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159| P a g e International Standard Serial Number (ISSN): 2319-8141
Full Text Available On www.ijupbs.com
International Journal of Universal Pharmacy and Bio Sciences 6(3): May-June 2017
INTERNATIONAL JOURNAL OF UNIVERSAL
PHARMACY AND BIO SCIENCES IMPACT FACTOR 2.96***
ICV 6.16***
Pharmaceutical Sciences RESEARCH ARTICLE …………!!!
DESIGN AND DEVELOPMENT OF ZAFIRLUKAST FAST DISSOLVING
TABLET
Dhvani R. Hadula*, Dr. Kanu R. Patel, Dr. Mukesh R. Patel, Dr. Alpesh D. Patel
Shri B. M. Shah College of Pharmaceutical Education and Research, 252
Dhansura Road, Modasa, Dist-Arvalli-383315.
KEYWORDS:
Zafirlukast, Fast
dissolving tablet,
Inclusion complex, β-CD,
Kyron T-314, 32 factorial
design.
For Correspondence:
Dhvani R. Hadula*
Address:
Shri B. M. Shah College
of Pharmaceutical
Education and Research,
252 Dhansura Road,
Modasa, Dist-Arvalli-
383315.
ABSTRACT
The aim of the research work was to formulate inclusion complex of
Zafirlukast with β-CD and to use this complex into the development of
fast dissolving tablets (FDT) for the treatment of Asthma. Inclusion
complex was prepared in different drug: β-CD ratio (1:0, 1:1, 1:2 and
1:3) by using Physical mixture and kneading method. Prepared inclusion
complex was characterized for saturation solubility and In-vitro
dissolution study. Tablet prepared by direct compression method using
different superdisintigrants in different concentration. The formulation
was optimized by 32 full factorial designs by selecting independent
variable. Different Ratio of drug to carriers (Zafirlukast: β-CD) selected
as factor X1 and different concentration of super disintegrants (Kyron-
314) selected as X2. Inclusion complexation of drug: β-CD in the ratio of
1:1 reported highest solubility and In-vitro dissolution in comparison
with other samples. For fast dissolving tablet, results of 32 full factorial
designs presented that batch F8 containing combination of 25mg drug:
β-CD and 5mg Kyron T-314 exhibited minimum disintegration time (16
sec) and wetting time (12 sec) along with maximum water absorption
ratio (98.07 %) and highest drug release (98.76 %) within 30 minute.
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1. INTRODUCTION
The oral route of administration is considered as the most widely accepted route because of its
convenience of self-medication, accurate dose, safest and economical route. Approximately one-
third of the population, primarily the geriatric and pediatric population, has swallowing difficulties,
resulting in poor compliance with oral tablet drug therapy which leads to reduced overall therapy
effectiveness.
This problem led to the development of novel type of dosage form known as fast dissolving tablet,
which rapidly disintegrate and dissolve in saliva. Fast dissolving tablets are ideal for all types of
people, including the people who have swallowing difficulties (dysphasia), pediatric, geriatrics and
bedridden patients. It also use for active patients who are busy, travelling and may not have access
water. Fast dissolving tablets are novel drug delivery system that dissolve or disintegrates in saliva
within few seconds with or without intake of water. The faster the drug dissolve into solution,
quicker the absorption and onset of clinical effect. Some drugs are absorbed from the mouth,
pharynx and esophagus as the saliva passes down into the stomach; in such cases bioavaibility of
drug is increased.
Zafirlukast is used for the prophylaxis and chronic treatment of asthma. Zafirlukast is rapidly
absorbed following oral administration. Peak plasma concentrations are generally achieved 3 hour
after oral administration. It is a BCS class IІ drug low solubility and high permeability. So, fast
dissolving drug delivery increase the dissolution rate, thus increasing the bioavailability of drug.
Zafirlukast has longer half-life so when dosage form is administrated, will give immediate effect.
