267

Research Article

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International Journal of
Pharmacy and Industrial
Research

2231 3648
2231 3656

FORMULATION AND OPTIMIZATION OF IMMEDIATE RELEASE

TABLET OF AN ANTI HYPERTENSIVE DRUG BY
DRY GRANULATION METHOD
*

Sowmya C, Suryaprakash Reddy C, Haranath C, Madhukar B

Raghavendra Institute of Pharmaceutical Education and Research,

Anantapur, Andhra Pradesh, India 515 721.
__________________________________________________________________________
Abstract
The present study is planned to develop Candesartan cilexetil into immediate release tablets. Generally dry
granulation is followed for the drugs that are sensitive to the moisture .Here the dry granulation was
developed as a cost effective step towards the manufacturing compared to the wet granulation. The stability
of the drug was also assured in the dry granulation process due to the absence of the moisture. So wet
granulation method was avoided. All the mentioned batches were done by dry granulation method by roller
compaction. Granules were evaluated for tests such as bulk density, tapped density, compressibility index
and Hausers ratio and sieve analysis before compression. Tablets were tested for weight variation,
thickness, hardness, friability and dissolution. In vitro dissolutions were performed and Difference factor (f1)
and similarity factor (f2) values were calculated. Dissolution profile of Trail V was found to have high
similarity with marketed (innovator) formulation. First order dissolution model was constructed.
Key words: Candesartan Cilexetil, Immediate release tablet, Dry granulation technique, Difference factor,
Similarity factor.
_______________________________________________________________________________________

Introduction

Candesartan blocks the vasoconstrictor1 and

membrane fastly. Candesartan Cilexetil, a

aldosterone-secreting effects of angiotensin II

prodrug4, is hydrolyzed to candesartan during

by

absorption from the gastrointestinal tract.

selectively

blocking

the

binding

of

angiotensin II to the AT1 receptor in many

tissues, such as vascular smooth muscle and

Direct compression5 of powders requires

the adrenal gland. Its action is, therefore,

materials

independent of the pathways for angiotensin II

compressibility.Those

synthesis. The present drug (API) is a class II

more critical when the formulation contains

molecule2, 3; it dissolves slowly in aqueous

large amounts of active substances with poor

environment and permeates over intestinal

compressional properties. Spray-dried extracts

exhibiting

Author for Correspondence:

Sowmya C,
Raghavendra Institute of Pharmaceutical Education and Research,
Saigram, KR Pally cross, Chiyyedu, Anantapur, Andhra Pradesh, India 515721.
Email: drsowmyariper@rediffmail.com

flowability
parameters

and
become

268

Sowmya C. et al., Int. Journal of Pharmacy & Industrial Research Vol 02 Issue 03 Jul Sep 2012

(SDEs) from medicinal plants are very fine,

tablet characteristics. Immediate release oral

light, and poorly compressible powders. Few

dosage forms are most widely used drug

studies have examined the use of dry

delivery systems available. These products are

granulation to enhance particle size and

designed to disintegrate in the stomach

consequently to improve flowability and

followed by their dissolution in the fluids of

compressibility

the gastrointestinal tract. In limited number of

of

such

materials.

Dry

an in-vitro

in-vivo correlation

granulation can be achieved either by slugging

cases,

using a tablet press or by roller compacter.

established between the drug release and drug

Both of these processes are used for materials

product absorption necessary for therapeutic

that ordinarily will not compresssing the more

effects. Disintegration test is a standardized

conventional wet granulation techniques and

test and is primarily used as a quality

require precompression to increase density or

assurance

exclude entrapped air due to porosity.

tool

to

confirm

is

complete

disintegration of solid oral dosage forms

within the prescribed time when placed in a

The granulation parameters can affect the

liquid

mechanical (compressional) properties of the

conditions described in their respective official

granules, which subsequently can influence the

monographs8. The methods for the comparison

tableting behavior and tablet characteristics 6.

of in vitro dissolution profiles can be classified

The desired particle size distribution can be

into three groups: methods based on analysis

adjusted
granulation

by

milling
parameters

and
can

sieving7.The
affect

medium

under

of variance (ANOVA)

the

9, 10

experimental

model-dependent

11

methods , and model-independent method12,

the

mechanical (compressional) properties of the

13

granules, which subsequently can influence the

release profiles was compared with a marketed

tabletting behavior and tablet characteristics.

formulation

Therefore, the evaluation of granule properties

model-independent methods.

