Formulation
Development and In-Vitro Evaluation
of Extended Release Tablets Containing Losartan
Potassium
B. Babu Rao*, P. Harish, Saikat Das, T. Ashwin Kumar, V. Raman Koundinya
Pathfinder
Institute of Pharmacy Education and Research, Beside Mamnoor
Camp, Warangal-506166
*Corresponding Author E-mail: babupharma79@gmail.com
ABSTRACT:
The objective of the present work was to
prepare and evaluate extended release matrix tablets of Losartan
potassium. Losartan potassium, an Angiotensin
receptor blocker used in the treatment of hypertension, has poor
bioavailability (33%) and has elimination half-life of 2 hrs. So, it is best
suited for extended release matrix formulation. The tablets were formulated to
reduce the frequency of dose administration and to improve the patient
compliance. Tablets were prepared by
direct compression method, using hydrophilic polymers like natural (Xanthan gum, Guar gum) and synthetic (HPMC K100 M) as the
release retarding polymers. The FTIR studies indicated the absence of drug
polymer interaction. The formulated tablets were evaluated for weight
variation, hardness, friability, drug content uniformity and swelling index. The
In Vitro drug release of the tablets was carried out in pH 6.8 buffer for 24
hrs. The influence of different polymers like Xanthan
gum, Guar gum and HPMC K100 M as well as their combinations on the drug release
profile was studied. Based on the dissolution studies optimised
formulae are F-12 and F-14. To analyze the mechanism of drug release from the
tablets, the In-Vitro dissolution data of optimised
formulations were fitted to zero order, first order, higuchi
release model and korsmeyer-peppas model based on
regression coefficient. The n values of the optimised
formulations F-12 and F-14 were 0.585 and 0.599 respectively. This indicates
the release of drug followed Non Fickian or anomalous
transport.
KEYWORDS: Extended release, Losartan potassium, Hydrophilic polymer.
INTRODUCTION:
Oral
administration of drugs has been the most common and preferred route for
delivery of most therapeutic agents. The popularity of the oral route is
attributed patient acceptance, ease of administration, accurate dosing, cost
effective manufacturing method and generally improved shelf-life of the
product. Extended release dosage forms are designed to achieve a prolonged
therapeutic effect by continuously releasing drug over an extended period of
time after administration of a single dose1. The advantages of
extended release dosage forms over conventional forms include the less
fluctuation in drug blood levels, frequency reduction in dosing, enhanced
convenience and compliance, reduction in adverse side effects and reduction in
overall health care costs2,3.
The
rate of drug release from solid dosage form may be modified by the technologies,
which in general are based on modifying drug dissolution by controlling access
of biologic fluids to the drug through the use of barrier coatings and
controlling drug diffusion rates from dosage forms. Generally the different
techniques employed to fabricate the modified release dosage forms are coated
beads, granules and microspheres, multi tablet system, micro encapsulated drug,
complex formation, ion exchange resins, and embedding drug in slowly eroding or
hydrophilic matrix system. The use of polymeric matrix devices to control the
release of a variety of therapeutic agents has become increasingly important in
the development of modified release dosage forms. This device may be a swellable, hydrophilic monolithic systems, erosion
controlled monolithic systems or non erodible systems. The hydrophilic gel
forming matrix tablets are extensively used for oral extended release dosage
forms due to their simplicity, cost effectiveness and reduction of the risk of
systemic toxicity due to dose dumping4-6
Table No. 1: Formulations [F1 to F15]
|
Ingredients
|
F1
|
F2
|
F3
|
F4
|
F5
|
F6
|
F7
|
F8
|
F9
|
F10
|
F11
|
F12
|
F13
|
F14
|
F15
|
|
Losartan
|
100
|
100
|
100
|
100
|
100
|
100
|
100
|
100
|
100
|
100
|
100
|
100
|
100
|
100
|
100
|
|
Guar gum
|
160
|
200
|
---
|
---
|
100
|
75
|
100
|
---
|
---
|
100
|
75
|
100
|
---
|
---
|
---
|
|
HPMC K100M
|
---
|
---
|
160
|
200
|
75
|
100
|
100
|
---
|
---
|
---
|
---
|
---
|
100
|
75
|
100
|
|
Xanthun gum
|
---
|
----
|
---
|
---
|
---
|
---
|
---
|
160
|
200
|
75
|
100
|
100
|
75
|
100
|
100
|
|
MCC
|
120
|
80
|
120
|
80
|
105
|
105
|
80
|
120
|
80
|
105
|
105
|
80
|
105
|
105
|
80
|
|
Mg.stearate
|
12
|
12
|
12
|
12
|
12
|
12
|
12
|
12
|
12
|
12
|
12
|
12
|
12
|
12
|
12
|
|
Talc
|
8
|
8
|
8
|
8
|
8
|
8
|
8
|
8
|
8
|
8
|
8
|
8
|
8
|
8
|
8
|
|
Total tablet wt in mg
|
400
|
400
|
400
|
400
|
400
|
400
|
400
|
400
|
400
|
400
|
400
|
400
|
400
|
400
|
400
|
Tan θ
= h/r
Where, h and r
are the height and radius of the powder cone.
