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Noor Ahmed VH. et al. / International Journal of Biopharmaceutics. 2013; 4(1): 1-9.

e- ISSN 0976 - 1047

Print ISSN 2229 - 7499

IJB
International Journal of Biopharmaceutics

Journal homepage: www.ijbonline.com

FORMULATION DESIGN, CHARACTERISATION AND IN VITRO

EVALUATION OF BILAYERED TABLETS CONTAINING
TELMISARTAN AND HYDROCHLORTHIZIDE
Noor Ahmed VH1*, Niharika G2, Deepak P3, Shaaz Nazan4, Soheib Afroz Mohammed5
Department of pharmaceutics,
1*
Sree Vidyanikethan College of pharmacy, A.Rangampet, Tirupati - 517102, AP, India.
2
Bharat College of Pharmacy, Ibrahimpatnam, Hyderabad, AP, India.
3
Sree Padmavathi School of Pharmacy, Tirupati, AP, India.
4
Shadan College of Pharmacy, Peerancheru, Hyderabad, AP, India.
5
Vaagdevi College of Pharmacy, Hanamkonda, Warangal, AP, India.

ABSTRACT
The primary aim of this development is to have a stable formulation of antihypertensive drugs of the Telmisartan
and Hydrochlorothiazide bilayer tablet, and to study the dissolution profile. The Formulation development work was
initiated with Wet granulation for telmisartan and direct compression for hydrochlorothiazide. Telmisartan is converted to
its sodium salt by dissolving in aqueous solution of Sodium hydroxide, to improve solubility and drug release. Various
grades of Polyethylene oxide was used as polymers for the modified release profile over a period of 3 h. In the direct
compression of Hydrochlorothiazide, microcrystalline cellulose is used as binder and crospovidone as super disintegrant.
Tablets were evaluated for physical properties, drug content and in vitro drug release. The excipients used in this
formulation did not alter physicochemical properties of drug, conformed by FTIR studies. This formulation also exhibited
the best fitted formulation into zero order kinetics and non-Fickian transport of the drug from the tablets was confirmed.
Bilayer tablets prepared from optimised formula (T4H5) was found to be best suited method for fixed dose combination of
Telmisartan and Hydrochlorothiazide.

Key words: Bilayer tablets, Telmisartan, Hydrochlorothiazide, Super disintegrant, Non-Fickian transport.

INTRODUCTION Taste masking of rapidly disintegrating tablets is

The study was under taken with an aim to
formulate combination of antihypertensive agents for
better bioavailability as bilayer tablets. The aim of drug
delivery system was to provide therapeutic amount of
drug to targeted site in body to achieve promptly and then
maintain the desired concentration (Nagaraju et al., 2009)
Corresponding Author
Noor Ahmed VH
E-mail: noor.pharmacon@gmail.com
accomplished by using sutable dilunts and
superdisintegrants (Shailesh et al., 2010). Bilayered
tablets are intented for sequential release of two drugs in
combination and separate two incompatable substances,
(Shiyani et al., 2008). Hypertension is designated as
primary hypertension and secondary hypertension
(Mullaicharam et al., 2010). Telmisartan is an
angiotensin II receptor antagonist (ARB) used in the
management of hypertension. Generally, angiotensin II
receptor blockers (ARBs) such as telmisartan bind to the
angiotensin II type 1 (AT1) receptors with high affinity,
causing inhibition of the action of angiotensin II on
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Noor Ahmed VH. et al. / International Journal of Biopharmaceutics. 2013; 4(1): 1-9.