. In this context, The discrimination of

using

model-dependent

plays an important role in the prediction of

Table 1: Formula used in the different formulations
Ingredients (mg/tab)
Intragranular Ingredients
Candesartan cilexetil
Lacto press Spray Dried 250
Corn starch
Starch1500
Carmellose calcium
Extragranular ingredients
Avicel PH-112
Carmellose calcium
Magnesium stearate
Starch1500
Colloidal silica
Total

F1

F2

F3

F4

F5

32
242.5
55
-8.00

32
239
25
-12

32
239
-55
--

32
235
55
-12.0

32
237.5
46
-20.0

8.5
-4.0
--350

8.0
-4.0
30
-350

4.0
4.0
4.0
12
-350

6.0
6.0
4.0
--350

6.0
4.0
4.0
--350

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and

Sowmya C. et al., Int. Journal of Pharmacy & Industrial Research Vol 02 Issue 03 Jul Sep 2012

Materials and methods

269

tablets were prepared for each formulation.

Cadilla),

Composition of prepared Candesartan cilexetil

Lactopress Spray Dried 250 (DMV-Fonterra),

immediate release tablets are presented in table

Corn starch (Roquette Freres), Carmellose

1 Physical properties of granules of different

calcium (Maple Biotech), Magnesium stearate

formulations were determined in table 2.

Candesartan

Cilexetil

(Zydus

(Ferro corporarion), Colloidal silica (Evonik

Evaluation of tablet properties

Industries GMBH).

The formulated tablets were evaluated for

Solubility studies of Candesartan cilexetil

uniformity of weight, thickness, hardness,

Maximal solubility of Candesartan cilexetil in

friability and disintegration time.

different media (0.7% polysorbate in pH6.5

Phosphate Buffer, 0.7% polysorbate in pH4.5

Weight variation test

Acetate Buffer, 0.7% polysorbate in 0.001N

The variation of the weight of individual tablet

HCl, 0.7% polysorbate in 0.1N HCl) was

is a valid indication of the drug content.

studied.

Candesartan

Weight variation studies of 20 tablets were

cilexetil was taken in 50 mL of above medium

done and resulting deviations were determined

and dissolved by triplicate sonication. The

and the results were shown in the table 3.

Excess

amount

of

maximal solubility of Candesartan cilexetil in

each medium was determined at different time

Thickness measurement

intervals (0, 15, 60, 120min) after filtering the

It is carried out on 20 tablets by measuring

content using HPLC method.

thickness using vernier calipers. Mean and

standard deviation were determined and the

Preparation of Candesartan cilexetil tablets

Immediate release

results were shown in table 3.

tablet of Candesartan

cilexetil were prepared by adopting dry

Hardness determination

granulation technique. Accurately weighed

20 tablets were taken randomly and hardness

quantities of pre-sieved drug and intragranular

was

materials (Candesartan cilexetil, Lactopress

measured

using

Hardness

tester

(Electrolab India Ltd). The mean and standard

Spray Dried 250, Corn starch, Carmellose

deviation of 20 tablets of each formulation is

calcium) were mixed & slugs were prepared,

shown in table 3.

and then passed through multimill screen

(1.5). The granules were sieved using #20

Friability test

sieves.

Friability was determined on 20 tablets. Tablet

samples were weighed accurately and placed
with

in fribilator (Electrolab India Ltd). After 100

extragranular materials (Magnesium stearate,

rotations (4 min at 25 rpm) loose dust was

Colloidal silica) and compressed using 9.5 mm

removed from the tablets. Finally tablets were

round flat standard concave Punches on Tablet

weighed. The loss in weight indicates the

Compression

ability of the tablets to withstand the wear. The

Tooling), Cadmach, INDIA.. Three batches of

percentage friability was determined by using

The

final

granules

Machine

were

(16

blended

Stations,

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270

Sowmya C. et al., Int. Journal of Pharmacy & Industrial Research Vol 02 Issue 03 Jul Sep 2012

following formula and the result was shown in

with intermittent shaking. Further dilute 5 mL

table 3.

of the above solution to 100mL. The solution

was mixed well and filtered through 0.45 m
nylon filter. After injecting the blank, standard
then the sample was injected and the drug
content was calculated using HPLC at 227 nm.