Losartan potassium is a potent, highly
specific angiotensin II type-1 receptor antagonist
with anti hypertensive activity. It is freely soluble in water and slightly
soluble in organic solvents. It is readily absorbed from the gastrointestinal
tract with oral bioavailability of about 33%. Protein binding is 99.7%,
primarily to albumin. Losartan is metabolized to a
5-carboxylic acid derivative (E-3174) via an aldehyde
intermediate (E-3179) primarily by cytochrome P450
(CYP) 2C9 and CYP3A4. E-3174 is an active metabolite with 10- to 40-fold higher
potency than its parent compound, losartan. After
single doses of losartan administered orally, about
4% of the dose is excreted unchanged in the urine and about 6% is excreted in
urine as active metabolite. Biliary excretion
contributes to the elimination of losartan and its
metabolites. The half-life of losartan is 2
hours and that of E-3174 is 6-9 hours7. The main objective of the
present work is to prepare losatan extended release
tablets and to evaluate different parameters like hardness, weight variation,
friability, drug content, swelling studies, drug dissolution and release
kinetics.
MATERIALS AND METHODS:
Losartan potassium was a gift sample from Hetero drugs Pvt. Ltd,
Hyderabad; Xanthun gums, HPMC K100M, Microcrystalline
cellulose are taken from Yarrow chemical Products, Mumbai; Guar gum was
received from Merck Specialties Pvt. Ltd, Mumbai.
PREFORMULATION
STUDIES
FTIR (Fourier transform infrared
spectroscopy): the studies done by Infra red spectroscopy is routinely used for
compound identification as a fingerprinting tool. IR spectroscopy also has its
application in studies of drug – excipient
interaction, contaminant analysis etc. IR spectrum with high quality is
acquired with the FTIR method. IR spectrum with high quality is acquired with KBr (pellet) method. The sample powder of drugs, excipients and mixture of they were prepared and placed on
glass plate and apply the infra red beam to record the spectra. The mixture
spectra were compared with that of the original spectra.
Preparation of
calibration curve
Accurately weighed quantity of Losartan Potassium (50mg) was dissolved in 50mL water
(stock solution). Transfer 1mL of solution from the above stock solution into
50mL volumetric flask and make up the volume to 50mL with 6.8 pH phosphate
buffer to give the concentration of 200mcg/ml. From the above solution transfer
1ml, 2ml, 3ml, 4ml, 5ml, 6ml, 7ml, 8ml, solution were transferred to 10ml
volumetric flask and diluted up to 10ml which forms 2, 4, 6, 8, 10,
12, 14 and 16 (mcg/ml) concentrations respectively. The absorbances
of these solutions were determined in UV spectrophotometer at 205nm and
calibration curve was plotted.
Preparation of
tablets by direct compression:
The ideal
process from a capital and operational cost basis is direct compression. This
is, at most, a two-step process involving screening and/or milling and final
mixing. The active ingredient i.e. Losartan Potassium
and each single polymer (HPMC K100M, Xanthan gum,
Guar gum) and also mixture of two polymers, filler(MCC), lubricant (Magnesium stearate), glidant (Talc) were
blended together by dry mixing in a laboratory mixer (poly bag) for 10 mins. The mixture was compressed by using – 8mm standard
flat round punch and die set at compression force 4-6 ton.
Pre-compression
evaluation parameters
Angle of repose:
The angle of repose of powder blend was
determined by the funnel method. The accurately weight powder blend were taken
in the funnel. The height of the funnel was adjusted in such a way the tip of
the funnel just touched the apex of the powder blend. The powder blend was
allowed to flow through the funnel freely on to the surface. The diameter of
the powder cone was measured and angle of repose was calculated using the
following equation 9.
Table No.2: Angle
of repose and flow properties
|
Angle of repose(θ)
|
Flow
|
|
<25
|
Excellent
|
|
25-30
|
Good
|
|
30-40
|
Moderate
|
|
>40
|
Poor
|
Bulk density and
Tapped density:
Both bulk
density (BD) and tapped density (TD) was determined. A quantity of 10 gm of
powder blend from each formula, which is previously shaken to break any agglomerates
formed, was introduced in to 50 ml measuring cylinder. After that the initial
volume was noted and the cylinder was allowed to fall under its own weight on
to a hard surface from the height of 2.5 cm at second intervals. Tapping was
continued until no further change in volume was noted. BD and TD were
calculated using the following equations.
