Development and Evaluation of Floating
Tablets of Lamivudine
Chinmaya Keshari Sahoo1*, Amiyakanta Mishra1,
Amaresh Prusty1, S. Ram Mohan Rao2, Jimidi Bhaskar3
1Department
of Pharmaceutics, College of Pharmaceutical Sciences,
(Affiliated to Biju Patnaik University of Technology),
Puri, Odisha.
2Department
of Engineering, Mekelle Institute of
Technology, Mekelle University, Mekelle, Ethiopia.
3Department
of Pharmaceutics, KLR Pharmacy College, Paloncha, Bhadradri Kothagudem, Telangana.
*Corresponding Author E-mail:
sahoo.chinmaya83@gmail.com
ABSTRACT:
The present study was undertaken to develop floating tablets
of lamivudine. The tablets were prepared by direct compression method. The prepared
tablets were evaluated for pre compression parameters, post compression parameters,
in vitro drug release study and in vitro buoyancy study. Among the
prepared formulations F4 batch show 90.98% drug release in 12 h. The in vitro
release kinetics were analyzed for different batches by different pharmacokinetic
models such as zero order, first order, Higuchi, and Korsmeyer Peppas. The result
of optimized formulation releases drug up to 12 h in a controlled manner and follows
Higuchi kinetics. Short term stability study at 40±2ºC/75±5% RH for three months
on the best formulation was performed showing no significant changes in thickness,
hardness, friability, drug content and in vitro drug release.
INTRODUCTION:
Controlled release dosage forms
offers prolong drug release of active ingredients at predetermined rate and predetermined
time1. Among various controlled drug delivery systems gastro retentive
drug delivery system is most promising to delay drug release in gastric region.
Gastric emptying of dosage forms is an extremely variable process and ability to
prolong and control the emptying time is a valuable asset for dosage forms, which
reside in the stomach for a longer period of time than conventional dosage forms.
Gastro retentive systems2 can remain in the gastric region for several
hours and hence significantly prolong the gastric residence time of drugs. Prolonged
gastric retention improves bioavailability, reduces drug waste, and improves solubility
for drugs that are less soluble in a high pH environment. It has applications also
for local drug delivery to the stomach and proximal small intestines. Gastro retention
helps to provide better availability of new products with new therapeutic possibilities
and substantial benefits for patients.
Lamivudine is a synthetic nucleoside analogue and
is phosphorylated intra cellularly to its active 5'-triphosphate metabolite, lamivudine
triphosphate (L-TP). This nucleoside analogue is incorporated into viral DNA by
HIV reverse transcriptase resulting in DNA chain termination3. The present research aimed to design floating tablets
of lamivudine by direct compression method containing dose of 100mg once daily for
hepatitis B infection. Lamivudine has bioavailability of 86%, protein binding of
36% and the biological half life is between 5-7 h. Hence it can be given to control
the concentration of drug at the site of action. The main objective of the present
study was to develop floating tablets of lamivudine.
MATERIALS
AND METHODS:
Materials:
Lamivudine
was obtained from Hetero Drugs Pvt. Ltd. India., Sodium bicarbonate, magnesium stearate,
talc, HPMC and PVP were purchased from S.D. Fine Chemicals Ltd, Mumbai, India.,
Microcrystalline cellulose (MCC) and starch were purchased from Signet Pharma, Mumbai,
India. All other solvents and reagents used were of analytical grade.
Methods:
Compatibility
studies:
Fourier Transform Infrared Spectroscopy (FTIR):
In this method individual samples4 as well as the mixture
of drug and excipients were ground mixed thoroughly with potassium bromide (1:100)
for 3-5 minutes in a mortar and compressed into disc by applying pressure of 10kg/cm to form a transparent pellet in
hydraulic press. The pellet was kept in the sample holder and scanned from 4000
to 400 cm-1 in FTIR spectrophotometer (Bruker, Germany).
Preparation
of floating tablets:
The
tablets were prepared by direct compression technique5. Accurately weighed
quantities of ingredients except lubricant (magnesium stearate), and glidant (talc)
were passed through sieve No. 30. Lubricant and glidant were passed through sieve
No. 80. All the ingredients except lubricant (magnesium stearate), glidant (talc)
were manually blended homogenously in a mortar by way of geometric dilution. To
this homogenous mixture lubricant and glidant were added finally and were subjected
to evaluation of pre compression parameters. The evaluated powders were compressed
into round tablets with standard concave punches using rotary compression machine.