Disintegration test
Disintegration time was determined to ensure
that the drug substance is fully available for
dissolution

and

gastrointestinal

absorption
tract.

The

from
tablets

the
were

examined using the USP- XXIV disintegration

apparatus (Electrolab India). Six tablets were
tested for each batch. The disintegration time
of tablets was compared to 15 minutes which
is accepted as the general tablet disintegration
time for the uncoated immediate release
tablets. The results of the disintegration time of

The drug content of the various formulations

was shown in table 3.
Model-independent methodsDetermination of dissolution data
equivalence
For the determination of dissolution data
equivalence,

FDA

guidance

documents

recommend approaches such as the modelindependent approach based on the calculation

of difference factor (f1) and similarity (f2)

the various formulations were shown in table 3.

factors, which is currently applied. From a

In-vitro release studies

be less discriminating than other methods,

In-vitro release study of Candesartan Cilexetil

was carried out using USP Type II dissolution
apparatus (Paddle type, model TDT-08L,
Electrolab, India) at 371C and 50 rpm using
900 mL with 0.7% polysorbate in pH 6.5
Phosphate Buffer. Aliquots were withdrawn at
predetermined

time

intervals

and

were

replenished immediately with the same volume

of

fresh

dissolution

medium.

Aliquots,

following suitable dilutions, were assayed by

statistical point of view, this method seems to

such

as

ANOVA

and

model-dependent

methods. According to the FDA guidance, f1

values of 015 and f2 values of 50100 ensure
sameness or equivalence of the two dissolution
profiles. In both equations, R and T represent
the dissolution measurements at P time points
of

the

reference

and

test,

respectively.

Difference factor (f1) and similarity (f2)

factors were calculated for every formulation
and they were shown in table 4

HPLC (Shimadzu, Japan) at 227 nm. The drug

f1 =

release profiles of the various formulations

f2 = 50 log

2 -1/2

100}

were shown in table 4.

Model-dependent methods

Drug content study

5 tablets or blend equivalent to 5 tablets were
weighed

and

transferred

into

100

ml

volumetric flask. To this 70 ml of diluent

(Phosphate buffer and Acetonitrile in the ratio
of 30:70) was added and sonicated to dissolve

Drug release kinetics was analyzed by firstorder kinetic model, which was applied
considering the amounts of drug released from
0 to 60 min. The following plot was made: log
cumulative % drug remaining versus time
(first-order kinetic model) and it was shown in

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271

Sowmya C. et al., Int. Journal of Pharmacy & Industrial Research Vol 02 Issue 03 Jul Sep 2012

the figure 02. K1 (First order release constant)

reference product. In the third formulation

calculated for all the formulations as shown in

disntegrant(Starch 1500) was used only intra

the table 5.

granularly and only 1.2% Carmellose calcium

was used extra granularly.The DT was found

Results and discussion

to increase by only 1 minute.There were no

Flow properties of the drug are important in

changes in DT with Starch1500.In the next

optimizing the method of granulation for the

formulations only corn starch and carmellose

drug product. Therefore, the flow of drug was

calcium were used

analyzed before the selection of granulation

(1.35),

In the fourth formulation 15% of the corn

compressibility index (30) and angle of

starch, 3.5% of Carmellose calcium was used

repose (45) indicates poor flowability of drug

intra granularly as disintegrant and 1.8%

candidate, the dry granulation technique, was

(Carmellose

selected to improve the flow ability of powder

granularly.In this formulation the DT was

mixture.

found to slighly match with that of the

technique.

