5.EXPERIMENTAL RESULTS Montelukast Sodium …shodhganga.inflibnet.ac.in/bitstream/10603/8378/12/13_chapter 5.pdf · 5.2.1 Solubility Studies of Montelukast Sodium ... Levocetirizine

5.EXPERIMENTAL RESULTS

5.1 Development of Analytical Methods

5.1.1 Analytical method for Estimation of Montelukast Sodium

Table 5.1: Calibration curve for the estimation of Montelukast Sodium in water with 0.5% Sodiumlauryl suphate

Montelukast SodiumConcentration (µg/ml)

Absorbance(350 nm)

5

7.5

10

12.5

15

0.190

0.286

0.384

0.480

0.580

Figure 5.1: Calibration curve for the estimation of Montelukast Sodium in water containing 0.5%

Sodium lauryl suphate.

5.1.2 Analytical method for Estimation of Levoceterizine dihydrochloride

Table 5.2: Calibration curve for the estimation of Levoceterizine dihydrochloride in water with 0.5%

Sodium lauryl suphate

y = 0.038x - 0.002R² = 0.999

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16A

bsor

banc

e

Conc (µg/ml)

LevoceterizinedihydrochlorideConc (µg/ml)

Absorbance

(231 nm)

2 0.076

4 0.160

Fig. 5.2: Calibration curve for the estimation of Levoceterizine dihydrochloride in water with 0.5%


y = 0.037x + 0.003R² = 0.998

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0 2 4 6 8 10 12

Abs

orba

nce

Conc (µg/ml)

6 0.226

8 0.304

10 0.371

5.1.3 Analytical method for Estimation of Zafirlukast

Table 5.3: Calibration curve for the estimation of Zafirlukast in water with 1.0% Sodium lauryl suphate

Figure 5.3: Calibration curve for the estimation of Zafirlukast in water with 1.0% Sodium lauryl

suphate

Zafirlukast

Conc (µg/ml)

Absorbance

(238nm)

2 0.159

4 0.320

6 0.478

8 0.641

10 0.798

5.2 Solubility Studies

5.2.1 Solubility Studies of Montelukast Sodium

Table 5.4 Solubility studies of Montelukast Sodium

y = 0.079x - 0.000R² = 1

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

0 1 2 3 4 5 6 7 8 9 10 11 12

Abs

orba

nce

Conc (µg/ml)

Solvent Solubility (mg/ml)Water 0.15

Methanol 0.70pH 1.2 HCl 0.50

pH 3 Glycine buffer 0.53pH 4.5 Acetic acid buffer 0.33pH 6.8 Phosphate buffer 0.25pH 7.4 Phosphate buffer 0.47

5.2.2. Solubility studies of Levocetirizine Dihydrochloride

Table 5.5 Solubility studies of Levocetirizine Dihydrochloride

5.2. 3 Solubility studies of Zafirlukast

Table 5.6 Solubility studies of Zafirlukast

Solvent Solubility (mg/ml)

pH 9.2 Alkaline borate buffer 0.54Water with 0.5%SLS 0.96

Solvent Solubility (mg/ml)0.001N HCl 0.75

0.1N HCl 0.94

pH 4.5 Acetate buffer 0.60

pH 6.2 Phosphate buffer 0.59



Water 0.92

Water with 0.5%SLS 0.99

Water 0.007pH 1.2 HCl 0.45

pH 3.0 Glycine buffer 0.49pH 4.5 Acetic acid buffer 0.38pH 6.8 Phosphate buffer 0.42pH 7.4 Phosphate buffer 0.47

pH 9.2 Alkaline borate buffer 0.681.0% Sodium lauryl sulfate in water 0.92

5.3 Preformulation studies

5.3.1 Preformulation studies Montelukast Sodium

Table 5.7 Sieve analysis of Montelukast Sodium Bulk Drug

Name of Drug Montelukast sodium

Amplitude 60

Time 5 min

Weight of sample taken in (g) 40.0

Sieve No. Initial Wt.(gm) Final Wt.(gm) Sample retained % Retained Cumm. %retained