MATERIALS AND METHODS
Zafirlukast was obtained from Dr. Reddy Laboratories. Beta cyclodextrin was obtained from
Triveni interchem, Pvt. Ltd. Kyron T 314 was obtained from Corel Pharma Chem., Ahmedabad.
Pregelatinized starch was obtained from Stallion laboratories Pvt. Ltd. Croscarmellose sodium and
Mannitol obtained from Lesar chemicals, Ahmedabad. Aspartame obtained from S. D. Fine
chemical Ltd. Microcrystalline cellulose obtained from Alembic Pharmaceutical Ltd. Vadodara.
Magnesium Stearate and Talc obtained from Acme Chemicals, Mumbai.
METHOD:
1. DRUG EXCIPIENT COMPATIBILITY STUDY
Fourier transform infrared spectroscopy has been used to study the physical and chemical
interactions between drug and the superdisintigrants used. Fourier transforms infrared (FTIR)
spectra of Zafirlukast and superdisintigrants were recorded using KBr mixing method on FTIR
instrument.
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2. DETERMINATION OF ABSORPTION MAXIMA (λmax):
UV spectrometric study of Zafirlukast was carried out to identify λmax of drug in 6.8 pH phosphate
buffer. The prepared solution was scanned from 200 to 400 nm in UV spectrophotometer.
Preparation of 6.8 pH Phosphate buffer
Weight accurately 28.80 gm of disodium hydrogen phosphate and 11.45 gm of potassium
dihydrogen phosphate in 1000ml up to distilled water as per IP.
Preparation of Stock Solution
Accurately weighed 10mg of Zafirlukast was transferred into 100ml volumetric flask and dissolved
in 20ml methanol & make up to 100ml with 6.8 pH phosphate buffer to prepare solution of
100µg/ml (stock solution).
Preparation of Different Dilution from Stock Solution
From stock solution, pipette out 0.5ml, 1ml, 1.5ml, 2ml, 2.5ml and 3ml dilute it up to 10ml with 6.8
pH phosphate to get concentration of 5, 10, 15, 20, 25 and 30 µg/ml respectively. The absorbance
of solutions were measured against 6.8 pH phosphate buffer blank at 239nm Wavelength using
double beam UV spectrophotometer.
Figure 1: Calibration curve of Zafirlukast in 6.8 Phosphate buffer
3. Preparation of Zafirlukast Inclusion Complex
A. Preparation of Drug: β-CD inclusion complexation
Selection of method for inclusion complex has been carried out in Preliminary work.
On the basis of information gathered from literature review two different methods
has been selected namely:
1. Physical mixture
2. Kneading method
y = 0.043x + 0.009R² = 0.996
0
0.2
0.4
0.6
0.8
1
1.2
1.4
0 10 20 30 40
Ab
sorb
ance
Cocentration (µg/ml)…
Calibration curve of Zafirlukast in
6.8 phosphate buffer
162 | P a g e International Standard Serial Number (ISSN): 2319-8141
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Physical mixture
In this method drug and β-cyclodextrin (β-CD) in different ratios were mixed and triturated in glass
mortar and pestle for about one hour. The powders were then sifted through sieve no.85 and stored
in desiccator till further use.
Kneading method
Zafirlukast and β-CD were triturated separately at different ratios in a mortar with a small volume
of methanol: water (3:2) solvent blend. The thick slurry was kneaded for 45 min and then the mass
was dried for 24 hrs. The dried product was crushed, pulverised and sieved through 100 mesh. The
complex were kept in desiccator at room temperature until further use.
B. Evaluation of Prepared Inclusion Complex
Saturation solubility studies
Inclusion complex equivalent to 10 mg of drug was added to 10 ml of 6.8 pH phosphate buffer and
mixtures were shaken for 24 hours on magnetic stirrer. After shaking the supernantant was filtered
through whatman filter paper. The filtrate was suitably diluted and analyzed on UV visible
spectrophotometer at 239nm.