Hausner’s Ratio:
It indicates the flow properties of the
granules and is measured by the ratio of tapped density to the bulk density.
Table No. 3: Scale
of Flowability according to Hausner’s
ratio
|
Hausner’s
ratio
|
Flow character
|
|
1.0-1.11
|
Excellent
|
|
1.12-1.18
|
Good
|
|
1.19-1.25
|
Fair
|
|
1.26-1.34
|
Passable
|
|
1.35-1.45
|
Poor
|
|
1.46-1.59
|
Very poor
|
|
>1.60
|
Very,very poor
|
Compressibility
index (Carr’s Index): CI
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 flowable it is. A
material having values of less than 20% has good flow property 9
Table No. 4: Scale of Flowability
according to Carr’s index
|
% Comp’ Index
|
Flow Character
|
|
5-12
|
Free
flowing
|
|
12-16
|
Good
|
|
18-21
|
Fair
|
|
23-35
|
Poor
|
|
33-38
|
Very
Poor
|
|
>40
|
Extremely
Poor
|
Post compression evaluation parameters
Weight variation:
The weight of the tablet being made was routinely
determined to ensure that a tablet contains the proper amount of drug. The USP
weight variation test is done by weighing 20 tablets individually, calculating
the average weight and comparing the individual weights to the average. The
tablets met the USP specification that not more than 2 tablets are outside the
percentage limits and no tablet differs by more than 2 times the percentage
limit. USP official limits of percentage deviation of tablet are presented in
the table.
Table No. 5: Weightvariation
limits
|
S.No
|
Avg wt of
tablet(mg)
|
Maximum% diff. allowed
|
|
1
|
130 or less
|
10
|
|
2
|
130-324
|
7.5
|
|
3
|
>324
|
5
|
Tablet hardness:
The resistance of tablets to shipping
or breakage under conditions of storage, transportation and handling before
usage depends on its hardness. The hardness of each batch of tablet was checked
by using Monsanto hardness tester. The hardness was measured in terms of
kg/cm2. 3 tablets were chosen randomly and tested for hardness. The average
hardness of 3 determinations was recorded.
Friability:
Friability generally refers to loss in weight of tablets in the
containers due to removal of fines from the tablet surface. Friability
generally reflects poor cohesion of tablet ingredients.
Method: 10 tablets were weighed and the initial weight of these tablets
was recorded and placed in Roche friabilator and
rotated at the speed of 25 rpm for 100 revolutions. Then tablets were removed
from the friabilator dusted off the fines and again
weighed and the weight was recorded
Where: w1=
weight of the tablet before test.
w2 = weight of the tablet after
test
Content Uniformity:
The tablets were tested for their drug content
uniformity. At random 20 tablets were weighed and powdered. The powder
equivalent to 100 mg of drug was weighed accurately and dissolved in 100ml of
phosphate buffer of pH 6.8. The solution was shaken
thoroughly. The undissolved matter was removed by
filtration through Whatman No.1 filter paper. Then transfer 1mL of above
solution into 100mL volumetric flask and make up the volume with
phosphate buffer of pH 6.8. The absorbance of the
diluted solutions was measured at 205nm. The concentration of the drug was
computed from the standard curve of the losartan
potassium in phosphate buffer of pH 6.8 11
In-vitro Dissolution studies:
Tablet
was introduced into dissolution test apparatus and the apparatus was set at
50rpm motion at 370C ± 0.50C. 5 ml of sample was withdrawn for every hour upto 12 hrs and after that the samples withdrawn for every
4 hrs upto 24 hrs.
Samples withdrawn were analyzed by UV spectrophotometer at 205nm using 6.8pH
buffer as blank 12, 13.
Swelling studies:
The
extent of swelling was measured in terms of % of weight gained by the tablet.
One tablet from each formulation was weighed and kept in Petri dish containing
50 ml of pH 6.8 buffer. At the end of specified time intervals tablets were
withdrawn from Petri dish and excess buffer blotted with tissue paper and
weighed. The % of weight gained by the tablet was calculated by using following
formula:
Where,
Mt – weight of tablets at time ‘t’; M0 – weight of tablets at time ‘0’12.
Release kinetics:
To
study the release kinetics of in-vitro drug release, data was applied to
kinetic models such as Zero order, First order, Higuchi and Korsmeyer-Peppas
model 14, 15.
RESULTS AND DISCUSSION:
Preformulation parameters
Standard curve of
the API:
Drug
solutions of different concentrations (2-16 µg/ml) in a buffer solution of pH
6.8 were prepared. The samples were analysed by using
UV Visible spectrophotometer at 205nm. A linear plot of drug absorbance and
solution
Concentration
was obtained with r2 = 0.999 in 6.8 pH with slope of 0.0576.