40 183.69 190.64 6.95 17.38 17.3860 169.9 185.9 16 40.00 57.38

80 174.85 179.6 4.75 11.88 69.25100 174.73 184.62 9.89 24.73 93.98120 173.82 175.66 1.84 4.60 98.58

Fines collector 137.03 137.36 0.33 0.83 99.40Total 39.76 99.40 99.40

Table 5.8 : Illustration of all the physico - chemical characterization of Montelukast sodium

Parameter Result

Bulk density 0.59gm/mlTapped density 0.73gm/mlCompressibility Index 19%Angle of repose 36ºHauser’s ratio 1.22

5.3.2 Preformulation studies of Levocetirizine Dihydrochloride

Table 5.9 Sieve analysis of Levocetirizine Dihydrochloride Bulk Drug

Name of Drug Levocitirizine di hydrochloride

Amplitude 60

Time 5 min

Weight of sample taken in(g) 10.0

Sieve No. InitialWt.(gm)

FinalWt.(gm)

Sampleretained

%Retained

Cumm. %retained

40 190.75 191.5 0.75 7.50 30.4060 180.63 182.36 1.73 17.30 47.7080 176.93 178.22 1.29 12.90 60.60100 174.37 175.03 0.66 6.60 67.20120 173.8 176.3 2.5 25.00 78.10

fines collector 137.03 137.81 9.78 97.80 97.80Total 9.78 97.80 97.80

Table 5.10 : Illustration of all the physico - chemical characterization of Levocitirizine di

hydrochloride

Parameter Result

Bulk density 0.49gm/ml

Tapped density 0.71gm/ml

Compressibility Index 21%

Angle of repose 34º

Hauser’s ratio 1.20

5.3.3 Preformulation studies Zafirlukast

Table 5.11 Sieve analysis of Zafirlukast Bulk Drug

Name of Drug Zafirlukast

Table 5.12 : Illustration of

all the physico -

chemical

characterization of Zafirlukast

Parameter Result





Amplitude 60

Time 5 min


Sieve No. Initial Wt.(gm) FinalWt.(gm)

Sampleretained

%Retained

Cumm. %retained

40 190.75 191.5 0.75 7.50 30.4060 180.63 182.56 1.93 19.30 49.7080 176.93 178.22 1.29 12.90 62.60100 174.37 175.03 0.66 6.60 69.20120 173.8 176.3 2.5 25.00 80.10fines

collector 137.03 137.81 9.98 99.80 99.80

Total 9.98 99.80 99.80


5.4. Drug – Excipient interaction study

Table 5.13 : Description of Drug – Excipient compatibility study

Ingredient Initial description Finaldescription

Montelukast sodium (D) White to off whitepowder No change

MS + Di calciumphosphate(1:5) White fine powder No change

MS + Lactose anhydrous (1:5) White fine powder No changeMS + Cross povidone (1:1) Off white fine powder No changeMS + Ac-di-sol (1:1) Off white fine powder No changeMS + β- CD (1:1) Off white fine powder No change

MS + SSG (1:1) White fine powder No change

MS + Pearlitol 200 (1:5) White fluffy crystals No changeMS + Acesulfame potassium(1:1) White fine powder No change

MS + Peppermint flavor (1:1) White fine powder No changeMS + aspartame (1:1) White fine powder No changeMS + Colloidal silicondioxide(1:1) White fine powder No change