In Vitro Dissolution Study of prepared inclusion complex
In vitro dissolution study of inclusion complex was performed as described in Indian
Pharmacopoeia 2010 using USP apparatus II (paddle). Quantity of inclusion complex equivalent to
10 mg of drug was kept in a flask of dissolution apparatus containing 900ml of 6.8 pH phosphate
buffer as a dissolution media maintaining the temperature at 37±0.5ºC and at a speed of 50 rpm.
Aliquot of 10ml dissolution medium was withdrawn at 5 minute time intervals and filter through a
whatman filter paper, diluted and assayed at 239nm against 6.8 pH phosphate buffer as a blank
using UV visible double beam spectrophotometer. The volume of dissolution fluid was adjusted to
900ml by replacing each 10ml aliquot withdrawn with 10ml of fresh 6.8 pH phosphate buffer.
C. Optimization of Ratio of Drug: β-CD Complexation:
On the basis of preliminary screening it was concluded that kneading method showed maximum
solubility enhancement than pure drug. To optimize drug: β-CD ratio, inclusion complex of
different ratios like 1:0, 1:1, 1:2 and 1:3 had been prepared using kneading method.
4. Optimization of variables using 32 full factorial design:
Table 1: Selection of level for independent variable
Coded value X1 (Drug :B-cd) X2 (Kyron T-314)
-1 1:0.5 3
0 1:1 5
1 1:1.5 7
163 | P a g e International Standard Serial Number (ISSN): 2319-8141
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4.1 Formulation of Zafirlukast fast dissolving tablet
Table 2: Formulation of factorial batch Ingredients
Ingredients Formulation( mg)
F1 F2 F3 F4 F5 F6 F7 F8 F9
Inclusion complex
equivalent to 10 mg
Zafirlukast
15 15 15 20 20 20 25 25 25
Kyron T-314 3 5 7 3 5 7 3 5 7
Mannitol 44 42 40 39 37 35 34 32 30
Microcrystaline
cellulose
30 30 30 30 30 30 30 30 30
Aspartame 2 2 2 2 2 2 2 2 2
Magnesium
Stearate
3 3 3 3 3 3 3 3 3
Talc 3 3 3 3 3 3 3 3 3
Total weight of one tablet is 100mg
4.2. Evaluation parameter for fast dissolving tablet
1. Pre-compression
Bulk Density (Db): It is the ratio of total mass of powder to the bulk volume of powder. It was
measured by pouring the weight powder (passed through standard sieve # 20) into a measuring
cylinder and initial weight was noted. This initial volume is called the bulk volume. From this the
bulk density is calculated according to the formula mentioned below. It is expressed in gm/ml and
is given by-
Db = M/ Vb
Where, M is the mass of powder Vb is the bulk volume of the powder.
Tapped Density (Dt): It is the ratio of total mass of the powder to the tapped volume of the
powder. Volume was measured by tapping the powder for 750 times and the tapped volume was
noted if the difference between these two volumes is less than 2%.
If it is more than 2%, tapping is continued for 1250 times and tapped volume was noted. Tapping
was continued until the difference between successive volumes is less than 2 % (in a bulk density
apparatus). It is expressed in gm/ml and is given by
Dt = M / Vt
Where, M is the mass of powder, Vt is the tapped volume of the powder.
Carr’s index (or) % compressibility: It indicates powder flow properties.
I = (Dt – Db)/ Dt *100
164 | P a g e International Standard Serial Number (ISSN): 2319-8141
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Dt is the tapped density of the powder. Db is the bulk density of the powder.
Hausner ratio: Hausner ratio is an indirect index of ease of powder flow.
Hausner ratio = Dt/ Db
Dt is the tapped density. Db is the bulk density.
