Lavanya et al.
Research Article
Article Received on
23 Oct 2014,
Revised on 18 Nov 2014,
Accepted on 14 Dec 2014
ABSTRACT
The present research work was aimed the formulation and evaluation
of
OptiZorb
dispersible
tablets
of
bisoprolol
fumarate,
an
*Correspondence for
lot of water, swells and leads to decay effect brought about. Calcium
carbonate reacts with the stomach acid, within 3 minutes it releases
Author
B. Lavanya
Department of
Pharmaceutics, Sri
Padmavathi School of
Pharmacy, Tiruchanur-
Pradesh, India.
were evaluated for precompressional parameters such as bulk density, tapped density, angle
of repose, Carrs index and Hausners ratio. The tablets were evaluated for weight variation,
thickness, hardness, friability, drug content, dispersion time, disintegration time and invitro
dissolution study. Invitro dissolution studies were performed by using USP dissolution
apparatus type II paddle in 900 ml of 0.1N Hydrochloric acid at 50 rpm. No chemical
interaction between drug and excipients was confirmed by FTIR studies. 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).
www.wjpps.com
561
Lavanya et al.
www.wjpps.com
562
Lavanya et al.
stearate and talc were added. The formulations were compressed with a sixteen station rotary
tablet punching machine.
Table No 1: Composition of different formulations of Bisoprolol fumarate.
S.NO Ingredients (mg)
1
2
3
4
5
6
7
Bisoprolol
fumarate
Alginic acid
Calcium carbonate
Lactose
Starch paste (Q.S)
Magnesium
stearate
Talc
F1
F2
Formulation code
F3
F4
F5
F6
10
10
10
10
10
10
10
10
10
3
159
20
6
156
20
9
153
20
10
152
20
20
142
20
30
132
20
3
3
156
20
6
6
150
20
9
9
144
20
F7
F8
F9
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
www.wjpps.com
563
Lavanya et al.
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.
Post Compression Technological Parameters
1. Weight Variation Test
From each batch twenty tablets were selected at a random and average weight was
determined. Then individual tablets were weighed and the individual weight was compared
with an average weight, the variation in the weight was expressed in terms of % deviation [12].
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]
Intial weight final Weight
Friability =
100
Intial weight
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]
www.wjpps.com
564
Lavanya et al.
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]
8. Invitro Drug Release
Dissolution rate of fast disintegrating tablet of Bisoprolol fumarate was studied by using USP
Type-II apparatus at 50rpm using 900 ml of 0.1N HCl as dissolution medium. Temperature of
the dissolution medium was maintained at 370C an aliquot of dissolution medium was
withdrawn at every specific time interval and filtered. The absorbance of filtered solution was
checked by UV spectrophotometer at 222 nm and concentration of the drug was determined
from standard calibration curve. [19]
Drug Release Kinetics
As a model-independent approach, comparison of the time taken for the given proportion of
the active drug to be dissolved in the dissolution medium and figures such as T50 and T90
calculated by taking the time points of 50% and 90% of the drug dissolved and another
parameter Dissolution Efficiency (DE) suggested by Khan were employed. DE is defined as
the area under the dissolution curve up to the time t expressed as a percentage of the area of
the rectangle described by 100% dissolution in the same time. [20]
t
y.dt
Dissolution Efficiency (DE) = 0
y .t
100
100
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.
www.wjpps.com
565
Lavanya et al.
www.wjpps.com
566
Lavanya et al.
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.
RESULTS AND DISCUSSION
Table No.2: Precompression studies of granules of bisoprolol fumarate.
Formulations
F1
F2
F3
F4
F5
F6
F7
F8
F9
Angle of
repose(0)
32.15
30.44
28.85
32.35
29.45
29.30
33.60
32.22
28.65
Bulk density
(g/ml)
0.40
0.40
0.43
0.43
0.41
0.38
0.40
0.41
0.41
Tapped
density (g/ml)
0.45
0.44
0.50
0.49
0.47
0.43
0.45
0.46
0.47
Carrs
index (%)
11.11
09.09
14.00
12.24
12.76
11.62
11.11
10.86
12.76
Hausner
s, ratio
1.12
1.10
1.16
1.13
1.14
1.13
1.12
1.12
1.13
The bulk density of all formulations powder containing drug and excipients was found to be
in the range of 0.40 to 0.43gm/ml, whereas the tapped density was observed between 0.43 to
0.50gm/ml. From the values of bulk density and tapped density the values for Carrs index
and Hausners ratio were calculated. The values for Carrs index were found between 09.09
and 14.00 %. The values for Hausners ratio were found to be between 1.10 and 1.16. All
these values are within the specified limits which indicate good flow properties. Angle of
repose was found to be less than 32 which indicate good flow of powder. Overall these values
indicate good flow properties of powder blend, uniform die fill and better compression
ability. Therefore, from this data so obtained, it was decided to go for compression of tablets
from the powder blends.
