Formulation
and In Vitro Evaluation of Floating
Matrix Tablets of Ofloxacin
Pramod
Patil*, Someshwara Rao B, Suresh V Kulkarni, Basavaraj, Chetan Surpur and Anand Ammanage
Department of Pharmaceutics, Sree Siddaganga College of
Pharmacy, B.H.Road, Tumkur-572102, Karnataka, India.
*Corresponding Author
E-mail: pramodpatil86@yahoo.com
ABSTRACT:
The present study concerns
the development of floating tablets of ofloxacin
which were designed to prolong the gastric residence time after oral
administration. Ofloxacin is a fluoroquinolone antibacterial agent
which is highly effective against gram positive and gram negative bacteria. Ofloxacin floating tablets were prepared by wet granulation
method incorporating natural polymer like guar gum, locust bean gum, either
alone or in combination with HPMC K100M as swelling polymers, with sodium
bicarbonate as gas generating agent and were evaluated for parameters such as
Weight variation, Hardness, Friability, Drug content, Swelling index, in
vitro buoyancy study, in vitro drug release study. All the
formulation showed compliance with pharmacopieal
standards. Based on the evaluation
results, F3 and F6 formulations were selected as the best formulations and were
checked for stability as per ICH guidelines. These results indicated that the
selected formulations were stable. The drug release profile of the best
formulations was well controlled and uniform throughout the dissolution
studies. The drug release of optimized formulation
follows the Higuchi kinetic model, and the mechanism is found to be non-Fickian/anomalous according to Korsmeyer–Peppas
equation.
INTRODUCTION:
The primary aim of oral controlled drug delivery
system is to deliver drugs for longer period of time to achieve better
bioavailability, which should be predictable and reproducible. But this is
difficult due to number of physiological problems such as fluctuation in the
gastric emptying process, narrow absorption window and stability problem in the
intestine1. To overcome these problems, different approaches have
been proposed to retain dosage form in stomach. These include bioadhesive or mucoadhesive
systems2, swelling and expanding systems3,4,
floating systems5,6 and other delayed gastric emptying devices. The
principle of floating preparation offers a simple and practical approach to
achieve increased gastric residence time for the dosage form and sustained drug
release7.
Floating drug delivery system also
known as hydrodynamically balanced system, have a
bulk density lower than gastric fluids and thus remain buoyant in the gastric
fluids for a prolonged period of time without affecting the gastric emptying
rate. While the system is floating on the gastric content, the drug is released
slowly at desired rate from the system.8
Received on 18.02.2011 Accepted
on 22.02.2011
© Asian Pharma Press All
Right Reserved
Asian J. Res. Pharm. Sci.
1(1): Jan.-Mar. 2011; Page 17-22
Hydrodynamically balanced drug delivery system, in either tablet or capsule form, is
designed to prolong gastrointestinal (GI) residence time in an area of GI
tract. It is prepared by incorporating a high level (20-70% w/w) of one or more
gel forming hydrocolloids. On contact with gastric fluid
hydrocolloid starts to become hydrate and build a gelled barrier around the
device. This gel barrier controls the release of drug from the device9.
Ofloxacin is a fluoroquinolone antibacterial agent
which is highly effective against gram positive and gram negative bacteria10.
Ofloxacin exhibits pH dependent solubility. The
solubility of ofloxacin in water is 60 mg/ml at pH value ranging from 2 to 5, falls to 4
mg/ml at pH 7 (near isoelectric pH)11.
Thus it is more soluble in acidic pH and slightly soluble at neutral or
alkaline condition (intestinal environment). Hence, in the present study various natural
polymers like guar gum, locust bean gum would be used either alone or in
combination with synthetic polymer like HPMC K100M along with gas generating
agent like sodium bicarbonate for the formulation of floating tablets of ofloxacin which would increase the bioavailability of ofloxacin
and also to reduce frequency of administration, thereby improving patient
compliance and therapeutic efficacy.
MATERIALS AND METHODS:
Materials:
Ofloxacin was obtained as gift sample
from Blue Cross Laboratories Ltd, Mumbai. Guar gum was obtained from Himedia Mumbai, Locust bean gum was obtained from Research
Lab Fine Chemical Industries Mumbai, HPMC K100M was
obtained from Colorcorn Asia Pvt
Ltd, Goa. All other ingredients used were of analytical grade.
