Abbaraju Prasanna Lakshmi et al.

IRJP 2012, 3 (2)

Page 117
INTERNATIONAL RESEARCH JOURNAL OF PHARMACY
www.irjponline.com ISSN 2230 8407
Research Article


FORMULATION DEVELOPMENT OF IRBESARTAN (POORLY WATER-SOLUBLE DRUG)
IMMEDIATE RELEASE TABLETS
Abbaraju Prasanna Lakshmi*, Meka Anand Kumar, M. Vamshi Krishna, K.Annie Vijetha,
G. Ashwini
Omega College of Pharmacy, Ghatkesar, Edulabad, Andhra Pradesh, India

Article Received on: 06/12/11 Revised on: 10/01/12 Approved for publication: 18/02/12

*Email: prasanna1707@gmail.com

ABSTRACT
The aim of the present study is to increase the solubility of poorly water soluble drug Irbesartan by using surfactants and formulating into immediate release
tablets by using super disintegrants. Surfactants such as sodium lauryl sulfate, polysorbate, and poloxamer 800 are used for increasing the solubility of drug in
water by micellisation technique. Super disintegrant such as croscarmellose sodium was used for fast disintegration. Physical properties for granules such as
Bulk density, Tapped density, Hausners ratio, % compressibility, % LOD and physical characteristics for Irbesartan IR tablets such as weight variation,
friability, hardness, thickness, disintegration, in-vitro dissolution were studied. % cumulative drug release of formulation T3 (having 2% Tween 80) matched
with the innovator product Avapro and the similarity factor between innovator and T3 was 97.
KEY WORDS: Irbesartan, Polysorbate, poloxamer, sodium lauryl sulphate.

INTRODUCTION
Solubility and dissolution are the key parameters for the
therapeutic effect of a drug. Solubility is one of the important
parameter to achieve desire concentration of drug in systemic
circulation for pharmacological response
1
. More than 92% of
the drugs listed in U.S pharmacopeia are having poor
solubility. It is commonly recognized in the pharmaceutical
industry that on average more than 40% of newly discovered
drug candidates are having poor solubility. Micronization,
Nanonization, salt formation, use of surfactants
2,3,4
, solvent
deposition, eutectic mixture, solid dispersion and molecular
encapsulation are the several methods for enhancement of
solubility of the drugs
5
.
Surfactant acts as an absorption enhancer and hence increases
both dissolution and permeability of the drug
6
. They enhance
the dissolution rate by promoting wetting and penetration of
dissolution fluid into the drug particles. Both ionic and
nonionic surfactants were used for solubility enhancement.
Among the ionic surfactants, anionic surfactants have high
solubility than cationic.
Further enhancement of dissolution can be done by using
super disintegrants. Super disintegrants, disintegrate the
tablet rapidly which enhances the dissolution rate of the
drug
7
.
Irbesartan is an angiotensin II receptor antagonist used in the
treatment of hypertension. It may also delay progression of
diabetic nephropathy and also indicated for the reduction of
renal disease progression in patients with type 2 diabetes
8
,
hypertension and micro albuminuria or proteinuria.
According to BCS classification Irbesartan belongs to class
II
9
. Since it has poor solubility in water, methods has been
developed for enhancement of solubility by using different
types and concentrations of surfactants by which the
solubility of Irbesartan has been increased.
The present work is to optimization of Irbesartan immediate
release tablets and comparing the best with the innovator
product by varying the concentration and type of surfactants.




