π) It

is expressed in gm/ml.

The percentage of volume variation was calculated by the following formula,

ρt =m/Vi

Where

ρt = Tapped density


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m = Mass of blend

Vi = Untapped Volume

c) Carr’s Compressibility Index

Compressibility is the ability of powder to decrease in volume of powder under pressure. For

poorer flowing materials, there are frequently greater inter particle interactions and a greater

difference between bulk and tapped densities will be observed. These differences are

reflected in the compressibility Index. Using untapped volume and tapped volume, the

percentage compressibility of granules were determined, which is given as

CI =Vi-Vo/Vi x 100

Where,

CI = Carr’s Index

Vo= Bulk density

Vi =Tapped density

Table No. 3: Carr’s Index is an indication of granule flow properties

Carr’s Index Type of Flow

5-15 Excellent

12-16 Good

18-21 Fair to passable

23-35 Poor

33-38 Very Poor

d) Hausner’s Ratio

It is measurement of frictional resistance of the drug. It was determined by the ratio of tapped

density and bulk density.

Hausner’s Ratio = Vi/Vo

Where

Vi = Tapped density

Vo = Bulk density

Table No. 4: Hausner’s Ratio is an indication of granule flow properties

Flow Character Hausner’s Ratio

Excellent 1.00-1.11

Good 1.12-1.18

Fair 1.19-1.25

Passable 1.26-1.34


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Poor 1.35-1.45

Very Poor 1.46-1.59

Very very >1.60

e) Angle of Repose

Angle of repose (θ) is the maximum angle between the surface of pile of powder and

horizontal plane. It is usually determined by fixed funnel method and is measure of

flowability of powder or granules. A funnel was kept vertically in a stand at a specified

height above a paper placed on a horizontal surface. The funnel bottom is closed and 10 gm

of sample powder is filled in funnel. Then funnel was opened to release the powder on the

paper to form a smooth conical heap, is found by measuring in different direction. The height

of the heap was measured by using scale.

(θ) = tan-1 (h/r)

Where,

θ = Angle of repose

h= Height of heap of pile

r= Radius of base of pile

Table No. 5: Relationship between angle of repose (θ) and flow ability

Angle of Repose (0) Type of Flow

<25 Excellent

25-30 Good

30-40 Poor

>40 Very Poor

For most pharmaceutical powders, the angle of repose values range from 25 to 45, with lower

values indicating better flow characteristics. Values of angle of repose ≤ 30 usually indicate a

free flowing material and angle ≥40 suggest a poorly flowing material.

Flow rate = weight of sample / Time required emptying the funnel.

Post compression parameter study

1. Thickness

The thickness of the tablets was determined using a Vernier caliper. Five tablets from each

type of formulation were used and average values were calculated. It is expressed in mm.

(Lachman et al, 1991).


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2. Hardness

The resistance of tablets to shipping, breakage, under conditions of storage, transportation

and handling before usage depends on its hardness. For each formulation, the hardness of 6

tablets was determined using the Monsanto hardness tester. The tablet was held along its

oblong axis in between the two jaws of the tester. At this point, reading should be zero

kg/cm2. Then constant force was applied by rotating the knob until the tablet fractured. The

value at this point was noted (Lachman et al, 1991).

3. Friability

Friability is the measure of tablet strength. Roche Friabilator was used for testing the

friability using the following procedure. This test subjects a number of tablets to the

combined effect of shock abrasion by utilizing a plastic chamber which revolves at a speed of

25 rpm, dropping the tablets to a distance of 6 inches in each revolution. A sample of pre

weighed 6 tablets was placed in Roche Friabilator which was then operated for 100

revolutions i.e. 4 minutes. The tablets were then dusted and reweighed. A loss of less than 1%

in weight in generally considered acceptable. Percent friability (% F) was calculated as

follows (Lachman et al, 1991).

4. Weight variation test

To find out weight variation, 20 tablets of each type of formulation wereweighed individually

using an electronic balance, average weight was calculated andindividual tablet weight was

then compared with average value to find the deviation in weigh. (Indian pharmacopoeia,

1996).