MS + Magnesium stearate White fine powder No changeLevocetirizine Dihydrochloride White fine powder No changeLCH+Kyron 104 (1:1) White fine powder No changeLCH+Kyron 114(1:1) White fine powder No changeLCH+ Cross povidone(1:1) Off white fine powder No changeLCH+ Lactose anhydrous (1:5) White fine powder No changeLCH+ Mg.Sterate(1:1) White fine powder No changeZafirlukast White fine powder No changeZk + γ -cd (1:1) White fine powder No changeZk + Lactose Anhydrous (1:5) White fine powder No changeZk + Kyron T314 (1:1) White fine powder No changeZk + Citric acid (1:1) White fine powder No changeZk + Sodium bicarbonate(1:1) White fine powder No changeZk +Tartaric acid (1:1) White fine powder No changeZk +Malic acid (1:1) White fine powder No changeZk +Talc (1:1) White fine powder No changeZk +Magnesium stearate White fine powder No changeZk + Xanthan gum(1:3) White fine powder No changeZk + TSP(1:3) White fine powder No changeZk + HPC(1:3) White fine powder No changeZk + EC T-10(1:3) White fine powder No changeZk + Mannitol (1:5) White fine powder No change

ZK + aspartame (1:1) White fine powder No changeZK + strawberry (1:1) White fine powder No change

Table 5.14 : Drug content estimation

IngredientDrug content (%)

Initial After 15 days After 30 days

Montelukast sodium (MS) 99 ± 0.24 98 ± 0.59 98 ± 0.68MS+Di calcium phosphate(1:5) 96 ± 0.58 96 ± 0.56 96 ± 0.56MS + Lactose anhydrous (1:5) 98 ± 0.59 98 ± 0.58 98± 0.58MS + Cross povidone (1:1) 97 ± 0.54 96 ± 0.56 97± 0.68MS + Ac-di-sol (1:1) 98 ± 0.26 98 ± 0.28 98 ± 0.59MS + β-cd (1:1) 97 ± 0.54 97 ± 0.65 96 ± 0.54MS + SSG (1:1) 97± 0.26 96 ± 0.58 96 ± 0.65MS + Pearlitol 200 (1:5) 98 ± 0.59 98 ± 0.78 98± 0.88MS+Acesulfamepotassium(1:1) 98 ± 0.79 98 ± 0.58 99± 0.48MS + Peppermint flavor (1:1) 98 ± 0.59 98 ± 0.18 98± 0.28MS + aspartame (1:1) 99 ± 0.26 99 ± 0.28 98 ± 0.79MS+Colloidalsilicondioxide(1:1) 99 ± 0.26 99 ± 0.28 98 ± 0.79MS + Magnesium stearate(1:1) 99 ± 0.24 98 ± 0.59 98 ± 0.68Levocetirizine Dihydrochloride(LCH) 98 ± 0.79 98 ± 0.58 99± 0.48

LCH+Kyron 104 (1:1) 98 ± 0.59 98 ± 0.58 98± 0.58LCH+Kyron 114(1:1) 97 ± 0.54 96 ± 0.56 97± 0.68LCH+ Cross povidone(1:1) 98 ± 0.26 98 ± 0.28 98 ± 0.59LCH+ Lactose anhydrous(1:5) 97 ± 0.54 97 ± 0.65 96 ± 0.54LCH+ Mg.Sterate(1:1) 98 ± 0.59 98 ± 0.58 98± 0.58Zafirlukast (Zk) 97 ± 0.54 96 ± 0.56 97± 0.68

Zk + γ -cd (1:1) 98 ± 0.59 98 ± 0.78 98± 0.88Zk + Lactose Anhydrous (1:5) 98 ± 0.79 98 ± 0.58 99± 0.48Zk + Kyron T314 (1:1) 98 ± 0.59 98 ± 0.18 98± 0.28Zk + Citric acid (1:1) 99 ± 0.26 99 ± 0.28 98 ± 0.79Zk + Sodium bicarbonate(1:1) 99 ± 0.26 99 ± 0.28 98 ± 0.79Zk +Tartaric acid (1:1) 99 ± 0.24 98 ± 0.59 98 ± 0.68Zk +Malic acid (1:1) 99 ± 0.24 98 ± 0.59 98 ± 0.68Zk +Talc (1:1) 96 ± 0.58 96 ± 0.56 96 ± 0.56Zk +Magnesium stearate 98 ± 0.59 98 ± 0.58 98± 0.58Zk + Xanthan gum(1:3) 97 ± 0.54 96 ± 0.56 97± 0.68Zk + TSP(1:3) 98 ± 0.26 98 ± 0.28 98 ± 0.59Zk + HPC(1:3) 97 ± 0.54 97 ± 0.65 96 ± 0.54Zk + EC T-10(1:3) 97± 0.26 96 ± 0.58 96 ± 0.65Zk + Mannitol (1:5) 99 ± 0.24 98 ± 0.59 98 ± 0.68ZK + aspartame (1:1) 96 ± 0.58 96 ± 0.56 96 ± 0.56ZK + strawberry (1:1) 99 ± 0.54 98 ± 0.50 98 ± 0.68

