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1
Department of Pharmaceutics, Sri Padmavathi School of Pharmacy, Tiruchanur- 517503,
Tirupati, Andhra Pradesh, India.
2
Faculty in Pharmaceutics, Sri Padmavathi School of Pharmacy, Tiruchanur- 517503,
Tirupati, Andhra Pradesh, India.
ABSTRACT
Article Received on
23 Oct 2014, The present research work was aimed the formulation and evaluation
INTRODUCTION
A novel tablet concept which offers ease of oral administration and benefits of increased
patient compliance is the fast dissolving/disintegrating tablet (FDDT). Dispersible tablets are
uncoated or film-coated tablets that can be dispersed in liquid before administration giving a
homogenous dispersion. Technology which allows the tablet to start disintegrating in as little
as 5 minutes is called Optizorb. OptiZorb disintegration technology is five times faster and
thus gets to work much more quickly. It is easily dispersed in stomach and work faster, relief
faster. OptiZorb technology is based on the use of super-disintegrants as alginic acid and
calcium carbonate that make it act within five minutes. Alginic acid is a hydrophilic that
draws acidic gastrointestinal fluid into the tablet as calcium carbonate reacts with gastric acid
to liberate carbon dioxide to help it disintegrate to provide faster relief. [1-6]
Preformulation
Identification of the drug was carried out by FTIR (Analytical Technologies, Mumbai,
Standardization of the drug was carried out using UV/Vis spectrophotometer (Shimadzu,
Japan). FTIR and DSC spectral analysis of the formulations was performed to assess drug
excipients compatibility. Preliminary studies were carried out on the tablets using different
concentrations of superdisintegrants. Thus, after evaluation of the quality parameters and
subjecting to in vitro disintegration and in vitro dissolution studies the final concentrations of
the superdisintegrants were optimized. Based on this Preformulation data the optimized
formulations for further investigations were decided.
stearate and talc were added. The formulations were compressed with a sixteen station rotary
tablet punching machine.
2. Tapped Density
The tapped density is calculated by the following formula. [8]
Tapped density = Weight of powder / Tapped volume.
Flow properties
1. Carrs Index [Compressibility Index]
It is one of the most important parameter to characterize the nature of powders and granules.
It can be calculated from the following equation. [9]
Carrs index = (Tapped density - Bulk density) X 100
Tapped density
2. Hausners Ratio
Hausners ratio is an important character to determine the flow property of powder and
granules. This can be calculated by the following formula. [10]
Hausners ratio = Tapped density / Bulk density
3. Angle of Repose
The angle of repose is defined as the maximum angle possible between the surfaces of pile of
powder and the horizontal plane. Angle of repose of granules is done by fixed funnel method
and is calculated by using following formula. [11]
= tan-1 h/r
Where, h = height of the pile; r = radius of the pile
The tangent of the angle is equal to the coefficient of friction (M) between the particles.
2. Hardness
Ten tablets from each formulation were selected for the hardness and it was determined by
using Monsanto hardness tester. [13]
3. Thickness
Ten tablets form each formulation was taken for thickness and it was measured using Vernier
callipers. [14]
4. Friability Test
The friability of the tablet was determined by Friabilator. Initially weighed 10 tablets after
dusting and placing them in a friability tester, which was rotated for 5 min at 25 rpm. After
dusting, the total remaining mass of tablets was recorded and the percent friability was
calculated by using the formula. [15]
5. Content Uniformity
Ten tablets were weighed individually and powdered. The powder equivalent to 20 mg of
Bisoprolol fumarate was weighed and extracted in water (100 ml) and the concentration of
drug was determined by measuring absorbance at 222 nm by spectrophotometer. [16]
6. Disintegration Time
The test was carried out on 5 tablets using the Disintegration Test Apparatus. Distilled water
at 37oC was used as a disintegration media and the time in second taken for complete
disintegration of the tablet by no palatable mass remaining in the apparatus was measured. [17]
7. Wetting Time
A piece of tissue paper folded twice was placed in a small Petri dish containing 6 ml of water.
A tablet was put on the paper and time required for complete wetting was measured. [18]
The dissolution efficiency can have a range of values depending on the time interval chosen.
In any case constant time intervals should be chosen for comparison. For example, the index
DE30 would relate to the dissolution of the drug from a particular formulation after 30
minutes could only be compared with DE30 of other formulations. Summation of the drug
dissolution data into a single figure DE enables ready comparison to be made between a large
numbers of formulations.
Bioequivalence Studies
Bioequivalence study was performed between the marketed products Carvedilol-3.125mg
(coreg) tablets and prepared OptiZorb dispersible tablets of bisoprolol fumarate.
The Bioequivalence study was done by performing disintegration, invitro studies between
marketed products and prepared OptiZorb dispersible tablets.