Table 3: Effect of Carr’s index and Hausner’s ratio on flow property
Flow Character Carr’s Index (%) Hausner’s Ratio
Excellent ≤ 10 1.00-1.11
Good 11-15 1.12-1.18
Fair 16-20 1.19-1.25
Passable 21-25 1.26-1.34
Poor 26-31 1.35-1.45
Very poor 32-37 1.46-1.59
Very, very poor >38 >1.60
Angle of Repose (ɵ): The friction forces in a loose powder can be measured by the angle of repose
(ɵ). It is an indicative of the flow properties of the powder. It is defined as maximum angle possible
between the surface of the pile of powder and the horizontal plane
tan (ɵ) = h / r , ɵ = tan-1
(h / r)
Where, ɵ is the angle of repose. h is the height in cms. r is the radius in cms. The powder mixture
was allowed to flow through the funnel fixed to a stand at definite height (h). The angle of repose
was then calculated by measuring the height and radius of the heap of powder formed. Care was
taken to see that the powder partical slip and roll over each other through the sides of the funnel.
Relationship between angle of repose and powder flow property.
Table 4: Relationship between angle of repose (θ) and flow property
Type of Flow Angle of Repose
Excellent <20
Good 20-30
Passable 30-34
Very poor >35
2. Post-compression:
General Appearance:
The general appearance of a tablet, its visual identity and over all "elegance" is essential for
consumer acceptance and tablet's size, shape, colour, presence or absence of an odour, taste, surface
texture, physical flaws and consistency and legibility of any identifying marking.
Thickness:
Tablet thickness is an important characteristic in reproducing appearance and also in counting by
using filling equipment. Some filling equipment utilizes the uniform thickness of the tablets as a
counting mechanism. Tablets were taken and their thickness was recorded using Vernier calipers.
165 | P a g e International Standard Serial Number (ISSN): 2319-8141
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Weight variation:
10 tablets were selected randomly from the lot and weighted individually to check for weight
variation.
Table 5.: weight variation and accepted % deviation
Average Weight of Tablet % Deviation
80 mg or less 10.0
More than 80 mg but less than 250 mg 7.5
250 mg or more 5.0
Hardness:
Hardness of tablet is defined as the force applied across the diameter of the tablet in the order to
break the tablet. The resistance of the tablet to chipping, abrasion or breakage under condition of
storage transformation and handling before usage depends on its hardness. Hardness of the tablet
should be lesser than conventional tablet falling in the range of 3-4kg/cm². Hardness of the tablet of
each formulation was determined using Monsanto Hardness tester.
Friability (F):
Friability of the tablet determined using Roche friabilator. This device subjects the tablet to the
combined effect of abrasion and shock in a plastic chamber revolving at 25 rpm and dropping a
tablet at height of 6 inches in each revolution. Pre -weighted sample of tablets was placed in the
friabilator and were subjected to the 100 revolutions. Friability should be within the range of 0.1-
0.9%. The friability (F) is given by the formula.
Friability = (I.W – F.W)/I.W × 100
Wetting Time:
Wetting time of dosage form is related to the contact angle. It needs to be assessed to give an
insight into the disintegration properties of the tablets; a lower wetting time implies a quicker
disintegration of the tablet. For this purpose, a tablet is placed on a piece of tissue paper folded
twice and kept in a small Petri dish (ID = 6.5 cm) containing 6 ml of water, and the time for
complete wetting is measured.
Drug Content:
Powder equivalent to 10 mg of drug was weighed and the weighed and added into 100 ml
volumetric flask. Then it was dissolved in 20 ml methanol and further made up volume with 6.8 pH
phosphate buffer. From this solution 1 ml was pipette out into 10ml volumetric flask and finally
volume was prepared to 10 ml with 6.8 pH phosphate buffer. The absorbance was noted down after
filtering of the solution at 239 nm using UV Visible spectrometer.