MATERIAL AND METHODS
Materials
Irbesartan(Aarey Drugs and Pharmaceuticals Ltd, Andhra
Pradesh), Lactose Monohydrate ( Surya Pharmaceuticals Ltd,
Himachal pradesh), Croscarmellose sodium(Sun
Pharmaceuticals Inds Ltd, Gujarath), Pregelatinized starch
(Bliss GVS Pharma Ltd,Mumbai), Sodium Lauryl Sulphate
(Neuland Laboratories, Andhra Pradesh), Poloxamer 800
(Neuland Laboratories, Andhra Pradesh),
Polysorbate(Neuland Laboratories, Andhra Pradesh), Aerosil
200(Sd fine chemicals, Mumbai), MCC (Avicel 101) (Ozone
International, Mumbai), Magnesium state(Rexer pharma
private Ltd, cherlapally).
Solubility studies of Irbesartan
Weigh accurately 300mg (i.e. highest dose of Irbesartan) of
Irbesartan (API) and transfer it in to 250ml flask containing
media (0.1N HCl, 0.01N HCl, pH 3.0Citrate buffer, pH4.5
Acetate buffer, pH 6.8 Phosphate buffer) and the flask is
subjected to sonication at 37C for 1hr. The solution was
filtered and supernatant solution is collected. From this
solution 1ml is pipette out and it was diluted to 10ml with
water, and the absorbance was checked at 220 nm for 3 times
and the average value of the absorbance was taken for
calculations to get concentration of drug.
Method of preparation
Sift Irbesartan, Lactose, Croscarmellose Sodium, Aerosil,
Pregelatinized starch, through # 30 mesh and dissolve
different surfactant as per table in water. Transfer material
into rapid mixing granulator and granulated by mixing with
surfactant solution and dried in FBD at 55-60C and
checking to LOD <2.0%, then Sift granules through #24
mesh and Sift the extra granular MCC, Cross careamellose
sodium, Aerosil through #30 mesh and blend the material.
Sift magnesium stearate through #60 mesh and added to the
blend. The blend was compressed by using 15.6x7.8mm
punch in 16 station, single rotary compression machine.
Prototype Formulation
In this formulation three different types of surfactants were
used at three different percentages 0.5%,1%,2%. The
different formulas and different ratios of surfactants were
given in the below table.
Abbaraju Prasanna Lakshmi et al. IRJP 2012, 3 (2)
Page 118


TABLE1: FORMULATION OF DIFFERENT CONCENTRATION OF SURFACTANTS
S.No Ingredients mg/tab (0.5%) Trail-1 mg/tab (1%) Trail-2 mg/tab (2%) Trail-3
S1 P1 T1 S2 P2 T2 S3 P3 T3
1.
2.
3.
4.
5.
6.
7.
8.
9.
Irbesartan
LactoseMonohydrate
Cross careamellose sodium
Pregelatinized Starch
Sodium lauryl sulfate
Poloxamer80
Polysorbate
Aerosil 200
Purified water.
300.0
76.5
15.0
90.0
3.0
-
-
12.0
q.s
300.0
76.5
15.0
90.0
-
3.0
-
12.0
q.s
300.0
76.5
15.0
90.0
-
-
3.0
12.0
q.s
300.0
76.5
15.0
90.0
6.0
-
-
12.0
q.s
300.0
76.5
15.0
90.0
-
6.0
-
12.0
q.s
300.0
76.5
15.0
90.0
-
-
6.0
12.0
q.s
300.0
76.5
15.0
90.0
12.0
-
-
12.0
q.s
300.0
76.5
15.0
90.0
-
12.0
-
12.0
q.s
300.0
76.5
15.0
90.0
-
-
12.0
12.0
q.s
Extragranular
1.
2.
3.
4.
MCC (Avicel101)
Crosscarmelosesodium
Aerosil 200
Magnesium Stearate
78.0
15.0
4.5
6.0
78.0
15.0
4.5
6.0
78.0
15.0
4.5
6.0
78.0
15.0
4.5
6.0
78.0
15.0
4.5
6.0
78.0
15.0
4.5
6.0
78.0
15.0
4.5
6.0
78.0
15.0
4.5
6.0
78.0
15.0
4.5
6.0
Total Tablet Weight 600 600 600 600 600 600 600 600 600
MCC: Micro crystalline cellulose

Drug excipient compatibility studies
Drug and excipients were weighed and sifted through sieve
no 40 separately. The drug and excipient mixture were placed
in glass vials and sealed with aluminum foil. These vials were
placed in different temperature conditions (25c/60%RH,
40c/75%RH, 50c/75%RH) for 15, 20 days. At the end of 15
and 30 days the samples were analyzed for physical change.
Evaluation of physical characteristic of granules
10

The granules were evaluated for % loss of drying, Bulk
density, Tapped density, Compressibility and Hausners ratio.
Evaluation of tablet properties
11