5.5 Preparation of Inclusion Complexes of Montelukast sodium with β CyclodextrinTable5.15: Montelukast sodium with β-cyclodextin in different ratios

Ingredients(mg) Control A(1:0.5) B(1:0.75) C(1:1) D(1:2) E (1:3)

Montelukast sodium 10.4 10.4 10.4 10.4 10.4 10.4

β-cyclodextin -- 5.2 7.8 10.4 20.8 31.2

Total 10.4 15.6 18.2 20.8 31.2 41.6

5.5.1 Compatibility analysis:

Characterization of Montelukast Sodium- β-cyclodextrin Kneaded complexes: FTIR, DSC and XRD

studies were performed to detect the possible molecular interaction between Montelukast sodium and beta

cyclodextrin. The FTIR, DSC and XRD spectrums of Montelukast sodium and β-cyclodextrin individual

samples as well as kneaded system in 1:1 ratio were shown in Figures 5.4 -5.12.

Fourier transform infra-red spectroscopy:

Fig 5.4 : FTIR of Montelukast Sodium

(a)Montelukast Sodium pure drug; (b)β-cyclodextrin; (c)Montelukast sodium and β-cyclodextrin complex (1:1)

Differential Scanning Calorimeter (DSC):

Differential scanning calorimetry of Montelukast Sodium:

DSC Thermograms:

Fig 5.5 : DSC of Montelukast Sodium

(a)Montelukast Sodium pure drug; (b) β-cyclodextrin; (c) Montelukast sodium- β-cyclodextrin complex (1:1)



DSC Thermograms:





DSC Thermograms:



X-ray Diffractometry (XRD):

Fig 5.6: XRD of Montelukast Sodium

(a)Montelukast Sodium pure drug; (b)β-cyclodextrin; (c)Montelukast sodium- β-cyclodextrin complex (1:1)







5.5.2 Determination of drug content in the complexes of Montelukast Sodium with β-CD:

Table 5.16: Drug content in the complexes of Montelukast Sodium and β-CD

Drug : β-CD (Inclusioncomplex)

Drug content inpercentage (%)

1:0.5 97

1:0.75 98

1:1 100

1:2 98.5

1:3 99

5.5.3 In-vitro drug release:

Table 5.17: Dissolution profile of the three ratio complexes and

Montelukast Sodium (pure drug)

Time(min)

% Drug released of Drug : β-CD (Inclusion complex)Control A(1:0.5) B(1:0.75) C(1:1) D(1:2) E(1:3)

5 21±0.07 62±0.12 70±0.15 77±0.71 75±0.63 76±0.17

10 35±0.10 69±0.39 76±0.77 80±0.49 78±0.52 79±0.19

15 50±0.35 73±0.49 81±0.69 85±0.35 83±0.15 84±0.32

20 58±0.49 78±0.13 85±0.33 93±0.32 91±0.29 92±0.22

30 68±0.52 81±0.66 90±0.22 100±0.19 98±0.31 99±0.16

45 91±0.11 93±0.76 94±0.14 100±0.16 98±0.41 99±0.19

Fig. 5.7 Dissolution profile of the Inclusion complexes and


(n=3, Error bars indicate standard deviation)