166 | P a g e International Standard Serial Number (ISSN): 2319-8141
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Water absorption Ratio:
A piece of tissue paper folded twice was placed in a small Petridish containing 6 ml of water. A
tablet was put on the paper & the time required for complete wetting was measured. The wetted
tablet was then weighed. Water absorption ratio, R, was determined using following equation,
R = 100 (wa-wb)/wb
Where, wa is weight of tablet before water absorption & wb is weight of tablet after water
absorption.
Disintegration test:
The time for disintegration of FDTs is generally less than 1 min and actual disintegration time that
patient can experience ranges from 5 to 30s. The disintegration test for FDT should mimic
disintegration in mouth within saliva.
In vitro Dissolution test:
In vitro dissolution study of fast dissolving tablet was performed as described in Indian
Pharmacopoeia 2010 by USP apparatus II at 50 rpm, using 900ml of 6.8 pH phosphate buffer as a
dissolution media maintaining the temperature at 37±0.5ºC. Aliquot of 10ml dissolution medium
was withdrawn at 5 min time intervals and filter through a whatman filter paper, diluted and
assayed at 239nm against 6.8 pH phosphate buffer as a blank using UV visible double beam
spectrophotometer. The volume of dissolution fluid was adjusted to 900ml by replacing each 10ml
aliquot withdrawn with 10ml of fresh 6.8 pH phosphate buffer.
5. RESULT AND DISCUSSION:
Drug excipients compatibility study using FTIR:
.
Figure 2: FTIR spectra of Zafirlukast
450600750900120015001800210027003300390045001/cm
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
105
110%T
3641
.73
3616
.65 30
30.2
7
2868
.24
2837
.38
2727
.44
2588
.56
1919
.24
1714
.77
1641
.48
1456
.30
1259
.56
1226
.77
1199
.76
1161
.19
1136
.11
1085
.96
1037
.74
966.
37
935.
51
875.
71
864.
14
796.
63
zafirlukast2
167 | P a g e International Standard Serial Number (ISSN): 2319-8141
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Figure 3: FTIR spectra of Zafirlukast formulation
FTIR peaks observed Zafirlukast sample, which correlates with the peaks of standard Zafirlukast
was found similar. Compatibility study of Zafirlukast with formulation carried out by FTIR. The
mixture of Zafirlukast with formulation showed that there was not found any kind of interaction
PRELIMINARY WORK
Screening for Selection of Method and Drug: β-CD Ratio of Inclusion Complex:
Preliminary studies were carried out using different drug: β-CD ratio and different methods for
preparation of inclusion complex. The selection was made from two different methods which are
physical mixture and kneading method. Inclusion complex of Zafirlukast was prepared in 1:0, 1:1,
1:2 and 1:3 drug: β-CD ratio. Method was selected from dissolution and solubility studies of
inclusion complex.
Saturation Solubility Studies:
Table 6: Saturation solubility studies
Ratio (Drug: β-CD) Solubility (mg/ml)
Pure drug 1:0 0.02
Physical mixture method 1:1 1.20
1:2 0.89
1:3 0.51
Kneading method 1:1 1.67
1:2 0.94
1:3 0.70
450600750900120015001800210027003300390045001/cm
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
105
110
115
120%T
11
61
.19
10
37
.74
35
8.7
7
39
52
.28
38
38
.47
28
68
.24
27
58
.30
26
29
.06
25
26
.83
23
86
.02
23
18
.51
18
99
.95
18
20
.86 17
26
.35
14
62
.09
12
59
.56
12
40
.27
12
26
.77
12
01
.69
11
59
.26
10
85
.96
10
35
.81
93
7.4
4
87
9.5
7
38
7.7
0
35
4.9
1
zafilukast11zafirlukast2 formulation11
zafirlukast
168 | P a g e International Standard Serial Number (ISSN): 2319-8141
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Figure 4: Saturation Solubility graph of inclusion complex
From the solubility data it was clearly revealed that the solubility of pure drug was 0.02 mg/ml. The
solubility of PM1, PM2 to PM3 showed 1.20, 0.89 and 0.51 mg/ml respectively. While Solubility
of KD1, KD2 to KD3 showed 1.67, 0.94 and 0.70mg/ml respectively. Hence, it can be concluded
that Kneading method with 1:1 Drug: β-CD ratio has improved the solubility of drug when
compared to pure drug and physical mixture.
