DESIGN AND DEVELOPMENT OF ZAFIRLUKAST …. RPA16172434016.pdfTriveni interchem, Pvt. Ltd. Kyron T 314 was obtained from Corel Pharma Chem., Ahmedabad. Pregelatinized starch was obtained

159| P a g e International Standard Serial Number (ISSN): 2319-8141

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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.

160 | P a g e International Standard Serial Number (ISSN): 2319-8141


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.



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



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



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



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.



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.



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



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



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



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)



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)



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



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



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



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



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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Documents

DESIGN AND DEVELOPMENT OF ZAFIRLUKAST …. RPA16172434016.pdfTriveni interchem, Pvt. Ltd. Kyron T 314 was obtained from Corel Pharma Chem., Ahmedabad. Pregelatinized starch was obtained