5.5.4 Taste evaluation of Montelukast Sodium and β-CD complexes:

Table 5.18 : Rating for Taste evaluation

RatingInitial taste After taste

Mouth feel OverallacceptabilityBitterness Bitterness

1 Extremely Bitter Extremely bitter Very gritty Worst

2 Highly bitter Highly bitter Gritty Poor

0102030405060708090

100110

0 5 10 15 20 25 30 35 40 45

Cum

. % D

rug

diss

olve

d

Time (min)

Control

A(1:0.5)B(1:0.75)C (1:1)

3 Acceptable/Tolerable Acceptable/Tolerable Acceptable Acceptable

4 Very slightly bitter Very slightly bitter Creamy Good

5Not at all bitter

Not at all bitter Very creamy

Very good

(GoodPalatability)

Table 5.19: Taste evaluation of Inclusion complexes

Formulationcode

Vol

unte

er1

Vol

unte

er 2

Vol

unte

er 3

Vol

unte

er 4

Vol

unte

er 5

Overall

acceptability

Control 1 1 1 1 1 Worst

A(1:0.5) 3 2 2 2 2 Poor

B(1:0.75) 3 2 3 3 3 Acceptable

C(1:1) 5 5 4 5 5 Good Palatability

D(1:2) 5 5 4 5 5 Good Palatability

E(1:3) 5 4 5 5 5 Good Palatability

5.6 Preparation and Evaluation of Taste Masked complexes of Levocetirizine Di Hydrochloride – Resin(Kyron - T114) complexes:5.6.1 Selection of Resin

Adsorbate preparation:

Complexation between the drug and resin is essentially a process of diffusion of ions between the resin and

surrounding drug solution.

Table 5.20: Selection of Resin

Resin Resin : Drug Percentage of drug boundto Resin

Kyron T 104 1:1 49.6

Kyron T 114 1:1 65.7

5.6.2 Effect of Resin Activation

Table 5.21: Effect of Resin Activation

Form of Resin Drug: Resin (%)Drug loading efficiency

Acid-activated resin 1:1 45.32

Alkali-activated resin 1:1 62.74

Without activation 1:1 77.36

5.6.3 Effect of Levocetirizine - Kyron T - 114 ratio on loading

Table 5.22: Effect of Drug: Resin ratio on drug loading

Resin Drug :Resin % of drug bound to Resin

Kyron T 114

1:1 65.711:1.5 73.331:2 78.62

1:2.5 80.121:3 82.51

5.6.4 Effect of volume of Distilled water on drug loading

Table 5.23: Effect of volume of Distilled water on drug loading

Resin Drug:Resin ratio Volume % of drug bound to Resin

KyronT 114

1:310 ml 91.1125 ml 96.2440 ml 88.12

60 ml 85.3475 ml 75.21

5.6.5 Effect of Kyron T-114 pH on Drug loading

Table 5.24 : Effect of Kyron T-114 pH on Drug loading

Resin Ratio pH % of Drug bound to Resin

Kyron T 114 1:3

2 83.13 85.34 87.6

4.5 89.25 93.5

5.5 96.96 94.2

7.5 93.88 88.3

Fig 5.8 Effect of Kyron T-114 pH on Drug Loading


5.6.6 Effect of Temperature on Drug loading

Table 5.25: Effect of Temperature on Drug loading

Resin Ratio Temperature(0C) % of Drug bound to Resin

Kyron T 114 1:3

27 96.79±0.2540 96.5±0.3750 96.2±0.2160 95.6±0.3770 95.2±0.7980 95.0±0.72

Fig 5.9: Effect of Temperature on Drug loading


0

20

40

60

80

100

120

0 2 4 6 8 10C

um. %

Dru

g bo

und

toR

esin

pH

5.6.7 Effect of soaking time of Resin on drug loading

Table 5.26: Effect of soaking time of Resin on drug loading

Resin Ratio Soaking time(min) % of drug bound to resin

KyronT 114

1:3

0 73.1±0.2210 78.3±0.2520 82.8±0.3430 91.3±0.2760 91.1±0.4290 91.0±0.52

Fig 5.10: Effect of soaking time of Resin on drug loading

0102030405060708090

100110

0 10 20 30 40 50 60 70 80 90

Cum

. % D

rug

boun

d to

Res

in

Temperature (0C)