In vitro Dissolution Study of Prepared Drug: β-CD Complex
Table 7: In vitro dissolution data of Physical mixture and Kneading method
TIME PURE
DRUG(1:0)
PM1
(1:1)
PM2
(1:2)
PM3
(1:3)
KM1
(1:1)
KM2
(1:2)
KM3
(1:3)
0 0 0 0 0 0 0 0
5 2.02 66.74 58.65 54.61 66.74 62.70 58.65
10 4.07 71.53 63.35 61.28 69.51 67.44 61.33
15 6.13 78.38 68.09 66.00 76.34 72.22 64.02
20 8.22 81.26 72.88 70.76 83.24 77.06 70.79
25 9.12 86.18 77.71 75.57 90.20 81.93 77.62
30 10.44 91.15 84.61 78.40 97.24 86.85 80.47
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
Solu
bili
ty(m
g/m
l)
Drug:B-CD ratio
Series1
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Figure 5: In Vitro Dissolution Study of prepared Inclusion complex
From the data it clearly indicated that the drug release from pure drug was up to 10.44%. Drug
release from PM1, PM2 to PM3 gave 91.15%, 84.61% and 78.40% respectively whereas drug
release from KD1, KD2 to KD3 gave 97.24%, 86.85% to 80.47%. Hence, it can be concluded that
kneading method (1:1) ratio improved drug dissolution when compared to pure drug and physical
mixture.
Evaluation Parameter for Fast Dissolving Tablet
Table: 8 Pre-compression parameter of Factorial batch
0
20
40
60
80
100
120
0 10 20 30 40
CP
R (
%)
Time(min)
PURE DRUG(1:0)
PM1(1:1)
PM2(1:2)
PM3(1:3)
KM1(1:1)
KM2(1:2)
KM3(1:3)
Batch
code
Bulk
density
( gm/ml)
Tapped
density
( gm/ml)
Hausner’s
Ratio
Carr’s
Index (%)
Angle of
Repose
F1 0.480±0.01 0.543±0.05 1.13±0.01 11.51±0.77 28.40±0.5
F2 0.523±0.02 0.600±0.02 1.14±0.07 12.78±0.91 29.30±0.3
F3 0.581±0.01 0.675±0.01 1.16±0.01 13.93±0.69 29.66±0.5
F4 0.473±0.01 0.539±0.01 1.14±0.02 12.27±0.34 28.84±0.2
F5 0.510±0.05 0.588±0.02 1.15±0.05 13.23±0.76 27.45±0.7
F6 0.568±0.06 0.661±0.02 1.16±0.03 14.03±0.44 28.34±0.5
F7 0.515±0.01 0.598±0.02 1.15±0.01 13.76±0.45 29.72±0.3
F8 0.600±0.04 0.675±0.01 1.12±0.02 11.18±0.56 27.03±0.4
F9 0.479±0.03 0.562±0.01 1.17±0.03 14.69±0.25 28.70±0.2
Results are the mean of three observation ± SD (n=3)
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Table: 9 Post-compression evaluation parameter of factorial batches
Batch code Disintigration
time(sec)
Wetting
Time (sec)
Drug Content
(%) ±SD, n=3
WAR
(%w/w)
F1 40 33 94.83±0.22 83.67
F2 33 26 95.43±0.34 92.63
F3 44 36 92.05±0.12 75.78
F4 31 23 96.85±0.22 94.68
F5 29 22 94.38±0.22 83.83
F6 58 47 93.25±0.22 80.64
F7 26 20 97.67±0.12 94.84
F8 16 12 99.77±0.22 98.07
F9 37 23 96.77±0.12 81.63
In determinations of tablet weights, according to the IP less than 7.5% weight variation is
acceptable in the tablet formulation having average weight between 80-250 mg. From data given in
Table, all formulations were found to be within IP limits as per weight variation test. Hardness of
tablets was determined and was found to be in the range of 3 - 4 kg/cm 2. Friability values of
formulations were less than 1% was an indication of good mechanical resistance of the tablets. The