Hausners

ratio

calcium)

was

used

extra

innovators DT (10-11 min).In the fifth

Experiments with solubility of Candesartan

formulation the extra granular disintegrants

Cilexetil in various medium revealed that

were slightly reduced and the DT was found to

Candesartan Cilexetil is more soluble in 0.7%

be matching with that of the innovators

polysorabte in 0.05M phosphate buffer pH 6.5.

product.By comparing the dissolution profiles

Hence, it was selected as ideal dissolution

fourth

medium, to study in-vitro release profile of

comparable to that of the innovators product.

Candesartan Cilexetil.This medium is the FDA

The fifth formulation was found to be

recommended for the dissolution of the

matching more in terms of the similarity

Candesarten Cilexetil tablets.

factor.

The optimization of the formula was done by

First order dissolution model was constructed

varying

and t50 and t90 were calculated.

the

the

concentrations

of

the

and

the

fifth

formulations

were

disintegrants like corn starch, Starch 1500,

Carmellose calcium both intra granularly and

Conclusion

extra granularly. MCC PH-112 was changed

Candesartan

only extra granularly.

tablets were prepared by dry granulation

Cilexetil

immediate

release

technique. In order to obtain the best,

In the first formulaion all the physical

Optimized product five different formulations

parameters were comparable to that of the

were developed. Different disintegrants and

innovator except the disintegration time. In the

their concentration were taken as the major

second formulation corn starch was used 7%

variables. An optimized product has been

intra granularly and 8.5% (starch 1500) was

formulated by varying the above variables and

used extra granularly. The disintegration time

determining

found to reduce substantially compared to the

mechanical properties of the final product.

www.ijpir.com

their

effect

on

physical/

272

Sowmya C. et al., Int. Journal of Pharmacy & Industrial Research Vol 02 Issue 03 Jul Sep 2012

Lower compressibility and poor flow of drug

product. t50, t90 values (time taken to reach

candidate was overcome by dry granulation

50% and 90% release simultaneously) were

(slugging). Release of the drug from the tablet

calculated and these values of the optimized

was found to follow the first order kinetics,

formulation were found to match with the

Similarity factor was calculated and the Trail

innovators product.

V was found to match with the innovator

Table 01: Flow properties (Pre compression parameters) of the different formulationsMean and standard deviations were included
Properties
Angle of repose
Bulk density (gm/mL)
Tapped density (gm/mL)
Compressibility Index
Hausners Ratio

Trail I
28.10.04
0.540.02
0.680.04
27.01.06
1.360.09

Trail II
26.60.06
0.550.08
0.690.03
26.11.07
1.300.18

Trail III
28.40.02
0.530.02
0.680.03
25.771.37
1.350.24

Trail IV
26.00.03
0.540.03
0.690.02
21.651.25
1.270.22

Trail V
23.80.09
0.550.03
0.690.02
23.521.52
1.330.19

Table 02: Physical Chemical parameters of the tablets of the various formulationsMean and standard deviations were included
Physical parameter
Hardness (N)
Thickness (mm)
DT (min)
Friability (%w/w)
Weight (mg)
Drug content(%w/w)

Trail I
593.40
4.250.13
5-6
0.48
351.233.1
98.173.55

Trail II
622.56
4.20.76
7-8
0.02
348.011.3
97.11.29

Trail III
644.5
4.260.35
8-9
0.12
3552.11
101.71.4

Trail IV
651.77
4.220.36
10-11
0.10
352.121.5
98.71.09

Trail V
672.33
4.2- 0.15
10-12
0.22
3521.55
98.90.34

Table 03: In vitro release studies of the various formulations

Time
10
20
30
45
60

Reference
27.1 0.65
63.6 0.77
88.81.34
99.9 2.33
98.43.02

% Mean cumulative drug release S.D.