Table No.6: Specifications for tablets as per Pharmacopoeia of India

Sr.No. Average Weight of Tablet % Deviation

1 80 mg or less 10

2 More than 80 mg but less that

250 mg 7.5

3 250 or more 5

5. Uniformity of drug content

Five tablets of each type of formulation were weighed and crushed in mortar and powder

equivalent to 50 mg of Etoricoxib was weighed and dissolved in 100 ml of 0.1N HCl (pH

1.2). This was the stock solution from which 0.2 ml sample was withdrawn and diluted to 10


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ml with 0.1N HCl. The absorbance was measured at wavelength 235 nm using double beam

UV-Visible spectrophotometer. Content uniformity was calculated using formula.

% Purity = 10 C (Au / As)

Where, C - Concentration,

Au and As - Absorbance‟s obtained from unknown preparation and standard Preparation.

6. In vitro disintegration time

The process of breakdown of a tablet into smaller particles is called as disintegration. The in-

vitro disintegration time of a tablet was determined using disintegration test apparatus as per

I.P. specifications. I.P. Specifications: Place one tablet in each of the 6 tubes of the basket.

Add a disc to each tube and run the apparatus using distilled water maintained at 37° ± 2°C as

the immersion liquid. The assembly should be raised and lowered between 30 cycles per

minute in the 0.1 N HCL maintained at 37° ± 2°C. The time in seconds taken for complete

disintegrationof the tablet with no palpable mass remaining in the apparatus was measured

and recorded.

In vitro Dissolution Studies

Dissolution for telmisartan Immediate release layer

The in vitro dissolution of immediate release layer was determined using USP XXIII (basket

method) dissolution apparatus. The basket was allowed to rotate at a speed of 100 rpm and

temperature of 37 ± 0.5°C was maintained.

The dissolution medium used was 900 ml of 0.1N HCl (pH 1.2) for 2 hours. Aliquots (5 ml)

of sample were collected at predetermined time intervals (5, 10, 15, 20, 25 and 30min) from

the dissolution apparatus and it was replaced with equal volume of fresh dissolution medium.

The aliquots withdrawn were filtered through 0.45μm Millipore filters. The concentration of

telmisartan in the dissolution media was estimated uv spectrometry at 296 nm.

Dissolution for metoprolol succinate sustained release layer

The in vitro dissolution of sustained release layer was determined using USP XXIII (basket

method) dissolution apparatus. The basket was allowed to rotate at a speed of 100 rpm and

temperature of 37 ± 0.5°C was maintained. The dissolution medium used was 900 ml of 0.1N

HCl (pH 1.2) for the initial 1 hours followed by study in simulated intestinal fluid Phosphate

buffer solution (pH 6.8). Aliquots (5 ml) of sample were collected at predetermined time


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intervals (1, 2, 3,4,5,6,7,8,9,10,11 and 12 hrs) from the dissolution apparatus and it was

replaced with equal volume of fresh dissolution medium. The aliquots withdrawn were

filtered through 0.45μm millipore filters. The concentration of Metoprolol in the dissolution

media was estimated by uv spectrometry at 222 nm.

RESULTS AND DISCUSSIONS

Analytical method for estimation of telmisartan

UV Spectrum of telmisartan in methanol

Fig.2. UV Spectrum of telmisartan in methanol

Analytical method for estimation of metoprolol succinate

UV Spectrum of metoprolol succinate in distilled water

Fig. 3. UV Spectrum of metoprolol succinate in distilled water


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Standard calibration data of telmisartan in methanol

Table 7: Standard calibration data of telmisartan in methanol

Concentration(μg/ml) Absorbance

0 0

2 0.080

4 0.184

6 0.267

8 0.353

10 0.450

12 0.526

Fig. 4: Standard calibration curve of telmisartan in methanol

Standard calibration data of metoprolol succinate in distilled water

Table no. 8: Standard calibration data of metoprolol succinate in distilled water

Concentration(μg/ml) Absorbance

0 0

2 0.144

4 0.254

6 0.375

8 0.485

10 0.625

12 0.731

Fig. no. 5: Standard calibration curve of metoprolol succinate in distilled water


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Table no. 9: results of pre-compressional flow properties

Sr.No Formulation

for ARB

Bulk Density

(gm/ml)

Tapped Density

(gm/ml)

Carr’s

Index

Hausner’s

Ratio

Angle of

Repose

1 F1 0.320 0.421 23.99 1.315 35016

’

2 F2 0.385 0.498 22.69 1.293 340 23’

3 F3 0.372 0.475 21.68 1.276 33 028’

4 F4 0.365 0.470 22.34 1.287 32 041’

5 F5 0.376 0.464 18.96 1.234 32 056’

Table 10: results of pre-compressional flow properties

Sr.No Formulation

for ARB

Bulk

Density

(gm/ml)