Preparation of Floating
tablets:
Floating
tablets were prepared by conventional wet granulation. The powder mix was
granulated with 5% w/w PVP-K30 in isopropyl alcohol. The wet mass was passed
through sieve # 16 and the granules were dried at 60°C for 1 hr in a hot air
oven. The dried granules were passed through sieve # 22 and lubricated with
magnesium stearate and talc by further blending for 3
min. Tablets were compressed at 550 mg weight on a 10 station mini rotary tableting machine with 12 mm flat-shaped punches. Tablets
of Batch F1 and F5 contain only single
natural polymer, whereas Batch F2-F4 and F6-F8 contain HPMC K100M with
increased concentration from 2.5 to 7.5% with corresponding decrease in
concentration of natural polymer.
Evaluation of
granules:
The angle of repose was measured by using funnel
method12, which indicates the flow ability of the granules. Loose
bulk density (LBD) and tapped bulk density (TBD)13
were measured using the formula: LBD= weight of the granules / volume of the packing. TBD= weight of
the granules / tapped volume of the packing. Compressibility index14
of the granules was determined by using the formula:
CI (%) = [(TBD-LBD/TBD)] ×100.
Evaluation
of tablets:
All
prepared floating tablets were evaluated for its uniformity of weight,
hardness, friability and thickness according to official methods.15 The weight variation was determined by taking 20 tablets
using an electronic balance (type ER182A, Afcoset,
Mumbai, India). Tablet hardness was determined using a Monsanto tablet hardness
tester (MHT-20, Campbell Electronics, Mumbai, India).
Friability was determined by testing 10 tablets in a friability tester (FTA-20,
Campbell Electronics) for 4 minutes at 25 rpm.
Drug content:
Five tablets were powdered in a mortar. An accurately
weighed quantity of powdered tablets (100 mg) was extracted with 0.1N HCl (pH 1.2 buffer) and the solution was filtered through
0.45 µ membranes. Each extract was suitably diluted and analyzed
spectrophotometrically at 294 nm.
In vitro buoyancy study:
In
Vitro buoyancy
studies were performed for all formulations as per the method described by Rosa
et al16 The randomly selected tablets from each formulation
was kept in a 100ml beaker containing simulated gastric fluid, pH 1.2 as per
USP. The time taken for the tablet to rise to the surface and float was taken
as floating lag time. The overall floating time was calculated during the
dissolution studies.
Swelling study of formulations17
Swelling study of individual batch was carried out using USP
dissolution apparatus-II (rotating paddle), in 900 ml of 0.1N HCl which
is maintained at 37±0.5°C, rotated at 50 rpm. Weight
of individual tablet was taken prior to the swelling study (W1). The tablet was
kept in a basket. The tablet was removed every
one hour interval up to 12 hour and excess water removed carefully using
filter paper. The swollen tablets were re-weighed (W2);
Percent hydration (swelling index) was calculated as shown in table 5 using
following formula,
% Swelling Index = {(W2) – (W1)/ (W1)} x 100
Where W1- initial
weight of tablet, W2- weight of the swollen tablet.
In vitro drug release study:
In-vitro drug release studies were
carried out using USP XXII dissolution apparatus type II (Electrolab,
Mumbai, India) at 50 rpm. The dissolution medium consisted of 900 ml of 0.1N HCl (pH 1.2), maintained at 37 + 0.5şC. The
dissolution samples were collected at every 1 hour interval and replaced with
an equal volume of 0.1N HCl to maintain the volume
constant. The sample solution was diluted sufficiently and analyzed at 294nm
using an UV spectrophotometer (Labindia, Mumbai,
India). The study was performed in triplicate.
Drug
release kinetics (Curve fitting analysis)
To
analyze the mechanism of the drug release rate kinetics of the dosage form, the
data obtained were fitted into zero order, first order Higuchi model and Korsmeyer’s equation release models.18, 19
Stability studies:
To
assess the drug and formulation stability, stability studies were done
according to ICH guidelines. 20 The optimized formulation was
subjected to stability study at 40 ± 2şC and 75 ± 5% RH for 90 days. The samples were evaluated for physical
changes, hardness, friability, drug content, buoyancy study and percentage drug
release during the stability studies.
RESULTS:
FTIR
spectroscopy:
The
pure drug ofloxacin and the solid admixture of drug
and various polymers used in the preparation of floating tablet formulations
were characterized by FT-IR spectroscopy to know the compatibility. The spectra
are shown in Fig 1-3.