vascular smooth muscle, ultimately leading to a reduction oval shaped punch

in arterial blood pressure. Bioavailability was found to be
45% only it is due to extensive first pass effect (Ashutosh
kumar et al., 2010). Hydrochlorothiazide is a thiazide
diuretic, half-life was found to be 6-8 hrs (Rangole et al.,
2008), which reduces the reabsorption of electrolytes
from the renal tubules. This results in increased excretion
of water and electrolytes, including sodium, potassium,
chloride and magnesium. It has been used in the
treatment of several disorders including edema,
hypertension, diabetes insipidus and hypoparathyroidism.
Using a low dosage of two different drugs minimises the
clinical effects that occurs with large doses of single drug
of combined tablet and thus dosage of single drug can be
reduced (Ramya et al., 2010).
MATERIALS
Telmisartan and Hydrochlorothiazide was
obtained as gift sample from Aurabindo pharma Pvt Ltd
,Hyderabad, Polyethylene oxide N80 Polyethyleneoxide
WSR 303, Mannitol, Aerosilwas obtained as gift sample
from MMC Health Care , Chennai, Hydroxy Propyl
Methyl Cellulose K15M ,Microcrystalline cellulose,
Povidone K 30, was obtained as gift sample from A-Z
Pharmaceuticals , Chennai, And all other chemicals used
in formulations are analytical grade.
METHODS
FORMULATION DEVELOPMENT
Formulation Development of Telmisartan and
Hydrochlorothiazide bilayered tablets
The formulation of telmisrtan and
hydrochlorothiazide bilayered tablets for the treatment of
hypertension were developed by using various swellable
polymers such as PEO N80, PEO WSR Coagulant, PEO
WSR 303, HPMC K15M to attain modified drug release
to the first layer. And hydrochlorothiazide layer was
formulated by using super disintegrants like
crospovidone to show immediate release of the drug. The
blend for Bilayer tablet was compressed using 13mm size
STEPS INVOLVED IN MANUFACTURING OF
BILAYER TABLETS
Granulation of first layer
Step 1: Sifting and mixing: Telmisartan and mannitol
are passed through sieve No.40# and mixed thoroughly
with the help of mortar and pestle.
Step 2: Preparation of binder:Dissolve sodium
hydroxide, followed by povidone in required quantity of
purified water
Step 3: Wet granulation:Granulate step 1 mixture with
step 2 binder.
Step 4: Drying:Dry the step-4 wet mass in a tray dryer
at 600C for about 15 minutes.
Step 5: Pass the dried granules through 25# and the
granules are formed.
Step 6: Polyoxy ethylene is passed through 40# and then
mix step-5 dried granules with PEO..
Step 7: Lubrication: Pass magnesium stearate through
60# and lubricate the step-6 with magnesium stearate.
Preparation of second layer
Step 8: Hydrochlorothiazide, microcrystalline cellulose,
aerosol, crospovidone are passed through 40# and are
mixed thoroughly.
Step 9: Also pass magnesium stearate through 60# and
add to the above mixture.
Step10: To the final blend add iron oxide and mix
properly.
BILAYER TABLET COMPRESSION
 Introducing the granules of the first layer formed in
step 6 into the tablet press and compress to form a
tablet layer.
 Introducing the other tablet layer composition i.e, the
final blend formed in step 9 into the tablet press. The
punch size of the press is 13mm and is oval in shape.
 Compressing both the tablet layers first layer
followed by second layer to form a bilayer tablet.

Table 1. Formulation of first layer using various polymers

S.No Ingedients (mg) T1 T2 T3
1 Telmisartan 40 40 40
2 Mannitol 334 334 334
3 Povidone K30 12 12 12
4 Sodium hydroxide 4 4 4
5 Purified water Qs Qs Qs
6 PEO WSR 303 100 - -
7 PEO WSR coagulant - 100 -
8 HPMC K15M - - 100
9 Magnesium stearate 10 10 10
TOTAL 500 500 500
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Table 2. Formulation of first layer using various concentrations of polyethylene oxide

S.No Ingredients (mg) T4 T5 T6
1 Telmisartan 40 40 40
2 Mannitol 334 284 234
3 Povidone k30 12 12 12
4 Sodium hydroxide 4 4 4
5 Purified water Qs Qs Qs
6 PEO N80 100 150 200
7 Magnesium stearate 10 10 10
TOTAL 500 500 500

Table 3. Formulation of second layer

S.No Ingredients(mg) H1 H2 H3
1 Hydrochlorthiazide 12.5 12.5 12.5
2 Microcrystalline cellulose 83.5 82.5 81.5
3 Aerosil 1.0 1.0 1.00
4 Crospovidone 1.0 2.0 3.0
5 Iron oxide 0.5 0.5 0.5
6 Magnesium stearate 1.5 1.5 1.5
Total 100 100 100