Stability Studies
The purpose of stability testing is to provide evidence on how the quality of a drug substance
or drug product varies with time under the influence of a variety of environmental factors
such as temperature, humidity and light, enabling recommended storage conditions, re-test
periods and shelf-lives. Generally, the observation of the rate at which the product degrades
under normal room temperature requires a long time. To avoid this undesirable delay, the
principles of accelerated stability studies are adopted. [21]
The selected formulations were closely packed in amber colour bottles and then stored at 400
C 20 C /75% RH 5% in stability chamber for 3 months and evaluated for their physical
appearance, drug content and in-vitro drug release studies at intervals of 1month. The shelf
life period of the prepared dispersible tablets is determined by using similarity factor.
The weight variation of all formulations was found to be passes as per I.P guidelines. None of
the tablet was found to deviate from the average weight of tablets (variation with deviation
less than 7.5, which complies with I.P specification) signifies that there is uniformity in
flow of powder blend which leads to uniform die fill. Hardness test for all formulations was
carried out and observations obtained were in the range of 3.5 to 3.8 kg/cm2. Hardness for all
formulations was observed to be proper, which signify that tensile strength of all formulations
was maintained after compression. Test for friability was conducted for all formulations, %
friability was found to be in the range of 0.21 to 0.35. Friability test for all formulations
indicated that % friability was less than 1%, which compiles the I.P specification and reveals
that all formulations have possessed good physical strength and can withstand the mechanical
shocks that can be observed during handling, shipping and transportation. The thickness of all
formulations was found to be uniform as it was obtained in the range of 3.2 to 3.7 mm. The
values for thickness and diameter signify uniformity and it was due to uniformity in die fill,
good flow properties, uniform pressure and appropriate punch movement.
Time (min) F1 F2 F3 F4 F5 F6 F7 F8 F9
5 13.92 22.41 28.07 32.32 35.15 37.98 42.22 46.47 50.71
10 26.80 38.19 41.03 45.30 48.15 50.99 63.80 69.49 76.61
15 46.87 56.90 61.18 65.47 69.76 72.62 78.38 85.53 92.68
20 52.82 65.75 67.21 70.10 75.83 78.71 85.93 90.27 94.61
25 58.80 70.38 71.85 73.33 79.09 81.99 92.09 95.03 97.98
30 67.66 73.61 76.51 78.00 82.37 85.28 94.01 96.97 98.51
In-vitro drug release studies were performed in 0.1N HCl for all the prepared formulations by
using USP dissolution test apparatus-Type II, Rotating Paddle method. The data for in-vitro
release profile of the entire prepared tablet formulations were shown in table No4, and the
graphs showing drug release profile for formulations were shown in the fig. 1. In-vitro
dissolution studies were conducted over a period of 30 mins. In formulations F1 to F3
containing Alginic acid, an increase in concentration was observed. In formulations F4 to F6
containing calcium carbonate an increase in concentration was observed. Formulations F7 to
F9 showed quick release as the concentration of disintegrants increased tablets alginic acid
and calcium carbonate.
Table No 5: Correlation coefficient (r) & rate constant (k) values of dispersible tablet.
Kinetic
F1 F2 F3 F4 F5 F6 F7 F8 F9
model
First r 0.9939 0.9872 0.9842 0.9702 0.9745 0.9771 0.9971 0.9978 0.9900
order k 0.0369 0.0483 0.0518 0.0553 0.0639 0.0699 0.0969 0.1170 0.1453
Zero r 0.9777 0.9355 0.9100 0.8706 0.8651 0.8518 0.8299 0.7835 0.7160
order k 2.4506 2.9042 3.0255 3.1438 3.3616 3.4947 3.8869 4.0778 4.2566
Hixson- r 0.9923 0.9758 0.9674 0.9463 0.9498 0.9498 0.9713 0.9651 0.9431
Crowell k 0.0106 0.0134 0.0142 0.0150 0.0168 0.0180 0.0226 0.0255 0.0290
r 0.9650 0.9855 0.9915 0.9906 0.9895 0.9892 0.9901 0.9810 0.9643
Higuchi
k 11.3686 13.6717 14.3233 14.9744 16.0227 16.6863 18.6138 19.6182 20.5928
r 0.9875 0.9850 0.9852 0.9809 0.9792 0.9795 0.9845 0.9735 0.9499
Peppas
k 3.5092 7.8546 11.2679 14.6060 15.9892 17.9278 21.5435 25.5588 30.4857
n 0.8915 0.6867 0.5812 0.5094 0.5017 0.4768 0.4525 0.4128 0.3698
DE 30 37.55 40.67 45.17 39.84 43.96 46.9 56.96 51.04 67.72
DE 60 50.43 51.48 57.75 53.32 56.35 58.95 70.19 71.82 76.88
T 50 13.13 11.52 10.24 12.33 10.26 9.50 7.14 6.73 5.53
Fig. 2: Correlation coefficient (r) & rate constant (k) values of dispersible tablet.