The prepared tablets were evaluated for weight variation,
friability by using Roche friabilator, Hardness (Monsanto
hardness tester), Thickness (vernier calipers), disintegration
(Electro lab India Ltd), and Dissolution (Schimadzu).
Weight Variation
Weight variation test is done by weighing 20 tablets
individually, calculating the average weight, and comparing
the individual tablet weight with the average. Any deviation
in the tablet weight indicates dose uniformity is not
Friability
Friability test was performed by taking 20 tablets. Pre weight
of the individual tablet was taken before subjecting to
friability test. Weighed tablet samples are transformed into
friabilator and subjected to combined effects of abrasion and
shock by revolving at 25rpm for 4min for 100revolutions.
Samples are withdrawn after set time completions and loose
dust powder was removed from the tablet and final weight is
noted and substituted in the formulae.
% friability= Initial weight-Final weight x 100
Initial weight
Hardness
20 tablets were selected randomly from a batch and hardness
was tested by placing the tablet between two anvils, and the
crushing strength that causes the tablet to break is noted.
Thickness
Thickness of the tablets was measured by using vernier
calipers. Mean and standard deviation were calculated.

Disintegration
Disintegration was performed for finding out the time taken
for tablets to broken down from large particle into small
particles. Test was performed by using. Tablets was placed in
6 glass tubes (1 tablet in each tube) and immersed in
simulated gastric fluid at 37c2c.
Dissolution
Drug release studies were done by using USP type 11
apparatus (paddle type). 900ml of dissolution medium was
transferred into round bottomed beaker and the temperature
was maintained at 37c2c and 50rpm. At regular time
interval 5ml sample was withdrawn and replaced with fresh
dissolution medium. Removed sampled was diluted and
observed in UV spectrophotometer at 220nm.
Assay of tablets
12

Estimation of drug content in tablet was carried out by using
UV/Visible spectrophotometer at 220-nm.
Procedure
Weigh and finely powder not fewer than 10 Tablets. Transfer
an accurately weighed portion of the powder, equivalent to
about 15 mg of Irbesartan, to a 100-mL volumetric flask. Add
methanol up to about three-fourths of the volume of the flask.
Sonicate for 15 minutes, with stirring at 5-minute intervals.
Dilute with methanol to volume, and pass a portion of this
solution through a glass microfiber membrane filter having a
0.45-m or finer porosity.
RESULTS AND DISCUSSION

TABLE 2: SOLUBILITY STUDY OF IRBESARTAN
S.No Dissolution Medium mg/250ml mg/900ml
1 SGF 297.34 1070.64
2 0.1N HCl 307.7 1107.73
3 0.01N HCl 98.58 354.9
4 pH 3.0 Citrate buffer 41.85 150.64
5 pH 4.5 Acetate buffer 26.09 93.91
6 pH 6.8 Phosphate buffer 212.22 764









Abbaraju Prasanna Lakshmi et al. IRJP 2012, 3 (2)
Page 119
TABLE 3: DRUG AND EXCIPIENT COMPATIBILITY STUDY
S.NO Name of the substance D:E
Ratio
25C/60%RH 40C/75%RH 50C/60%RH

Initial 15
days
30
days
15
days
30
days
15
days
30
days
1 Irbesartan As such no change NCC NCC NCC NCC NCC NCC
2 Lactose Monohydrate 1:2 no change NCC NCC NCC NCC NCC NCC
3 Avicel PH 101 1:2 no change NCC NCC NCC NCC NCC NCC
4 Croscarmellose sodium 1:1 no change NCC NCC NCC NCC NCC NCC
5 Colloidal Silicon Dioxide 1:0.25 no change NCC NCC NCC NCC NCC NCC
6 Magnesium stearate 1:0.25 no change NCC NCC NCC NCC NCC NCC
7 Carnauba wax 1:1 no change NCC NCC NCC NCC NCC NCC
8 Poloxamer 188 2:1 no change NCC NCC NCC NCC NCC NCC
9 SodiumLauryl Sulphate 2:1 no change NCC NCC NCC NCC NCC NCC
10 Sodium Starch Glycollate 1:1 no change NCC NCC NCC NCC NCC NCC
11 Starch 1500 1:5 no change NCC NCC NCC NCC NCC NCC
12 Tween 80 2:1 no change NCC NCC NCC NCC NCC NCC
D:E : Drug Excipient ratio, NCC (No conformational change), RH: Relative Humidity.

