formulation and evaluation of bisoprolol fumarate …

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561

Lavanya et al. World Journal of Pharmacy and Pharmaceutical Sciences

FORMULATION AND EVALUATION OF BISOPROLOL FUMARATE

OPTIZORB DISPERSIBLE TABLET TO IMPROVE TABLET

DISINTEGRATION

B. Lavanya*1

and V. Shanmugam2

1Department of Pharmaceutics, Sri Padmavathi School of Pharmacy, Tiruchanur- 517503,

Tirupati, Andhra Pradesh, India.

2Faculty in Pharmaceutics, Sri Padmavathi School of Pharmacy, Tiruchanur- 517503,

Tirupati, Andhra Pradesh, India.

ABSTRACT

The present research work was aimed the formulation and evaluation

of OptiZorb dispersible tablets of bisoprolol fumarate, an

antihypertensive agent. The OptiZorb technology is based on the use of

excipients of Alginic acid and calcium carbonate. 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 this compared with only 10-15% in

marketed paracetamol. Optizorb technology is five times faster in

tablet disintegration and thus gets to work much more quickly.

Dispersible tablets were prepared by wet granulation method by using

Alginic acid and calcium carbonate as disintegrants in different

concentrations. Compatibility studies of drug and excipients were

carried out by using FT- IR spectroscopy and DSC. The formulations

were evaluated for precompressional parameters such as bulk density, tapped density, angle

of repose, Carr’s index and Hausner’s 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).

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 2.786

Volume 4, Issue 1, 561-576. Research Article ISSN 2278 – 4357

Article Received on

23 Oct 2014,

Revised on 18 Nov 2014,

Accepted on 14 Dec 2014

*Correspondence for

Author

B. Lavanya

Department of

Pharmaceutics, Sri

Padmavathi School of

Pharmacy, Tiruchanur-

517503, Tirupati, Andhra

Pradesh, India.


562


KEYWORDS: Alginic acid, antihypertensive, Bisoprolol fumarate, calcium carbonate,

dispersible tablet, OptiZorb technology.

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]

MATERIALS AND METHODS

Bisoprolol fumarate was obtained as gift sample from A-Z pharmaceuticals, Chennai. Alginic

acid and calcium carbonate were obtained from Himedia Pvt. Ltd, Mumbai. All other

chemicals used were of analytical grade.

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.

Preparation of OptiZorb Dispersible Tablets

Dispersible tablets of Bisoprolol fumarate were prepared by wet granulation method. The

drug and excipients were passed through sieve (#22) to ensure better mixing. Super

disintegrant like Alginic acid and calcium carbonate were used in different concentrations.

All the ingredients were mixed in mortar and pestle starch paste is added then magnesium


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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) Formulation code

F1 F2 F3 F4 F5 F6 F7 F8 F9

1 Bisoprolol

fumarate 10 10 10 10 10 10 10 10 10

2 Alginic acid 3 6 9 - - - 3 6 9

3 Calcium carbonate - - - 10 20 30 3 6 9

4 Lactose 159 156 153 152 142 132 156 150 144

5 Starch paste (Q.S) 20 20 20 20 20 20 20 20 20

6 Magnesium

stearate 4 4 4 4 4 4 4 4 4

7 Talc 4 4 4 4 4 4 4 4 4

Precompression Technological Parameters

Density Measurement

1. Bulk Density

10 g of Bisoprolol fumarate granules were weighed separately and transferred into a

graduated measuring cylinder via a large funnel and measure the volume of the powder. The

bulk densities of the granules were calculated by given formula. [7]

Bulk density = Weight of powder / Bulk volume.

2. Tapped Density

The tapped density is calculated by the following formula. [8]

Tapped density = Weight of powder / Tapped volume.

Flow properties

1. Carr’s 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]

Carr’s index = (Tapped density - Bulk density) X 100

Tapped density

2. Hausner’s Ratio

Hausner‟s ratio is an important character to determine the flow property of powder and

granules. This can be calculated by the following formula. [10]

Hausner’s ratio = Tapped density / Bulk density


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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]

θ = 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]


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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]

Dissolution Efficiency (DE) = 100 .

.

100

0

ty

dty

t

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.


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Characterization of Dispersible Tablets

FTIR Studies for drug

FTIR spectra are recorded from KBr disks. This ground KBr powder was use because the

background in the measurements beneath identical conditions. The measured wave number

range was from 4000 to 400cm-1

.

DSC Thermal Analysis

Thermal analysis of Bisoprolol fumarate and their drug and excipients were recorded with

Netzsch DSC 200PC (Netzsche, Selb, German). The temperature axis and cell constant of

DSC were previously calibrated with Indium. A heating rate of 5/min was employed over a

temperature range of 0- 3500C with nitrogen purging. The sample was weighed into an

aluminium pan was used as reference.

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]

ICH specifies the length of study and storage conditions.

Long-Term Testing: 250 C ± 2

0 C / 60% RH ± 5% for 12 Months

Accelerated Testing: 400 C ± 2

0 C /75% RH± 5% for 6 Months

Stability studies were carried out at 400C ± 2

0C /75% RH ± 5% for all the formulations for a

period of 3 months.

