formulation and evaluation of bilayer tablet of
TRANSCRIPT
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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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