Table No.3: Evaluation of bisoprolol fumarate tablets.
Parameters
%Wt. Variation
Hardness (kg/cm2)
Thickness (mm)
Friability (%w/w)
Disintegration (mins)
Dispersion Time (mins)
Wetting Time min)
Drug content (%)
Formulation code
F1
F2
F3
F4
F5
F6
F7
F8
F9
PASS PASS PASS PASS PASS PASS PASS PASS PASS
3.6
3.5
3.6
3.5
3.8
3.8
3.7
3.8
3.8
3.3
3.4
3.3
3.5
3.2
3.5
3.3
3.2
3.3
0.24
0.21
0.24
0.35
0.27
0.27
0.25
0.24
0.25
6
7
7
6
5
4
4
3
2
7
8
8
7
6
3
4
2
2
6
7
7
6
5
4
4
3
2
84.86 86.12 88.20 86.40 86.30 98.30 98.23 98.32 98.50
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
www.wjpps.com
567
Lavanya et al.
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.
Table No.4: Dissolution profile of F1-F9
Time (min)
5
10
15
20
25
30
F1
13.92
26.80
46.87
52.82
58.80
67.66
F2
22.41
38.19
56.90
65.75
70.38
73.61
F3
28.07
41.03
61.18
67.21
71.85
76.51
F4
32.32
45.30
65.47
70.10
73.33
78.00
F5
35.15
48.15
69.76
75.83
79.09
82.37
F6
37.98
50.99
72.62
78.71
81.99
85.28
F7
42.22
63.80
78.38
85.93
92.09
94.01
F8
46.47
69.49
85.53
90.27
95.03
96.97
F9
50.71
76.61
92.68
94.61
97.98
98.51
www.wjpps.com
568
Lavanya et al.
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.
Drug Release Kinetics
Table No 5: Correlation coefficient (r) & rate constant (k) values of dispersible tablet.
Kinetic
model
First
order
Zero
order
HixsonCrowell
F1
F2
F3
F4
F5
F6
F7
F8
F9
Fig. 2: Correlation coefficient (r) & rate constant (k) values of dispersible tablet.
www.wjpps.com
569
Lavanya et al.
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
www.wjpps.com
570
Lavanya et al.
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.
www.wjpps.com
571
Lavanya et al.
0.000
10.5mJ/mg 50.9mJ/mg
350.0
-1.000
80.1Cel
-1.718mW
-2.000
300.0
250.0
-4.000
-5.000
DDSC mW/min
DSC mW
-3.000
200.0
-6.000
150.0
-7.000
-8.000
0.0
102.4Cel
-8.163mW
100.0
Temp Cel
50.0
100.0
150.0
200.0
250.0
300.0
280.0
1.000
28.8mJ/mg
10.9mJ/mg
0.000
260.0
240.0
-1.000
DSC mW
200.0
-3.000
180.0
-4.000
DDSC mW/min
220.0
80.3Cel
-1.601mW
-2.000
160.0
-5.000
140.0
101.5Cel
-5.651mW
-6.000
120.0
100.0
-7.000
80.0
-8.000
-100.0
-50.0
0.0
50.0
100.0
150.0
Temp Cel
200.0
250.0
300.0
350.0
www.wjpps.com
572
Lavanya et al.
Bioequivalence Studies
Disintegration Time
Table No.6: Bioequivalence studies of Disintegration time.
S. NO
1
2
3
4
5
6
Time
(min)
5
10
15
20
25
30
Marketed products
Carvedilol
4
5
4
4
5
4
Prepared dispersible
tablets (B.F)
3
2
2
3
2
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.
Table No.7: Bioequivalence studies invitro drug release studies.
S.NO
1
2
3
4
5
6
Time
(min)
5
10
15
20
25
30
Marketed products
Carvedilol
45.39
65.62
75.36
85.25
91.25
95.52
Prepared dispersible
tablets (B.F)
50.71
76.61
92.68
94.61
97.98
98.51
www.wjpps.com
573
Lavanya et al.
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.