The drug release profiles from the bisoprolol fumarate dispersible tablets were fitted to
various kinetic models. The values of correlation coefficient (r) and release rate constants (K)
from different models for bisoprolol fumarate dispersible tablets are given in Table 1. From
the data of correlation coefficient and rate constant values, it was found that bisoprolol
fumarate release from their tablets has obeyed the first order release followed by the Peppas
model.
FT-IR spectroscopy
Fig. 6: FT-IR spectrum of bisoprolol fumarate with Alginic acid and Calcium
carbonate.
From the FT-IR results, Pure bisoprolol fumarate showed principal absorption peaks at
3348.61cm-1, NH (stretching), 3402.62cm-1OH (stretching), 1091.77cm-1 (stretching) and
1145.78 cm-1C-O (stretching). Same peaks of NH, O-H, C-O-C, and C-0 bonds were present
as that of pure drug without much shifting in the spectra of bisoprolol fumarate suggested no
chemical interaction between the drug and disintegrants.
0.000
10.5mJ/mg 50.9mJ/mg
350.0
-1.000
80.1Cel
-2.000
-1.718mW 300.0
-3.000
DDSC mW/min
250.0
DSC mW
-4.000
-5.000
200.0
-6.000
150.0
-7.000
-8.000
100.0
102.4Cel
-8.163mW
0.0 50.0 100.0 150.0 200.0 250.0
Temp Cel
1.000 280.0
240.0
-1.000
220.0
-2.000 80.3Cel
-1.601mW
DDSC mW/min
200.0
DSC mW
-3.000
180.0
-4.000
160.0
-5.000 140.0
101.5Cel
-6.000 120.0
-5.651mW
100.0
-7.000
80.0
-8.000
-100.0 -50.0 0.0 50.0 100.0 150.0 200.0 250.0 300.0 350.0
Temp Cel
From DSC thermograms the melting point of pure drug bisoprolol fumarate was found to be
102.4C which the value reported in literature hence the procured drugs are pure forms and
were shown in Fig No.7. The dispersible tablets DSC thermograms of bisoprolol fumarate
indicate that there are no interaction between the drugs and excipients which can be accessed
from the peaks in the DSC thermograms (Fig. No. 8).
Bioequivalence Studies
Disintegration Time
Table No.6: Bioequivalence studies of Disintegration time.
Time Marketed products Prepared dispersible
S. NO
(min) Carvedilol tablets (B.F)
1 5 4 3
2 10 5 2
3 15 4 2
4 20 4 3
5 25 5 2
6 30 4 2
The prepared dispersible tablets are having disintegration time between 2-3 min and the
marketed tablet of Carvedilol-1.325 mg (coreg) dispersible tablet having disintegration time
between 4-5min. Hence the prepared dispersible tablets are having less disintegration time
than that of marketed formulation.
Stability Studies
The optimized F9 formulation was kept for stability studies. Accelerated stability studies
were carried out at 400/75%RH for 3 months. The tablets were then evaluated for weight
variation for the period of initial, disintegration, hardness and drug content for initial, 1
month, 2 month and 3 month. The results indicated that there was no significant change in
physical evaluation. Evaluations of formulations by parameters including Weight Variation,
hardness, friability, disintegration were within the limits as per prescribed specifications. The
optimized F9 formulation is evaluated for In-vitro drug release studies; the results indicated
that there was no significant change in In-vitro drug release studies which is similar to the
formulations under optimum conditions.
CONCLUSION
OptiZorb dispersible tablets of bisoprolol fumarate were prepared by wet granulation method.
From the present work it concludes that the OptiZorb technology is based on the use of
excipients of Alginic acid and calcium carbonate as disintegrants in different concentrations.
Alginic acid absorbs lot of water, swells and leads to decay effect brought about. Calcium
carbonate reacts with the stomach acid, within 3 minutes it releases 90% of the active
ingredient. OptiZorb technology is five times faster and thus gets to work much more
quickly. After study of all formulations F9 showed short dispersion time with maximum drug
release in 15 min and it contains alginic acid and calcium carbonate (1:1). FT-IR study
reveals that there is no interaction between drug and excipients and can be used for
preparation of OptiZorb dispersible tablets of bisoprolol fumarate.
ACKNOWLEDGEMENT
The authors extend their deep sense of thanks to the Principal, Dr. D. Ranganayakulu and
the Management, Sri Padmavathi School of Pharmacy for their extended support during this
project work.
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