Figure 1: FTIR
Spectroscopy of pure drug
Table 1: Composition of different formulations
Ingredients (mg
/tablet) |
Formulation |
|||||||
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
|
Ofloxacin |
200 |
200 |
200 |
200 |
200 |
200 |
200 |
200 |
Guar gum |
248 |
234 |
220 |
206 |
- |
- |
- |
- |
Locust bean gum |
- |
- |
- |
- |
248 |
234 |
220 |
206 |
HPMC K100M |
- |
14 |
28 |
36 |
- |
14 |
28 |
36 |
Sodium Bicarbonate |
60 |
60 |
60 |
60 |
60 |
60 |
60 |
60 |
Magnesium stearate |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
Talc |
5.5 |
5.5 |
5.5 |
5.5 |
5.5 |
5.5 |
5.5 |
5.5 |
MCC |
13 |
13 |
13 |
13 |
13 |
13 |
13 |
13 |
PVP K30 |
12.5 |
12.5 |
12.5 |
12.5 |
12.5 |
12.5 |
12.5 |
12.5 |
Total weight of tablet-550mg
Table 2: Granules properties of formulations F1 to F8
of Ofloxacin floating tablets
Formulation No. |
Angle of repose* |
Loose bulk density (LBD) * (g/ml) |
Tapped bulk density (TBD) * (g/ml) |
Compressibility index (%)* |
F1 |
29.24
± 0.78 |
0.4098
± 0.006 |
0.4716
± 0.011 |
13.10
± 0.75 |
F2 |
27.47 ± 1.27 |
0.4032 ±0.007 |
0.4504 ± 0.010 |
10.47
± 1.26 |
F3 |
26.56 ± 1.21 |
0.4132 ± 0.004 |
0.4761 ± 0.011 |
13.21
± 1.63 |
F4 |
29.05
± 1.08 |
0.3937
± 0.004 |
0.4638
± 0.014 |
15.11
± 1.23 |
F5 |
27.40
± 1.81 |
0.4201
± 0.009 |
0.4761
± 0.012 |
11.76
± 1.35 |
F6 |
28.30 ± 1.57 |
0.4032 ±0.008 |
0.4504
± 0.014 |
10.49
± 0.49 |
F7 |
29.74
± 0.73 |
0.3968
± 0.007 |
0.4418
± 0.013 |
11.97
± 0.65 |
F8 |
27.47
± 1.03 |
0.4065
± 0.003 |
0.4761
± 0.015 |
14.65
± 0.71 |
* (n=3, ±S.D.)
Table 3: Tablet properties of
formulations F1 to F8 of Ofloxacin floating tablets
Formulation No. |
Hardness* (kg/cm2) |
Thickness* (mm) |
% Friability |
Weight Variation*(mg) |
% Drug content |
F1 |
5.7±0.3 |
4.15±0.05 |
0.24 |
549.8±1.687 |
99.06 |
F2 |
5.6±0.2 |
4.17±0.05 |
0.30 |
550.2±1.370 |
97.89 |
F3 |
5.9±0.4 |
4.16±0.07 |
0.24 |
550.3±1.767 |
98.13 |
F4 |
6.1±0.3 |
4.15±0.08 |
0.52 |
548.9±2.132 |
99.68 |
F5 |
5.8±0.2 |
4.16±0.05 |
0.36 |
549.2±2.394 |
97.81 |
F6 |
6.1±0.3 |
4.17±0.02 |
0.31 |
550.3±1.494 |
99.37 |
F7 |
5.7±0.2 |
4.16±0.05 |
0.39 |
550.2±2.044 |
100.31 |
F8 |
5.9±0.4 |
4.15±0.03 |
0.18 |
548.5±2.251 |
98.50 |
* (n=3, ±S.D.)
Figure 2: FT-IR
Spectroscopy of Formulation 3
Figure 3: FT-IR Spectroscopy
of Formulation 6
Characterization of granules:
Granules prepared for
compression of floating matrix tablets were evaluated for their flow properties
like angle of repose, bulk density, tapped density and compressibility index.
The results were shown in Tables 2. Angle of repose was in the range of 26.56 ±
1.21to 29.74 ± 0.73. The bulk density of the granules was in the range of
0.3937 ± 0.004 to 0.4201 ± 0.009 gm/ml; the tapped density was in the range of
0.4418 ± 0.013 to 0.4761 ± 0.015gm/ml, which indicates that the granules were
not bulky. The Compressibility index was found to be in the range of 10.47 ±
1.26 to 15.11 ± 1.23.