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


567


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 Angle of

repose(0)

Bulk density

(g/ml)

Tapped

density (g/ml)

Carr’s

index (%)

Hausner’

s, ratio

F1 32.15 0.40 0.45 11.11 1.12

F2 30.44 0.40 0.44 09.09 1.10

F3 28.85 0.43 0.50 14.00 1.16

F4 32.35 0.43 0.49 12.24 1.13

F5 29.45 0.41 0.47 12.76 1.14

F6 29.30 0.38 0.43 11.62 1.13

F7 33.60 0.40 0.45 11.11 1.12

F8 32.22 0.41 0.46 10.86 1.12

F9 28.65 0.41 0.47 12.76 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 Carr’s index

and Hausner’s ratio were calculated. The values for Carr’s index were found between 09.09

and 14.00 %. The values for Hausner’s 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 Formulation code

F1 F2 F3 F4 F5 F6 F7 F8 F9

%Wt. Variation PASS PASS PASS PASS PASS PASS PASS PASS PASS

Hardness (kg/cm2) 3.6 3.5 3.6 3.5 3.8 3.8 3.7 3.8 3.8

Thickness (mm) 3.3 3.4 3.3 3.5 3.2 3.5 3.3 3.2 3.3

Friability (%w/w) 0.24 0.21 0.24 0.35 0.27 0.27 0.25 0.24 0.25

Disintegration (mins) 6 7 7 6 5 4 4 3 2

Dispersion Time (mins) 7 8 8 7 6 3 4 2 2

Wetting Time min) 6 7 7 6 5 4 4 3 2

Drug content (%) 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


568


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

Fig. 1: Dissolution profile of F1-F9.

Bisoprolol fumarate dispersible tablets were prepared by wet granulation method. All the

formulations viz. F1-F9 has shown increased cumulative dissolution profiles as shown in

Table No.4 and Fig. 1.

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


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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 F1 F2 F3 F4 F5 F6 F7 F8 F9

First

order

r 0.9939 0.9872 0.9842 0.9702 0.9745 0.9771 0.9971 0.9978 0.9900

k 0.0369 0.0483 0.0518 0.0553 0.0639 0.0699 0.0969 0.1170 0.1453

Zero

order

r 0.9777 0.9355 0.9100 0.8706 0.8651 0.8518 0.8299 0.7835 0.7160

k 2.4506 2.9042 3.0255 3.1438 3.3616 3.4947 3.8869 4.0778 4.2566

Hixson-

Crowell

r 0.9923 0.9758 0.9674 0.9463 0.9498 0.9498 0.9713 0.9651 0.9431

k 0.0106 0.0134 0.0142 0.0150 0.0168 0.0180 0.0226 0.0255 0.0290

Higuchi r 0.9650 0.9855 0.9915 0.9906 0.9895 0.9892 0.9901 0.9810 0.9643

k 11.3686 13.6717 14.3233 14.9744 16.0227 16.6863 18.6138 19.6182 20.5928

Peppas r 0.9875 0.9850 0.9852 0.9809 0.9792 0.9795 0.9845 0.9735 0.9499

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.


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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. 3: FT-IR spectrum of bisoprolol fumarate.

Fig. 4: FT-IR spectrum of bisoprolol fumarate with Alginic acid.


571


Fig. 5: FT-IR spectrum of bisoprolol fumarate with Calcium carbonate.

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-1

OH (stretching), 1091.77cm-1

(stretching) and

1145.78 cm-1

C-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.


572


Differential Scanning Calorimetry

Temp Cel250.0200.0150.0100.050.00.0

DS

C m

W

0.000

-1.000

-2.000

-3.000

-4.000

-5.000

-6.000

-7.000

-8.000

DD

SC

mW

/min

350.0

300.0

250.0

200.0

150.0

100.0

80.1Cel-1.718mW

102.4Cel-8.163mW

10.5mJ/mg50.9mJ/mg

Fig. 7: DSC of bisoprolol fumarate.

Temp Cel350.0300.0250.0200.0150.0100.050.00.0-50.0-100.0

DS

C m

W

2.000

1.000

0.000

-1.000

-2.000

-3.000

-4.000

-5.000

-6.000

-7.000

-8.000

DD

SC

mW

/min

300.0

280.0

260.0

240.0

220.0

200.0

180.0

160.0

140.0

120.0

100.0

80.0

80.3Cel-1.601mW

101.5Cel-5.651mW

10.9mJ/mg28.8mJ/mg

Fig. 8: DSC of optimized formulation.

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).


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Bioequivalence Studies

Disintegration Time

Table No.6: Bioequivalence studies of Disintegration time.

S. NO Time

(min)

Marketed products

Carvedilol

Prepared dispersible

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.

Table No.7: Bioequivalence studies invitro drug release studies.

S.NO Time

(min)

Marketed products

Carvedilol

Prepared dispersible

tablets (B.F)

1 5 45.39 50.71

2 10 65.62 76.61

3 15 75.36 92.68

4 20 85.25 94.61

5 25 91.25 97.98

6 30 95.52 98.51

Fig. 9: Bioequivalence studies invitro drug release studies.


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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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formulation and evaluation of bisoprolol fumarate …

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