Table
1: Composition of floating tablets of lamivudine
|
Ingredients (mg)
|
F1
|
F2
|
F3
|
F4
|
|
Lamivudine
|
100
|
100
|
100
|
100
|
|
MCC
|
235
|
185
|
135
|
85
|
|
HPMC K4M
|
40
|
80
|
120
|
160
|
|
PVPK30
|
20
|
20
|
20
|
20
|
|
Sodium bicarbonate
|
10
|
20
|
30
|
40
|
|
Citric acid
|
5
|
5
|
5
|
5
|
|
Magnesium stearate
|
5
|
5
|
5
|
5
|
|
Talc
|
5
|
5
|
5
|
5
|
|
Total weight (mg)
|
420
|
420
|
420
|
420
|
Evaluation
of pre compression parameters of dry powders:
The
prepared granules6 were evaluated for pre compression parameters such
as angle of repose, bulk density, tapped density and compressibility index (Carr’s
index). Fixed funnel method was used to estimate angle of repose. The bulk density
and tapped density were evaluated by bulk density apparatus (Sisco, India).
The Carr’s index [8] is calculated by the following formula.
Where etap is the tapped density of granules
and ebulk is bulk density of granules.
According to the specifications the Carr’s index7
values between 5-15 indicates excellent flow whereas between 12-16 indicates good
flow. Values between 18-21 indicates fair passable where as between 23-35 indicates
poor and values between 33-38 indicates very poor and greater than 40 indicates
extremely poor. Hausner’s ratio was calculated
by the taking the ratio of tapped density to the ratio of bulk density. According
to specifications values less than 1.25 indicate good flow (= 20% of Carr’s index)
whereas greater than 1.25 indicates poor flow (=33% of Carr’s index).
Post
compression parameters of different floating tablets:
General
appearance of the tablets:
From
each batch and from each formulation tablets were randomly selected and examined
under lens for the surface texture, shape, its overall elegance, consistency color
and odor of tablets.
Thickness8:
The thickness of individual tablets is measured by using
Vernier Calipers. The limit of the thickness deviation of each tablet is ±5% of
standard value.
Hardness:
The
hardness of a tablet is associated with the resistance of the solid specimen towards
fracturing and attrition. The hardness of tablets can be determined by using Monsanto
hardness tester and measured in terms of kg/cm2.
Friability:
Friability9 of tablets was performed in a Roche
friabilator. Ten tablets were initially weighed (W0) together and then
placed in the chamber. The friabilator was operated for 100 revolutions and the
tablets were subjected to the combined effects of abrasion and shock because the
Plastic chamber carrying the tablets drops them at a distance of six inches with
every revolution. The tablets are then dusted and reweighed (W). The percentage
of friability was calculated using the following equation.
Where,
W0 and W are the weight of the tablets before and after the test respectively.
For any compressed uncoated tablet, loss between 0.1 to 0.5% and maximum up to 1%
of the tablet weigh are considered as acceptable.
Weight
variation test10:
All
formulated floating tablets were evaluated for weight variation as per USP monograph.
The weight variation test is done by weighing 20 tablets individually calculating
the average weight and comparing the individual tablet weights to the average. The
percentage weight deviation was calculated and then compared with USP specifications.
The tablets meet the USP test if not more than 2 tablets are outside the percentage
limit and if no tablet differs by more than 2 times the percentage limit.
Uniformity
of drug content test:
Ten
tablets from11 each batch of floating formulations were taken and triturated
to form powder. The powder weight equivalent to one tablet was dissolved in a 100ml
volumetric flask filled with 0.1N HCl using magnetic stirrer for 24 h. Solution
was filtered through Whatman filter paper No. 1 diluted suitably and analyzed spectrophotometrically.
In vitro buoyancy study:
The time taken by the tablet to emerge onto the surface12
of the medium after adding to the dissolution medium is called Buoyancy lag time
(BLT). Duration of time by which the dosage form constantly emerges on surface of
medium called Total floating time (TFT) Both BLT and TFT were determined by placing
the tablet in 900ml of simulated gastric fluid without pepsin, at pH 1.2, temperature
37±0.5ºC, USP type II apparatus
In vitro dissolution study (IVDS):
IVDS was carried out by using USP type II (paddle) apparatus.