5.6.8 Effect of Stirring time on drug loading

Table 5.27: Effect of Stirring time on drug loading

Resin Ratio Stirring time(min) % of drug bound to resin

30 60.4±0.41

60 67.3±0.39

0

20

40

60

80

100

0 10 20 30 40 50 60 70 80 90 100

Cum

. % D

rug

boun

d to

Res

in

Soaking time (min)

Kyron T 114 1:3

90 72.5±0.27

120 81.2±0.16

150 83.6±0.10

180 88.4±0.09

210 91.8±0.52

240 97.1±0.69

300 97.0±0.12

Fig 5.11: Effect of Stirring time on drug loading


5.6.9 Molecular properties of drug resin complexCharacterization of Levocetirizine-Kyron T114 complex:Fourier Transform Infra-red Spectroscopy (FTIR):

Fig 5.12: FT- IR spectra of Levocetirizine

(a) Levocetirizine pure drug; (b) Kyron T114; (c)DRC

0

20

40

60

80

100

120

0 50 100 150 200 250 300 350C

um. %

Dru

g bo

und

toR

esin

Stirring time (min)

5.6.10 Estimation of drug content from DRC in 0.1N HCl

Table 5.28 Estimation of drug content from DRC in 0.1N HCl

Medium Drug Content (%)

0.1 N HCl 96.47

5.6.11 In-vitro dissolution study of Drug release from DRCIn vitro release of Levocetirizine from the Drug-Resin complex in 0.1N HCl

Table 5.29: In vitro release of Levocetirizine from the Drug-Resin complex in 0.1N HCl




0.1 N HCl 96.47






0.1 N HCl 96.47



Time(min) % cumulative drug release5 52.41±1.4010 75.24±0.3215 86.64±0.1430 99.78±0.78

Fig 5.13 : Invitro release of Levocetirizine from the Drug-Resin complex in 0.1N HCl


5.6.12 Taste evaluation

Table 5.30: Bitterness evaluation by Taste panel

0102030405060708090

100110

0 5 10 15 20 25 30 35

Cum

. % D

rug

rele

ased

Time (min)

Formulation Volunteer Overall performance1 2 3 4 5 6

Pure drug 4.0 4.0 4.0 4.0 4.0 4.0 BitterDRC 1.0 0.0 0.0 1.0 1.0 0.0 Good palatability

0=tasteless, 1=acceptable bitterness, 2=slight bitterness, 3=moderately bitterness and 4=strong bitterness

5.7 Preparation and Evaluation Inclusion Complexes of Zafirlukast with γ- cyclodextrin

5.7.1 Phase solubility studies:

Table 5.31: Phase solubility of Zafirlukast in aqueous γ -cyclodextrin solution

Molar conc of γ- CD Absorbance (238 nm)0.002 0.0280.004 0.0440.006 0.0580.008 0.0720.01 0.089

control 0.007

Fig 5.14 : Phase solubility diagram of Zafirlukast

in aqueous γ -cyclodextrin solution

5.7.2 Preparation of Inclusion complex of Zafirlukast withγ – Cyclodextrin and Drug content analysis:

Table 5.32: Drug content of prepared Zafirlukast Inclusion complexes

5.7.3 In vitro dissolutionstudies:

Table 5.33(a) CumulativePercent Drug Released data of

Zafirlukast from Inclusioncomplexes in 1.0% Sodium lauryl sulfate in water

Time(min)

Puredrug

Physical mixtures Solvent evaporation Kneading mixturePM1 PM2 PM3 SE1 SE2 SE3 KM1 KM2 KM3

5 2±0.35 4.4±0.13 4.7±0.05 9.2±0.26 10.1±0.22 20.6±0.16 22.7±0.37 25.2±0.29 30.9±0.42 32±0.31

y = 0.007x + 0.01R² = 0.995

0

0.02

0.04

0.06

0.08

0.1

0 2 4 6 8 10 12Solu

bilit

y of

Zaf

irlu

kast

Conc of Gamma Cd (mM)