FTIR spectra of
pure Losartan Potassium
FTIR Spectra of drug + HPMC K100M
FTIR Spectra of drug + Xanthan gum
FTIR Spectra of drug + Microcrystalline cellulose
FTIR Spectra of drug + Xanthan gum +
HPMC K 100M + MCC
FTIR Spectra of
drug + Xanthan gum + Guar gum + MCC
Pre-compression
evaluation parameters
The
granules prepared for compression of extended release tablets were evaluated
for their flow properties. Angle of repose was in the range of 290.52 to 330.58
which indicates excellent flow of the granules for all formulations.
The
bulk density of the granules was in the range of 0.401 ± 0.002 to 0.423 ± 0.003
g/cc, the tapped density was in the range of 0.471 ± 0.009 to 0.497 ± 0.001
g/cc, which indicates that the powder was not bulky.
The
Carr’s index was found to be in the range of 10.67±0.05 to 16.33 ± 0.05%.
The Hausner ratio was found to be in the range of 1.12 ± 0.01
to 1.19 ± 0.05; indicating compressibility of the tablet blend is good. These
values indicate that the prepared granules exhibited good flow properties.
Post-compression
evaluation parameters
Losartan potassium extended release tablets were evaluated for weight
variation as, hardness in kg/cm2, friability in Percentage, drug content in
Percentage, in vitro drug dissolution studies and swelling studies. All the
studies were performed and results are expressed as mean ±SD.
Table
No. 6: Results of Post Compression parameter evaluation
|
Formulation
code
|
Wt
variation Avg±SD
|
Hardness
|
Friability
|
Drug
content
|
|
F-1
|
400.85±3.37
|
4.5-5
|
0.49
|
97±0.81
|
|
F-2
|
400.15±4.84
|
4-4.0
|
0.62
|
101±0.50
|
|
F-3
|
399.35±4.05
|
4.5-5
|
0.37
|
98.4±0.80
|
|
F-4
|
399.75±4.12
|
5-5.5
|
0.49
|
96.7±1.30
|
|
F-5
|
399.55±4.88
|
4.5-5
|
0.37
|
100.8±2.20
|
|
F-6
|
400.95±3.95
|
5-5.5
|
0.37
|
100.06±4.10
|
|
F-7
|
401.35±4.42
|
4-4.5
|
0.50
|
99.79±1.25
|
|
F-8
|
400.05±3.96
|
5-5.5
|
0.25
|
98.63±2.15
|
|
F-9
|
400.30±4.16
|
4.5-5
|
0.31
|
99±0.36
|
|
F-10
|
400.20±3.67
|
5-5.5
|
0.40
|
99.2±0.52
|
|
F-11
|
399.40±3.73
|
5-5.5
|
0.36
|
98.5±60.47
|
|
F-12
|
399.00±3.41
|
5-5.5
|
0.44
|
98.8±0.95
|
|
F-13
|
400.30±3.90
|
5-5.5
|
0.37
|
100.06±2.46
|
|
F-14
|
399.60±2.96
|
5-5.5
|
0.27
|
97.73±2.13
|
|
F-15
|
400.60±3.95
|
5-5.5
|
0.32
|
98.1±1.49
|
Swelling
studies:
All the tablets were carried out
throughout the period of swelling (12 to 24 hrs) in pH6.8 buffer. The
percentage of swelling index was proportionate to the polymer level
irrespective of the polymer. The swelling index was found to be higher with the
tablets prepared using Xanthan gum (F9, 272.40%) than
the HPMC K100M (F4, 199.09%) and Guar gum (F2, 166.49). The best formulation
figure shows below.
Table No. 7:
values of cumulative percentage drug release
In-Vitro drug release studies of all
formulations
Graphical representation of all
formulations
The Drug Release Mechanism:
In-vitro drug release kinetics of all
formulations
The drug release kinetics was
applied to all formulations. All the formulations followed zero order drug
release kinetics and fitted to non-fickian transport.
CONCLUSION:
Matrix tablets of Losartan
Potassium using different hydrophilic polymers prepared by direct compression
method were found to be good without chipping, capping and sticking. The drug
content was uniform in all the formulations of tablets prepared. The low values
of standard deviation indicate uniform distribution of drug within the
matrices. Infrared spectroscopic studies indicated that the drug is compatible
with the polymers. The drug-polymer ratio was found to influence the release of
drug from the formulations.
As the polymer level is increased, the drug
release rates were found to be decreased. The mechanism of the drug release for
most of the formulation was found to be non - Fickian
diffusion controlled process
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