The tablet is kept in 900ml of dissolution fluid of 0.1N HCl (pH1.2) and stirrer
rotating with 75rpm and maintaining the temperature 37±0.50C of dissolution
media for desired hours. In specified time
intervals aliquots of 5ml samples of the solution
were withdrawn through 0.45-μm CA filter from the dissolution apparatus and
with replacement of fresh fluid to dissolution medium. Absorbance of these solutions
was measured at specific λmax using a UV/Visible Spectrophotometer. The %CDR
was plotted against time to determine the release profile of various batches.
In vitro
drug release kinetic studies:
For the determination of the drug release kinetics13,
14 from the floating tablet, the in vitro release data were analyzed
by zero order, first order, Higuchi, Korsmeyer and Peppas equations, and Hixson-Crowell
equations.
Accelerated stability studies:
The optimized formulation was subjected to accelerated
stability studies as per ICH (The International Conference of Harmonization) guidelines15
by packing in air tight bottles that can withstand stressed conditions. The packed
tablets in air tight container were placed in stability chambers (Thermo lab Scientific
equipment Pvt. Ltd., Mumbai, India) maintained at 40±2ºC, 75±5% RH (Climatic Zone
III conditions for accelerated testing) for 3 months. Tablets were periodically
removed and evaluated for physical characteristics, drug content, in‐vitro
drug release etc.
RESULTS AND DISCUSSION:
FTIR
study:
The study of the FTIR spectra of lamivudine demonstrated
that the characteristic absorption peaks for the C-H stretching at 2843.83 cm-1,
N-H bending at 1640.32 cm-1, C-N stretching at 1010.71 cm-1,
O-H in plane bending at 1054.55 cm-1 and amine group stretching at 3326.6
cm-1. Major peaks of HPMC were found at 3880.71, 3810.87, 3713.83, 3669.20,
3601.84, 3566.74, 3557.95, 3473.68, 3222.79, 3117.03, 3066.96, 2982.59, 2887.86,
2847.2710.75, 2444.13, 1661.47, 1536.52, 1500.67, 1071.87, 781.05 and 584.97 cm-1.
Out of four formulations the optimized formulation was found to be F4. In the formulation
F4 peak at 3692.11, 3569.67, 3064.71, 2724.75 and 780.06 cm-1 were due
to presence of the polymer HPMC. Peaks at 3302.92, 1666.14, 1063.82 and 1023.51
cm-1 were due to presence of the drug lamivudine in the optimized formulation.
So from the study it can be concluded that the major peaks of drug 3302.92, 1666.14,
1063.82 and 1023.51 cm-1 remain intact and no interaction was found between
the drug, and polymer. Hence drug-excipient mixture is compatible.
Evaluation of lamivudine floating formulations:
Precompression parameters of lamivudine floating powders:
All the compressible
excipients for various batches were evaluated for angle of repose, bulk
density, tapped density, Carr’s index and
Hausner’s Ratio. All the pre compression parameters for developed formulations were
within pharmacopoeial limits showing good flow characteristics for easy manufacturing
of floating tablets. It is given in Table 2.
Table 2: Pre compression parameters of lamivudine floating
powders
|
Formulation code
|
Angle of repose (degree)a ± S.D
|
Bulk density (g/ml)a ± S.D
|
Tapped density
(g/ml)a ± S.D
|
Carr’s Index (%)a ± S.D
|
Hausner’s Ratioa±
S.D
|
|
F1
|
28.22±0.13
|
0.523±0.01
|
0.589±0.03
|
11.20±0.09
|
1.12±0.13
|
|
F2
|
27.08±0.04
|
0.519±0.06
|
0.581±0.09
|
10.67±0.07
|
1.11±0.08
|
|
F3
|
29.11±0.08
|
0.511±0.13
|
0.555±0.11
|
7.92±0.08
|
1.08±0.06
|
|
F4
|
25.32±0.06
|
0.512±0.14
|
0.551±0.12
|
7.07±0.08
|
1.07±0.08
|
N.B.-All values
are expressed as mean
S.D, a n = 3
Post compression parameters of lamivudine floating tablets:
All the post compression parameters for various batches
evaluated accordingly such as thickness, coat thickness, hardness, friability, weight
variation, drug content and diameter of tablet etc. All the post compression parameters of developed formulations
were found to be within the pharmacopoeial limits. It is mentioned
in table 3 and table 4.