Physicochemical evaluation of floating
tablets:
The
results of physicochemical characterizations are shown in Tables 3. The
thicknesses of floating tablets were measured by vernier
caliper and were ranged between 4.15±0.03 to 4.17±0.05 mm. The hardness of the
floating tablets was measured by Monsanto tester and was controlled between
5.6±0.2 to 6.1±0.3 kg/cm2. The friability was below 1% for all the
formulations. Weight variation for different formulations were found to be
548.5±2.251 to 550.3±1.767mg,. The percentage of drug
content for F1 to F9 was found to be in between 97.81%
to 100.37% of ofloxacin it complies with official specifications.
Table 4: Buoyancy studies of formulations F1-F8
Formulation
code |
Floating
lag time (min) |
Floating
duration |
F1 |
7.83 |
Disintegrated
after 8 hrs. |
F2 |
5.71 |
Disintegrated
after 10 hrs. |
F3 |
3.32 |
>12
hrs |
F4 |
2.45 |
>12
hrs |
F5 |
5.05 |
>12
hrs |
F6 |
2.45 |
>12
hrs |
F7 |
1.66 |
>12
hrs |
F8 |
1.07 |
>12
hrs |
Buoyancy Studies:
The floating lag time
determined by keeping tablet in 100ml beaker containing 0.1N HCl. Whereas total floating duration determined during
dissolution studies. The results are shown in table 4.
Swelling index:
Figure 4: Swelling Index of floating
tablets F1-F8
Figure 5: Drug release profile of
floating tablets F1-F8
Table 5: Swelling Index of floating tablets F1-F8
Time in ‘hrs’ |
Swelling index (%) Formulation code |
|||||||
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
|
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
86.18 |
110.36 |
119.9 |
150.36 |
80.61 |
95.98 |
103.81 |
120.87 |
2 |
119.6 |
148.54 |
175.73 |
219.2 |
112.18 |
120.25 |
127.81 |
153.72 |
3 |
148.18 |
180.90 |
234.18 |
265.8 |
133.8 |
145.43 |
152.72 |
186.20 |
4 |
180.18 |
203.27 |
275.8 |
302.5 |
140.76 |
176.64 |
186.36 |
215.78 |
5 |
124.0 |
225.63 |
304.9 |
343.8 |
164.45 |
197.0 |
209.40 |
241.01 |
6 |
84.36 |
250.45 |
315.4 |
378.36 |
186.59 |
216.9 |
231.81 |
263.70 |
7 |
|
203.81 |
330.4 |
400.36 |
209.05 |
239.23 |
248.72 |
284.02 |
8 |
|
160.18 |
350.5 |
417.27 |
226.26 |
262.59 |
270.72 |
300.72 |
9 |
|
108.18 |
341.1 |
429.0 |
208.87 |
284.12 |
292.54 |
316.87 |
10 |
|
|
330.4 |
418.3 |
193.84 |
268.24 |
285.0 |
331.39 |
11 |
|
|
320.6 |
407.8 |
178.07 |
252.73 |
279.09 |
333.75 |
12 |
|
|
309.0 |
399.09 |
164.13 |
237.59 |
267.81 |
340.65 |
Table 6: Kinetic values obtained from different plots
of formulations F1 to F8
Formulations |
Zero order plots◘ |
First order plots▪ |
Higuchi’s plots● |
Korsmeyer et al’s
plots□ |
|
R2 |
R2 |
R2 |
R2 |
Slope(n) |
|
F1 |
0.858 |
0.635 |
0.991 |
0.990 |
0.48 |
F2 |
0.902 |
0.857 |
0.998 |
0.992 |
0.45 |
F3 |
0.948 |
0.889 |
0.998 |
0.997 |
0.57 |
F4 |
0.960 |
0.952 |
0.997 |
0.998 |
0.604 |
F5 |
0.896 |
0.817 |
0.993 |
0.995 |
0.46 |
F6 |
0.948 |
0.896 |
0.995 |
0.989 |
0.569 |
F7 |
0.965 |
0.947 |
0.990 |
0.985 |
0.60 |
F8 |
0.969 |
0.983 |
0.995 |
0.997 |
0.67 |
◘Zero order equation,
C=K0 t, ▪First order equation, Log C=log
Cₒ-Kt/2.303, ●Higuchi’s equation, Q= Kt˝, □Korsmeyer et al’s equation, Mt/Mα= Ktn
In vitro release study
Drug Release Kinetics:
The
drug release data were fitted to models representing zero order (cumulative
amount of drug released vs. time), first order (log percentage of drug
unreleased vs. time), Higuchi’s (cumulative percentage of drug released vs.
square root of time), and Korsmeyer’s equation (log
cumulative percentage of drug released vs. time) kinetics to know the release
mechanisms. The results were shown in table 6.