REFERENCES
1. Wilson C.G, Cyril P. Clarke, Yan Yan L, Starkey, Geoffrey D. Clarke. Comparison of a
novel fast-dissolving acetaminophen tablet formulation (FD-APAP) and standard
acetaminophen tablets using gamma scintigraphy and pharmacokinetic studies. Drug
Develop Ind Pharm, 2011; 37(7): 747-753.
2. 2011-06-28, English, Article, Journal or magazine article edition: Glaxo launches fastacting crocin (the company has used the OptiZorb disintegration technology).
www.wjpps.com
574
Lavanya et al.
3. www.gsk-ch.in/crocin.aspx.
4. www.pharmacynz.co.nz/panadol-optizorb-100s.html.
5. Dongzhou J, Liu, Mitchell Kotler, Scott Sharples. Pharmacokinetic and Bioequivalence
Study Evaluating a New Paracetamol/Caffeine Formulation in Healthy Human
Volunteers. JBB, 2011; 3(11): 251-257.
6. Patel Badalkumar R, Jatav Rajesh K, Jatav Rakesh K, Sheorey Rajendra V. Formulation
development & evaluation of Cefpodoxime Proxetil Dispersible Tablets. Int. J. Drug Dev.
& Res, 2012; 4(2): 124-131.
7. Mundad A, Meshram D, Banbale H, Bhalekar M, Avari J. Formulation and evaluation of
dispersible taste masked tablet of Roxithromycin. Asian J Pharm, 2008: 116-119.
8. Sawarikar PP, Sridhar BK and Shivkumar S. Formulation and evaluation of fast
dissolving tablets of isoxsuprine hydrochloride. J Curr Pharm Res, 2010; 3(1): 41-46.
9. Puttewar TY, Kshirsagar MD, Chandewar AV and Chikhale RV. Formulation and
evaluation of orodispersible tablet of taste maskeddoxylamine succinate using ion
exchange resin. J King Saud Univ Sci, 2010; 22: 229240.
10. Simone S and Peter CS. Fast dispersible ibuprofen tablets. Eur J Pharm Sci, 2002; 15:
295-305.
11. Schiermeier S, Schmidt PC. Fast dispersible ibuprofen tablets. Eur J Pharm, 2002; 15:
295305.
12. Sureh Bhandari, Rajendra Kumar Mittapali, Ramesh Gannu, Yamsai Madhusudhan Rao.
Orodispersable tablet. Asian J Pharm, 2008: 1-11.
13. Furtado S, Deveswaran R, Bharath S, Basavaraj BV, Abraham S. and Madhavan V.
Development and characterization of Orodispersible tablets of famotidine containing a
subliming agent, Trop J Pharm Res, 2009; 8(2): 153-159.
14. Polli JE, Rekha GS, Augsburger LL, Shah VP. Methods to compare dissolution profiles
and a rationale for wide dissolution specifications for metaprolol tartrate tablets. Int J
Pharm, 1997; 86(6): 690-700.
15. Brittain H. Spectral methods for the characterization of polymorphs and solvates. Int J
Pharm, 1997; 2(6): 405412.
16. Kakumanu V and Bansal A. Enthalpy relaxation studies of celecoxib amorphous
mixtures. Int J Pharm Tech Res, 2002; 1(9): 18731878.
17. Seager H. Drug Delivery Products and Zydus Fast Dissolving Dosage Forms: J Pharm
Pharmacol, 1998; 50: 375-382.
www.wjpps.com
575
Lavanya et al.
18. Schiermer S., Schmidt P.C. Fast dispersible Ibuprofen tablets. Eur J Pharm Sci, 2002; 15:
295-305.
19. Harish R, Lukkad, Pravin K, Bhoyar, Jagdish R, Baheti, Nitin D, Somnathe Dhanashri B,
Nagulwar, Prasad P, Kathade. Formulation and evaluation of aceclofenac orodispersible
tablets using natural disintegrant. WJPPS, 2012; 1(2): 601-609.
20. Tiwari Bhupendra R, Rane Bhushan R, Pawar Sunil P. Formulation and evaluation of
cefadroxil disprsible tablet. Int J Pharm Sci, 2013; 4(4): 1.
21. Shashidhar KR, Anup Kumar Roy, Roopa Kark, Kebajyoti Bhattacharya, Ruchi shakya.
Formulation and evaluation of fast dispersible tablets of Prochlorperazine maleate using
natural disintegrants. Int J Pharm Tech, 2013: 234-249.
www.wjpps.com
576