Table 3: Post compression parameters of lamivudine floating
tablets
|
Formulation code
|
Thickness (mm)a ± S.D
|
Hardness
(kg/cm2)a ± S.D
|
%Friability
(%)b ± S.D
|
%Weight variation
(%)b ± SD
|
%Drug content (%)a
± S.D
|
|
F1
|
3.562±0.01
|
4.5±0.13
|
0.75±0.04
|
2.51±0.23
|
96.31±1.04
|
|
F2
|
3.564±0.02
|
4.9±0.16
|
0.76±0.03
|
2.42±0.17
|
98.74±1.06
|
|
F3
|
3.565±0.03
|
4.1±0.12
|
0.74±0.02
|
2.08±0.16
|
99.07±1.30
|
|
F4
|
3.501±0.01
|
4.2±0.14
|
0.79±0.04
|
2.87±0.32
|
99.82±1.2
|
N.B.- All values
are expressed as mean
S.D, a n = 10, b n = 20
Table 4: Buoyancy study
of floating matrix tablets of lamivudine
|
Formulation code
|
Floating lag time (min)
|
Floating time (h)
|
|
F1
|
< 1
|
<12
|
|
F2
|
< 2
|
<12
|
|
F3
|
< 2
|
˃ 12
|
|
F4
|
< 2
|
˃ 12
|
In vitro dissolution studies
of lamivudine floating tablets:
The dissolution study of all the floating formulations
was presented in table 8. The % CDR for F1,
F2, F3 and F4 were 98.14, 96.17, 91.26 and 90.98 % respectively of lamivudine at
the end of respective hours. It is observed that the drug release is controlled
in F8 because it contains more concentration of polymer HPMCK4M. Hence it was confirmed
that the drug release depends upon polymer concentration of formulations. Out of
4 formulations F4 showing controlled release up to at the end of 12 h. This release
profile also fulfilled the requirements of lamivudine floating tablets. The graphs were plotted between cumulative percentage
drug release (Y axis) with respect to time (X-axis) and shown in figure 1.
Figure 1: In vitro dissolution study showing lamivudine
release from various fabricated formulations F1-F4 (n=3)
In vitro release kinetic
studies of lamivudine floating tablets:
Out of 4 developed formulations the optimized formulation
was found to be F4. The in vitro dissolution
data of optimized formulation F4 were fitted in various kinetic models. The R2
values for zero order, first order, Higuchi, and Korsmeyer-Peppas model were 0.870,
0.979, 0.986, and 0.981 respectively. It was found that R2 value was
maximum in Higuchi model having high linearity comparing to other models. Hence
it follows Higuchi kinetics. The release exponent of Korsmeyer-Peppas model n for
optimized formulation F4 was found to be 0.376 (n<0.45) which appears to indicate
Fickian diffusion. The regression values and rate constants for all the formulations
of lamivudine floating tablets were presented in table 5.
Table 5: Fitting of IVDR data in various mathematical models
|
Models
|
Zero order
|
First order
|
Higuchi
|
Korsmeyer-Peppas
|
Mechanism of release
|
|
Batches
|
R2
|
K0
|
R12
|
K1
|
RH2
|
KH
|
RK2
|
Kp
|
n
|
|
F1
|
0.933
|
14.87
|
0.852
|
0.564
|
0.991
|
39.40
|
0.974
|
37.75
|
0.512
|
Non Fickian transport
|
|
F2
|
0.922
|
10.42
|
0.880
|
0.329
|
0.995
|
33.02
|
0.993
|
32.06
|
0.51
|
Non Fickian transport
|
|
F3
|
0.832
|
7.038
|
0.933
|
0.209
|
0.958
|
26.24
|
0.913
|
41.87
|
0.308
|
Fickian
diffusion
|
|
F4
|
0.870
|
6.205
|
0.979
|
0.191
|
0.986
|
25.51
|
0.981
|
35.56
|
0.376
|
Fickian
diffusion
|
Stability
studies
It was observed that all the physiochemical parameters
for the formulation show very little change that was within acceptable range. So
the results of stability studies indicated that the floating tablets under present
investigation were stable.
CONCLUSION:
Lamivudine floating tablets were successfully developed.
Out of several formulations F4 was successfully comply with the rate of drug release
of floating tablets. Thus F4 can provide more prolong and expected to perform therapeutically
better with improved patient compliance.
ACKNOWLEDGEMENTS:
The authors would like to acknowledge the contributions
of Pharmaceutics department, College of Pharmaceutical Sciences, Puri, Odisha, India
for providing necessary facilities to carry out the research work.
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