uniformity of content was found to be within pharmacopeial limits of 90-110%. All the batches had
disintegration time within less than 3 minutes. Wetting time of Fast dissolving tablet is another
important parameter, which needs to be assessed, to give an insight into the disintegration
properties of the tablet. A lower wetting time implies quicker disintegration of the tablet. From the
wetting time study it was reported that a linear relationship exists between wetting time and
disintegration time. By studying the water absorption ratio, it was reported that as the water
absorption ratio increases, disintegration time decreases. From all the batches evaluated,
Batch
code
Thickness
(mm)
Hardness
(Kg/cm2)
Weight Variation
(mg)*
Friability
(%)
F1 2.6±0.05 3.3±0.10 97.7±1.65 0.70±0.72
F2 2.6±0.05 3.3±0.05 98.0±3.04 0.68±1.51
F3 2.8±0.10 3.4±0.05 97.4±4.77 0.95±0.44
F4 2.7±0.05 3.2±0.10 97.7±4.90 0.78±2.41
F5 2.7±0.05 3.2±0.15 98.2±1.72 0.51±0.48
F6 2.6±0.10 3.5±0.1 96.7±3.4 0.84±0.63
F7 2.8±0.10 3.3±0.05 98.0±2.31 0.66±1.45
F8 2.6±0.10 3.1±0.15 99.0±3.88 0.51±0.44
F9 2.7±0.05 3.4±0.10 97.9±3.73 0.82±0.44
All values are of mean ± SD (n=3) *All values are of mean ± SD (n=20)
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formulation containing F8 (Drug: β-cd): Kyron T-314 (25mg: 5mg) formulation gives good results
i.e. showed minimum disintegration time, minimum wetting time and maximum water absorption
ratio.
Table no. 10 In vitro dissolution study of factorial batches:
Cumulative percentage release
Time
(min)
F1 F2 F3 F4 F5 F6 F7 F8 F9
0 0 0 0 0 0 0 0 0 0
5 34.38 36.40 28.31 40.45 42.47 38.43 44.49 46.52 32.36
10 44.88 46.92 38.74 51.01 51.03 46.94 53.08 57.15 48.90
15 53.46 59.57 49.28 61.69 65.75 59.60 63.78 67.89 59.55
20 64.16 66.29 59.93 72.47 74.56 68.34 78.63 78.74 68.29
25 76.99 79.15 70.70 83.37 85.48 75.15 89.60 89.71 77.12
30 81.87 84.04 77.53 86.29 88.43 77.98 94.61 98.76 84.02
From the dissolution profile of all the batches it was found that there was fast drug release at initial
state of dissolution. The initial rise in the drug release was dependent upon the concentration of
superdisintegrant. From this study it was reported that decrease in the disintegration time showed
faster drug release. Among the nine batches, F8 batch containing combination of 25mg Drug: β-cd
and 5mg Kyron T-134 was selected as optimized batch because of its lowest disintegration time,
minimum wetting time, maximum water absorption ratio and faster drug release within 30 minutes.
Figure 6: In vitro dissolution studies of factorial batches (F1 to F9)
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35
CP
R(%
)
Time (min)
F1
F2
F3
F4
F5
F6
F7
F8
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STATISTICAL ANALYSIS OF FACTORIAL BATCHES
Table 11: Result of dependent variables
Response Surface plot of Dependent Variables:
Figure 7: Response Surface plot of Dt.