TABLE 4: PHYSICAL CHARACTERISTICS OF INNOVATOR
Parameters Observation
Colour White
Shape Caplet
Weight 6011.14
Thickness 7.00.1
Hardness 115-120
Length 15.3
Width 7.1
Disintegration time 2min

TABLE 5: PHYSICAL CHARACTERISTICS OF GRANULES
Trial
No.
%LOD Bulk density
(gm/cm2)
Tapped density
( gm/cm2)
% Compressibility Hausner Ratio
S1 1.56 0.487 0.565 13.80 1.160
S2 1.64 0.469 0.531 11.67 1.132
S3 1.46 0.5 0.545 8.0 1.09
P1 1.71 0.444 0.558 20.43 1.25
P2 1.52 0.486 0.567 14.2 1.166
P3 1.62 0.443 0.554 20.03 1.25
T1 1.47 0.469 0.531 11.67 1.132
T2 1.74 0.51 0.543 6.07 1.064
T3 1.65 0.485 0.567 12.13 1.138

TABLE 6: PHYSICAL CHARACTERISTICS OF IRBESARTAN IR TABLETS:
Trial Weigh variation
( mg)
Friability
(%)
Hardness
(Newtons)
Thickness
(mm)
Disintegration
(min)
Drug content (%)
S1 6022.35 0.14 110 - 120 7.20.1 7.30 99.8
S2 6012.04 0.12 110 - 120 7.10.1 7.27 101
S3 6032.03 0.17 110 - 120 7.20.1 7.29 99.6
P1 6022.06 0.2 110 120 7.30.1 2.40 99.9
P2 6042.41 0.24 110 120 7.10.1 2.36 100.2
P3 6022.13 0.26 110 120 7.10.1 2.24 99.5
T1 6012.35 0.23 110 120 7.20.1 2.14 99.8
T2 6042.15 0.24 110 120 7.20.1 2.02 99.9
T3 6022.38 0.28 110 120 7.20.1 1.50 100.1



Fig 1: Comparing dissolution profile of innovator and trial S1, P1 and
T1






Fig 2: Comparing dissolution profile of innovator and trial S2, P2 and
T2, T3







Abbaraju Prasanna Lakshmi et al. IRJP 2012, 3 (2)
Page 120


Fig 3: comparing dissolution profile of innovator and trial S3, P3 and

TABLE 7: SIMILARITY FACTOR OF DIFFERENT
FORMULATIONS
SNO Trails Similarity factors
1 S1 19.1
2 P1 42.9
3 T1 48
4 S2 20
5 P2 56
6 T2 68.4
7 S3 22
8 P3 63
9 T3 97


RESULTS AND DISCUSSION
Preformulation studies are conducted for pure drug
Irbesartan; it revealed that the drug exhibits poor flow
properties and compressibility. To enhance the flow property
wet granulation method is used for the preparation of
Irbesartan immediate release tablets.
The drug content in the formulation is within the limits and it
was given in the table 6. Solubility of Irbesartan in different
media is given in the table2. Solubility is high in 0.1 N HCl
compared to other medium. So the dissolution studies were
conducted in 0.1 N HCl.
Physical properties of granules such as bulk density, tapped
density, hausners ratio, %LOD, and compressibility were
found to be within the range. All the formulations shown
good flow properties and the results were shown in the table
5.
Drug excipient compatibility studies showed that there was
no interaction or physical change between the drug and
excipient. The selected excipient was found to be compatible
with the drug.
The evaluated IR tablets weight variation was within the
range of 6012.04-6042.41, friability falls between 0.2-
0.17, hardness and thickness of the tablets were found to be
between 110-120 and 7.1-7.2.
Disintegration time of all the nine formulations was 7.30,
7.27, 7.29, 7.40, 2.36, 2.24, 2.14, 2.20, 1.50min. Among all
the formulations, T3 disintegrated within 1.50 min. the
disintegration concentration in all the formulation was same
but the disintegration was varied in the formulation due to the
change in the concentration and type of surfactant.
Dissolution studies of all the formulations are compared with
the marketed product AVAPRO. 2% polysorbate
(formulation T3) showed the same release profile as that of
the marketed product AVAPRO. The comparative release
rate profile of marketed product and T3 were shown in fig 3.
2% of polysorbate has the capability to form micelles, which
enhances the solubility of the drug. This infers that as the
concentration of surfactant increases the micellar
concentration increases, as micellar concentration of
surfactant increases the rate of release of the drug is increased
due to the fast absorption of the dissolution medium by the
tablets and greater disintegration, which enhances the drug
release. Surfactant helps in solubility of drug and dissolution
rate also.
The similarity factor of different formulations with innovator
product has been checked. Among all the formulation the
similarity factor between formulator T3 and innovator is
found to be 97. The similarity factor for all the formulations
and innovator were given in table7.
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Source of support: Nil, Conflict of interest: None Declared