DISCUSSION:
The
present study was aimed to make the formulation remain in the stomach for
longer period of time, gastro retentive dosage form was designed, to release
the drug in sustained manner in gastric fluid.
FT-IR
study were carried out to know the compatibility As shown in figure 1-3, there
was no significant difference or the characteristic peaks of pure drug were
unchanged in spectrum of optimized formulation. The granules of different
formulations were evaluated for angle of repose, LBD, TBD, compressibility
index. The results of angle of repose indicate reasonably good flow property
of granules. The results of bulk and tapped density which
indicates that the granules were not bulky. The Compressibility index
results, indicating compressibility of the tablet blend is good. The resuts of Granular properties of formulation F1-F8 were
shown in table 2.
The
ofloxacin floating tablets were off-white, smooth,
and flat shaped in appearance. According to table 3 the results of hardness and
friability were an indication of good mechanical resistance of the
tablets. The weight
variation test showing satisfactory results as per Indian Pharmacopoeia (IP)
limit. Good uniformity in drug content was found among different
formulation of the tablets.
For
buoyancy gas generating agent plays important role, the gas generating agents
immediately evolves carbon dioxide
in presence of HCl solution generating sufficient
porosity which helped the dosage unit to float. Formulation F1 prepared with
guar gum started floating after 7.83min and remains buoyant for 8 hr till they
were completely eroded. On the other hand, formulation F2-F4 prepared with
combination of guar gum and HPMC K100M show decrease in floating lag time and
increased floating duration time. This might be due to high viscosity polymer
HPMC K100M maintains the integrity of the tablets for longer duration by
reducing the effect of erosion thus resulting in increase in floating time.
Similar results were obtained with batches prepared from locust bean gum. The
selected formulations F3 and F6 shows floating lag time 3.32min and 2.45min
respectively with floating duration time >12 hrs. the
results for buoyancy study were shown in table 4.
According
to table 5 F4 and F8 showed maximum swelling in 12 hr with sharp increase up to
8 hr, this may due to increased concentration of HPMC K100M which retains water
and form thick swollen mass. The selected formulations F3 and F6 show maximum
swelling up to 8 hr followed by decrease in swelling index. Reason behind this
may be erosion process initiation at the end of 8 hr attributing gradual
decrease in percent swelling after 8hr.
Formulations
F3 and F6 (97.8% and 97.33% in 12 hr) show reasonable drug release when
compared to other formulations. Also all other parameters like hardness,
thickness, friability, drug content and weight variation for these formulations
were within the range. So, formulations F3 and F6 were selected as the
optimized formulations. It is evident from the in vitro dissolution
data that increase in HPMC K100M
concentration decreases the release rate
this might be due to increase in diffusional path
length, which the drug molecule may have to travel. Comparative dissolution
profile is presented in fig 5.
As
per table 6 all the formulations in this investigation could be best expressed
by Higuchi’s classical diffusion equation, as the plots showed high linearity
(R2 : 0.990 to 0.998) indicates that the drug release follows
diffusion mechanism. To confirm the diffusion mechanism, the data were fitted
into Korsmeyer–Peppas equation. All the formulations
showed values ranging from 0.45 to 0.67, indicating that non-Fickian/anomalous diffusion (If
the exponent n=0.45, then the drug release follows the Fickian
diffusion, and if 0.45 < n < 0.89, then it is said to be non-Fickian or anomalous release).
CONCLUSION:
Floating
matrix tablets containing ofloxacin can be
prepared successfully by using wet granulation technique. Tablets were
subjected to various evaluation parameters such as Weight variation, Hardness,
Friability, Drug content, Swelling index, in vitro drug release study, in
vitro buoyancy study. It was revealed that tablets of all batches had
acceptable physical parameters. FT-IR studies revealed that there was no
interaction between ofloxacin and other excipients used in the tablets. It was found that increase in the HPMC K10M
concentration will decrease floating lag time and increases floating duration
but decrease drug release. Tablets of batch F3 and F6 have considerable in
vitro drug release, and also showing good floating lag time. The drug
release kinetics follows Higuchi model and the mechanism was found to be non Fickian/anomalous. The stability studies were carried out
according to ICH guideline which indicates that the selected formulation was
stable.
ACKNOWLEDGEMENT
The
authors are thankful to the Management, Sree Siddaganga College of Pharmacy Tumkur
for providing necessary facilities to carry out this work.
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Received on 17.01.2011 Accepted on 20.02.2011
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J. Res. Pharm. Sci. 1(1): Jan.-Mar.
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