Tapped

Density

(gm/ml)

Carr’s

Index

Hausner’s

Ratio

Angle of

Repose

1 F1 0.354 0.360 16.66 1.016 29 025’

2 F2 0.372 0.447 16.77 1.201 29 075’

3 F3 0.358 0.450 20.44 1.256 28 020’

4 F4 0.347 0.453 23.39 1.305 27 025’

5 F5 0.370 0.445 22.02 1.202 25 085’

Table No. 11: Post Compression Parameters for Bilayer Tablets

Sr.No Specifications F1 F2 F3 F4 F5

1 Description A pink colour on one side & white colored on other

side, round, beveled edge uncoated bilayer tablet

2 Thickness (mm)

3 Hardness (kg/cm2) 4-5 4-5 4-5 4-5 4-5

4 Friability (%w/w) 0.41 0.86 0.77 0.64 0.58

5 Weight (in mg) 630 630 630 630 630

6 Disintegration time (min.) 4-5 5-6 6-7 5-6 5-6

Table No. 12: Content uniformity of both blend

Table No. 13: In Vitro Dissolution Profile for fast Release Tablet (ARB)

Time (min) F1 F2 F3 F4 F5

0 0 0 0 0 0

5 27.44 29.46 28.94 26.14 25.94

10 33.29 36.12 35.45 39.28 36.20

15 53.97 56.70 57.28 65.35 56.94

20 63.36 79.20 80.15 85.46 80.35

Sr.No Formulation for

β1-SARB part

(CU) for β1-

SARB part

Formulation for

ARB part (CU) for ARB

1 F1 92.6% F1 96.5%

2 F2 98.4% F2 99.1%

3 F3 96.7% F3 91.3%

4 F4 95.4% F4 93.0%

5 F5 98.1% F5 100.2%


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25 73.45 88.28 94.30 95.10 89.00

30 81.72 91.25 100 .20 102.25 91.14

Fig 6. Dissolution comparison between F1,F2,F3,F4,F5

Table No. 14: In Vitro Dissolution Profile for sustained Release Tablet (β1-SARB)

Time (hrs) F1 F2 F3 F4 F5

0 0 0 0 0 0

1 31.88 36.32 30.09 32 31.45

2 39.14 39.85 36.14 40 37.15

3 44.49 47.11 45.14 49.25 45.40

4 54.48 56.30 58.02 60.14 59.25

5 61.04 63.36 65.40 69.45 62.19

6 73.45 75.67 71.32 75.28 74.32

7 79.20 80.21 79.89 80.49 82.19

8 82.33 83.74 80.65 85.65 85.45

9 83.23 87.98 82.14 89.92 89.20

10 88.28 90.20 88.23 93.45 92.21

11 91.81 97.86 95.97 99.20 96.69

12 93.32 99.38 101.28 100.49 99.25

Fig. no. 7. Dissolution between f1,f2,f3,f4,f5


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Infra Red Spectral analysis

Fig. no. 8: Infrared spectrum of telmisartan drug

Fig. no.:-9 FT IR of pure drug telmisartan with exicipients

Fig.no. 10: Infrared spectrum of metoprolol succinate drug


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Fig. no.: 11- FT IR of pure drug metoprolol succinate with exicipients

Infrared Spectroscopy Result

FTIR studies were conducted and the spectrum was recorded in the range of 4000-400 cm-1.

No significant interaction between the drug and excipients was observed. All the spectrum

i.e. drug and excipients were concordant with that of the standard IR spectra of pure drug of

telmisartan and metoprolol succinate.

CONCLUSION

In present work, a bilayers tablet of telmisartan and metoprolol succinate developed by direct

compression method using various polymers, Superdisintegrants. In the preliminary part, FT-

IR study was carried out which suggested that there was no significant drug interaction

between telmisartan and metoprolol succinate with, Superdisintegrants and other excipients.

UV scan of had shows telmisartan absorption at wavelength 296nm in methanol and

metoprolol succinate absorption at wavelength 222nm in distilled water. Physical parameters

like hardness, weight variation, thickness and friability were within pharmacopoeial limit.

The optimized formulation F-2 had 91.25% of drug release for ARB layer and 99.38% drug

release for β1-SARB layer. IR spectrum and DSC studies revealed that there is no

disturbance in the principal peaks of pure drugs Metoprolol succinate and telmisartan.

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