EVALUATION Hausner’s ratio

Powder flow properties
Angle of repose
In order to determine the flow property, the Angle of
repose was determined. It is the maximum angle that can
be obtained between the free standing surface of the
powder heap and the horizontal plan  = tan -
1
(h/r)
Where, h= height, r = radius,  =
Angle of repose.
Determination of bulk density and tapped density
A quantity of 5g of the powder (W) from each formula
was introduced into a 25 ml measuring cylinder. After the
initial volume was observed, the cylinder was allowed to
fall under its own weight onto a hard surface from the
height of 2.5 cm at 2 sec intervals. The tapping was
continued until no further change in volume was noted.
The bulk density, and tapped density were calculated
using the following formulas
Bulk density = W / VO
Tapped density = W / Vf
Where, W = weight of the powder, VO = initial
volume, Vf = final volume
Compressibility index (carr’s indices)
Compressibility index is an important measure
that can be obtained from the bulk and tapped densities.
In theory, the less compressible a material the more flow
able it is. A material having values of less than 20 to 30%
is defined as the free flowing material.
CI = 100 (VO – Vf)/V
Where, CI = Compressibility index, VO = initial
volume, Vf = final volume.
It indicates the flow properties of the powder
and is measured by the ratio of tapped density to the bulk
density.
SHAPE OF TABLETS
The compressed tablets were examined under
the magnifying lens for the shape of the tablet.
TABLET DIMENSIONS
Thickness and were measured using a calibrated
vernier caliper. Three tablets of each formulation were
taken randomly and thickness was measured individually.
HARDNESS
Hardness indicates the ability of a tablet to
withstand mechanical shocks while handling. The
hardness of the tablets was determined using Monsanto
hardness tester. It is expressed in KiloPascals. Three
tablets were randomly picked and hardness of the tablets
was determined.
FRIABILITY TEST
The friability of tablets was determined using
Roche friabilator. It is expressed in percentage (%).
Twenty tablets were initially weighed (w0 initial) and
transferred into friabilator. The friabilator was operated at
25rpm for 4 minutes or run up to 100 revolutions. The
tablets were weighed again (w). The % friability was
then calculated by
Percentage of Friability = 100 (1-w/w0)
Percentage friability of tablets less than 1% is
considered acceptable.
WEIGHT VARIATION TEST
Twenty tablets were selected at random and the
average weight was determined. Not more than two of
the individual weights deviate from the average weight

Noor Ahmed VH. et al. / International Journal of Biopharmaceutics. 2013; 4(1): 1-9.
by more than the percentage deviation shown in table and
none deviates by more than twice the percentage. USP
official limits of percentage deviation of tablet are
presented in the table.
SWELLING STUDIES
The swelling behavior of dosage unit can be
measured either by studying its dimensional changes,
weight gain or water uptake. The water uptake study of
the dosage form was conducted by using USP dissolution
apparatus-II in a 900ml of distilled water which was
maintained at 37o + 0.5oc, rotated at 50 rpm. At selected
regular intervals the tablet was withdrawn and weighed.
Percentage swelling of the tablet was expressed as
percentage water uptake (%WU) (Chavanpatil et al.,
2006).
%WU = (Wt - Wo) * 1= (Wt - Wo) *
100 / Wo
Where,
Wt is the weight of tablet at time ‘t’.
Wo is initial weight of tablet.
DISSOLUTION STUDIES
Preparation of solutions
Standard solution
Weigh accurately and transfer 40 mg of
Telmisartan and 12.5 mg of Hydrochlorthiazide into a
100ml volumetric flask and add sufficient amount of
Fig 1. FTIR scan of pure Telmisartan
Fig 2. FTIR scan of pure Hydrochlorothiazide
4
diluent, sonicate to dissolve and make up to the volume
with diluent.From this pipette out 1ml and make upto
10ml using diluent. Sonicate the solution and filter it and
transfer it to a HPLC vial.
Sample solution
Six tablets are kept individually in six
dissolution flasks with sinkers containing 900ml of the
medium that has been equilibrated to 37±0.5 0C. care is
taken to exclude air bubbles from the surface of the
tablet, apparatus is started immediately. Samples have
been collected after the specified time, from a zone
midway between the surface of the medium and top of
the rotating blade and not less than 1 cm from the vessel
wall and filter through 0.23μ membrane filter, and inject
the solution directly into HPLC vial.
Procedure
Separately inject equal volume of standard and
sample preparation,,record the chromatograms, and
measure the areas for the telmisartan and
hydrochlorthiazide.Calculate the quantity of telmisartan
and hydrochlorthiazide
RESULTS AND DISCUSSION
Drug-Polymer compatibility studies by Fourier
transform infrared spectroscopy
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Fig 3. FTIR scan of Telmisartan mixed with Hydrochlorothiazide

Fig 4. FTIR scan of Telmisartan mixed with Mannitol

Fig 5. FTIR scan of Hydrochlorothiazide mixed with Crospovidone

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Fig 6. FTIR scan of Hydrochlorothiazide mixed with Aerosil