Batch
Code
Variable level Disintegration
time (sec)
(Y1)
Wetting
time(sec)
(Y2)
Drug release at
5 min (%)
(Y3)
X1 X2
F1 -1 -1 40 33 34.38
F2 -1 0 33 26 36.4
F3 -1 1 44 36 28.31
F4 0 -1 31 23 40.45
F5 0 0 29 22 42.47
F6 0 1 58 47 38.43
F7 1 -1 26 20 44.49
F8 1 0 16 12 46.52
F9 1 1 37 23 32.36
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Figure 8: Response Surface plot of Wt
Figure 9: Response Surface plot of drug release at 5 min.
RESULT OF ACCELERATED STABILITY STUDY:
The samples of optimized batch (F8) were kept in accelerated condition (40ºC ± 2ºC /75% ±
5%RH) for 25 days. Then samples were analyzed for Physical evaluation, Drug content, Hardness,
Disintegration time, Wetting time and dissolution.
Table 12: Results of tablet parameters of Stability Study
Parameter Initial After 25 day
Hardness (kg/ cm2) 3.1±0.15 2.9±0.18
Friability (% ) 0.51±0.44 0.50±0.46
Disintegration time (sec ) 16 14
Wetting time (sec) 12 10
Drug content (%) 99.77±0.22 98.65±0.51
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Table 13: In-vitro dissolution data of batch F8 after Stability Study
.
Figure 10: In vitro dissolution study of optimized batch F8
before and after stability study
From the results of evaluation of batch F8 after stability study, reveals that there was no significant
difference in to the drug content and in vitro release of drug when compared with the prior results
and the values of similarity factor was 97.37 indicating good similarity of dissolution profile
initially and after stability studies. Hence, the prepared Zafirlukast fast dissolving tablet was found
stable at 40ºC/75% RH.
CONCLUSION
Fast dissolving tablets have started gaining popularity and acceptance as new drug delivery
systems, due to their ease of administration and ultimately better patient compliance. Recent
0
20
40
60
80
100
120
0 10 20 30 40
CPR(Initial)
CPR(After 25 days)
Time (min) CPR
(Initial)
CPR
(After 25 day)
0 0 0
5 46.52 43.21
10 57.15 54.43
15 67.89 64.65
20 78.74 76.18
25 89.71 86.54
30 98.76 95.77
Dissimilarity Factor(ƒ1)=1.14
Similarity Factor(ƒ2 )=97.37
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development in fast dissolving technology mainly works to improve the disintegrating quality of
these delicate dosage forms without affecting their integrity.
Zafirlukast is used to treat asthma. In the present study, fast dissolving tablets of Zafirlukast were
prepared by direct compression method. Inclusion complexation of drug with β-CD was prepared to
improve solubility and dissolution of drug. The complex was prepared using physical mixture and
kneading method. From the above data it was concluded that kneading method (with 1:1 drug: β-
CD ratio) gave quick solubility and drug release when compared to other method. Moreover, to
evaluate that whether the combination of superdisintegrants can give far better results or not, a 32
full factorial design was applied. Kyron T-314 was used in different concentration like (3, 5, 7)
with drug to β-CD ratio of inclusion complex (1:0.5, 1:1, 1:1.5). The concentration of 3 to 5% that
increase dug release & decrease the disintigration time but further concentration of Kyron T-314
increase from 5 to 7% it shows slightly decrease in drug release with increase disintigration time.
So finally it concluded that optimized concentration for Kyron T-314 5%. So from the release study
of factorial batches F8 batch containing 5% Kyron T-314 with drug to β-CD ratio (1:1.5) of
inclusion complex shows higher drug release (98.76%) with less disintigration time (16 sec)
compared to other batches. So, prepared fast dissolving tablet enhance the absorption and increase
the bioavaibility of Zafirlukast.
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