Trail I
Trail II
Trail III
Trail IV
18.30.45 45.50.48 44.80.37 29.90.59
41.51.88 70.30.97 82.11.33 59.50.66
61.91.67 92.71.78 88.51.65 79.61.29
79.52.56 93.41.88 94.22.21 87.72.5
89.73.77 95.23.89 96.43.78 92.03.01

Trail V
280.76
63.10.56
82.81.77
91.32.47
98.43.02

Table 04: f1 and f2 Values for Each Comparison

Formulation
Trail I
Trail II
Trail III
Trail IV
Trail V

f1
22.75
11.41
9.95
8.89
3.92

f2
36.5
46.60
51.36
56.54
68.31

Dissolution profile
Dissimilar
Dissimilar
Similar
Similar
Similar

Table 05: Release characteristics

Trail
I
II
III
IV
V
Reference

First order Equation

y = -0.0168x + 2.0606
y = -0.0244x + 1.9012
y = -0.0232x + 1.9011
y = -0.0192x + 1.9862
y = -0.0294x + 2.1086
y = -0.0359x + 2.1203

First order R2
0.9887
0.9549
0.8915
0.9799
0.9731
0.9519

K1(min-1)
0.038
0.056
0.053
0.0442
0.0677
0.0826

t50 (min)
24.5
11.5
12.2
16.5
16.8
17.2

t50 (min): Time taken to reach 50% cumulative drug release

t90 (min): Time taken to reach 90% cumulative drug release
N.A.: Not applicable

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t90 (min)
N.A.
28.5
32.5
48
38
34

Sowmya C. et al., Int. Journal of Pharmacy & Industrial Research Vol 02 Issue 03 Jul Sep 2012

273

Figure 01: Release profile of different formulations

Figure 02: First-order plots for different formulations.

ARR Amount remaining to be released

References
1.

2.

H.P. Rang, M.M. Dale, J.M. Ritter, R.J.

Sixth Edition; 305-310.

dosage forms tablets, Vol3, Second

Gilbert S. Banker Christopher T. Rhodes;

edition, Marcel Dekker,Inc, New York

fourth edition, Marcel Dekker,Inc, New

,pp: 195-245.
6.

B.Schwartz,

Pharmaceutical

Joseph

Bultmann J M; Multiple compaction of

Vijaykumar N, Venkateswarlu V and

microcrystalline cellulose in a roller

Raviraj

compactor. Eur J Pharm Biopharm. 2002;

Research

Journal

of

54:59-64.

Pharmaceutical, Biological and Chemical

Sciences October December 2010

7.

Description

of

Candesartan

Freitag F, Kleinebude P; How do roll

compaction/dry granulation affect the

RJPBCS 1(4) Page No. 952-63.

4.

Herbert.A. Liebermen, Leon Lachman,

Flower; Rang and Dales Pharmacology.

York ; pp:55-57.
3.

5.

cilexetil;

http://www.drugbank.ca/drugs/DB00796

tablet behavior of inorganic materials?

Comparison

of

four

magnesium

carbonates. Eur J Pharm Sci. 200319:281289.

www.ijpir.com

274

Sowmya C. et al., Int. Journal of Pharmacy & Industrial Research Vol 02 Issue 03 Jul Sep 2012

8.

United States Pharmacopeia 30/National

Formulary

25.

Pharmacopeial
9.

2008.

The

Convention,

11. Sathe, P. M.; Tsong, Y.; Shah, V. P. In

U.S.

vitro

dissolutionprofile

comparison:

Inc.

statistics and analysis, model dependent

Rockville, MD. (www.usp.org)

approach. Pharm. Res. 1996, 13,1799

Mauger, J. W.; Chilko, D.; Howard, S. On

1803.

the analysis of the dissolution data. Drug

12. Podczeck, F. Comparison of in vitro

Dev. Ind. Pharm. 1986, 12,969992.

dissolution profiles by calculating mean

10. Polli, J. E.; Rekhi, G. S.; Augsburger, L.

dissolution time (MDT) or mean residence

L.; Shah, V. P.Methods to compare

time (MRT). Int. J. Pharm. 1993, 97, 93

dissolution profiles and arationale for

100.

wide

dissolution

specifications

for

metoprolol tartrate tablets. J. Pharm. Sci.

13. Moore,

1997, 86,690700.

J.

W.;

Flanner,

H.

H.

Mathematical comparison of dissolution

profiles. Pharm. Technol. 1996, 6, 6474.

www.ijpir.com