Table 4. Flow propeties of telmisartan granules

S.No Parameters T1 T2 T3 T4 T5 T6
1 Angle of repose(ɵ) 26.71 26.73 27.93 25.99 25.99 25.99
Bulk density (g/cm3) Untapped 0.74 0.75 0.73 0.76 0.76 0.76
2
Tapped 0.8 0.81 0.79 0.82 0.82 0.82
3 Compress- ibility index 7.5 7.4 7.5 7.3 7.3 7.3
4 Hausner’s ratio 1.08 1.07 1.08 1.09 1.09 1.08

Table 5. Flow properties of hydrochlorothiazide blend

S.No Parameter H1 H2 H3 H4 H5
Angle of repose(ɵ) 26.90 28.85 29.67 31.06 32.08
1
Bulk density (g/cm3) Untapped 0.40 0.425 0.435 0.430 0.425
2
Tapped 0.515 0.515 0.522 0.524 0.532
3 Compressibility index (%) 16.68 17.48 16.67 17.94 21.99
4 Hausner’s ratio 1.19 1.21 1.20 1.22 1.28

Table 6. Assay values

Assay BP specification Results
Telmisartan 99 .0 – 101 of LA 100.05%
Hydrochlorothiazide 98.0 - 102 of LA 99.6%

Table 7. Evaluation parameters

Tablet Hardness Thickness Friability Disintegration
S. No Formulations Drug Content (%)
weight (mg) (neutons) (mm) (%) (seconds)
1 T4H1 579.63 180.0 7.06 0.15 150.0 T4-98.53 H1-97.39
2 T4H2 580.60 162 6.84 0.13 120 T4-97.91 H2-97.45
3 T4H3 580.20 153.3 6.73 0.12 90 T4-97.45 H3-99.03
4 T4H4 580.30 156.6 6.24 0.11 60 T4-98.01 H4-99.11
5 T4H5 582 152.67 6.10 0.10 50 T4-99.10 H5-99.37

Table 8. Percentage swelling for various formulations

Time(mins) T1 T2 T3
0 0 0 0
30 13.15 10.15 19.20
60 36.15 36.14 37.87
120 58.22 79.15 61.12
180 85.46 100.15 82.58
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Table 9. Percentage swelling for various formulations

Time(mins) T4 T5 T6
0 0 0 0
30 36.56 42.30 46.27
60 45.26 56.86 59.35
120 68.29 72.20 76.23
180 102.60 105.10 110.62
Table 10. Percentage drug release of Telmisartan formulations
% Drug release
Time(min)
T1 T2 T3 T4 T5 T6
15 7.22 6.76 6.33 55.24 11.65 5.14
30 13.56 13.67 9.52 70.53 20.17 15.74
45 25.34 20.94 13.91 79.91 28.29 21.33
60 34.23 28.69 20.72 86.28 32.31 24.41
90 47.76 34.21 24.54 91.0 35.57 26.63
120 56.82 36.74 28.19 92.65 39.36 29.16
180 60.57 40.99 32.35 94.12 40.29 31.84

Table 11. Dissolution profile of bilayered tablets

%Drug release
Time(min)
T4H1 T4H2 T4H3 T4H4 T4H5
15 42.53 46.78 52.65 59.74 77.55
30 57.87 64.76 69.22 70.42 82.86
45 69.28 76.34 80.45 77.65 91.45
60 74.0 82.28 88.38 86.74 94.22
90 80.17 89.13 91.47 92.31 95.98
120 82.92 90.50 92.53 93.27 97.1
180 84.45 91.79 92.21 94.47 98.32

Fig 7. Dissolution profile of bilayered tablets Fig 8. Zero order plot for T4

Table 12. Drug release kinetics

R2 values
Batch no. Korsemeyer
Zero order First order Higuchi Hixon Crowell
R2 value n value
T-1 0.982 0.929 0.935 0.984 0.840 0.931
T-2 0.843 0.879 0.944 0.981 0.759 0.867
T-3 0.906 0.931 0.963 0.991 0.694 0.923
T-4 0.512 0.282 0.811 0.854 0.878 0.726
T-5 0.736 0.785 0.932 0.961 0.742 0.769
T-6 0.751 0.787 0.920 0.957 0.713 0.775
H-5 0.364 0.241 - - - -
Fig 9. First order plot for T4 Fig 10. Higuchi plot for T4

Noor Ahmed VH. et al. / International Journal of Biopharmaceutics. 2013; 4(1): 1-9.
Fig 11. Krosmeyer peppas plot for T4
The FTIR spectra of both the drugs, drug loaded
optimized formulation were shown in Fig no (1-6) . The
characteristic peaks of the optimized formulation
followed the same trajectory as that of the drug alone
with minor differences. Thus there was no drug-excipient
interactions found.
Flow properties of the granules can be judged
from the angle of repose, compressibility index and
hausner ratio shown in Table no (4-5). The angle of
repose <30° indicates free flowing material and >40°
with poor flow properties. The compressibility index (%)
<10 indicates excellent flow properties and >38 with
poor flow properties. The hausner ratio 1.00—1.11
indicates free flowing and >1.60 with poor flow
properties. Values for angle of repose, compressibility
index (%) and hausner ratio for all prepared granules
were found to be in the range of 25.99 to 27.93°, 7.3 to
7.5, and 1.07 to 1.09 which showed that the granules was
free flowing and can be used for compression.
Bulk density was found to be between 0.40-
0.435gm/cm3 and tapped density between 0.515 and
0.532 gm/cm3 for all formulations. From density data %
compressibility was calculated and was found to be
between 16.67%- 21.99%. Angle of repose was found to
be in the range of 26.90-32.08. Hausner ratio was found
below 1.28. All the formulation shows the good blend
8
Fig 12. Hixson-Crowel plot for T4
properties for direct compression and hence tablets were
prepared by using direct compression technology.
The swelling of the polymers used were
determined by water uptake of the tablet. The percent
swelling of the tablet was determined at the end of 3 h.
Increase in percent swelling was found with increasing
concentration of polymers, The formulation with PEO
N80 showed good swelling when compared with others.
With increasing concentration, the swelling was also
increased. The swelling index of T1-T3 and T4-T6 are
shown in table (8-9). Assay results shown in Table no (6)
were 100.05% for Telmisartan and 98.85% for
Hydrochlorothiazide. The drug release studies were
performed by dissolution apparatus, shon in (Fig 7). In
T1-T6 formulations, PEO WSR 303, PEO WSR
Coagulant, PEO N80,HPMC K 15M were used as a
hydrophilic swellable polymers to attain better
bioavailability. From drug release profile T4 formulation
using PEO N80 (100mg) showed better release and was
found to be optimized. The T4 optimised formulation of
first layer was then allowed for direct compression with
various formulations for second layer. Here crospovidone
was used as super disintegrant. Disintegrant when used in
5%w/w concentration showed better release. Hence
T4H5 formulation was the final formulation for which
various other parameters were also evaluated. Average
weight of all the formulations were within the range of
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Noor Ahmed VH. et al. / International Journal of Biopharmaceutics. 2013; 4(1): 1-9.

579.63-582 mg. Friability was also within the range of mechanism.

0.10-0.15%. Disintegration for all the formulations were
in the range of 50-150 sec.drug content in each of the
formulations were within the limits.In all the
formulations T4H5 showed better results and hence
considered as the best formulation.
The R2 values of zero order kinetics shown in
Table no (12) ranged from 0.364 – 0.982 for formulations
T1 – H5. The values for first order kinetics for T1 – H5
ranged from 0.241 – 0.931. The values for Higuchi model
ranged between 0.811 – 0.963. The values for Hixson-
crow model ranged between 0.726- 0.931 and the values
for Peppas model ranged between 0.854-0.991. All
formulations showed diffusion coefficient less than
1.For the optimized formulation T4, showed zero order
release kinetics with the R2 value of 0.512 and the R2
value of Krosmeyer Peppas is 0.854 (nearer to 1) is
dominant than the other models which indicates drug
release depended on the log of time. Hence the drug
release follows zero order and non fickian release
CONCLUSION
In the present study, PEO N80 was found to
play a major role in increasing the bioavailability of
telmisartan. PEO N80, a hydrophilic polymer, swells and
increases the size of the tablet thereby retains in the
stomach for much time and releases the drug over a
period of time, thus enhancing the bioavailability. With
the data from tables and graphs, the formulation of
telmisartan layer with good drug release profile was
taken as optimized formulation and was compressed with
various formulations of hydrochlorothiazide blends. Here
telmisartan layer is prepared by wet granulation method
and hydrochlorothiazide is prepared by direct
compression method. From the results, it can be
concluded that formulation T4H5 showed the desired
results. Accordingly, it can be concluded that the final
formulation is a robust one and the performance is less
likely to be affected by various study factors.

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