Zafirlukast: γ -CD Ratio Formulation code % drug Content

Physical Mixture1:0.51:0.75

1:1

PM1PM2PM3

97.2±1.0699.6±0.0896.9±0.03

Solvent evaporationmethod

1:0.51:0.75

1:1

SE1SE2SE3

99.5±0.0598.3±0.0595.0±0.07

Kneading method1:0.51:0.75

1:1

KM1KM2KM3

96.1±0.0498.4±0.0899.1±0.09

10 4.0±0.59 8.4±0.68 8.6±0.71 19.3±0.64 22.2±0.41 42±0.38 44.1±0.83 50±0.25 61.4±0.22 63±0.16

20 8.1±0.58 12±0.13 14±0.96 21.1±0.15 28.3±0.28 49.2±0.69 49.9±0.75 56.9±0.68 62.1±0.26 68.6±0.37

30 11.3±0.22 22±0.66 24.2±0.63 26.2±0.49 47±0.77 51.9±0.01 70.6±0.49 72.8±0.31 74.8±0.38 82±0.83

45 15.4±0.84 27.1±0.47 30.4±0.31 41.8±0.09 54.6±0.49 69.5±0.93 71.5±0.28 75.1±0.17 77.1±0.52 88.6±0.69

60 18.8±0.51 34.2±0.18 38.7±0.49 43.4±0.63 60.9±0.71 73±0.59 76.1±0.73 78.2±1.03 81±0.47 99±0.15

Table 5.33(b) ANOVA Table % DRUG RELEASED AFTER 60 min.Pure drug PM 1:1 SE 1:1 KM1:1

18 43 76 9920 45 78 10116 41 74 97

One-way analysis of varianceP value < 0.0001P value summary ***Are means signif. different? (P < 0.05) YesNumber of groups 4F 956.5R square 0.9972

ANOVA Table SS df MSTreatment (between columns) 11478 3 3826Residual (within columns) 32.00 8 4.000Total 11510 11

Dunnett's Multiple Comparison Test Mean Diff. q Significant? P < 0.05? Summarypure drug vs PM 1:1 -25.00 15.31 Yes ***pure drug vs SE 1:1 -58.00 35.52 Yes ***pure drug vs KM 1:1 -81.00 49.60 Yes ***

Fig 5.15 : Cumulative Percent Drug Release of Zafirlukast from Inclusion complexes(n=3, Error bars indicate standard deviation)


Characterization of Zafirlukast and γ-CD inclusion complex:


Fig 5.16 : FTIR Spectra of Zafirlukast

(a) Zafirlukast; (b) γ –cd; (c) Zafirlukast - γ cd (1:1) complex.

0102030405060708090

100110

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70C

um. %

Dru

g re

leas

ed

Time (min)

Pure Drug

PM - 1

PM - 2

PM - 3

SE - 1

SE - 2

SE - 3

KM - 1

Differential scanning calorimetry of Zafirlukast:

Fig 5.17: DSC thermogram of Zafirlukast

(a) Zafirlukast; (b) γ –CD; (c) Zafirlukast: γ- CD (1:1) complex.

5.8. Development of Orally Disintegrating Tablets

Development of Orally Disintegrating Tablets of Montelukast sodium

A basic formula for orally disintegrating tablets of Montelukast sodium was developed based on the literature

and preliminary experimental work, consisting of Pearlitol 200, Acesulfame potassium, Primojel and

Peppermint flavor.

5.8.1. Optimization of Diluents:

Table 5.34: Evaluation of directly compressible blends

Parameter Formulation CodeD1 D2





Peppermint flavor.








Peppermint flavor.




Angle of repose(◦ ) 34 29Bulk density (g/ml) 0.58 0.56Tapped density (g/ml) 0.71 0.68% compressibility 19 15Haussner’s ratio 1.22 1.18low ability Good Good

5.EXPERIMENTAL RESULTS

5.1 Development of Analytical Methods

5.1.1 Analytical method for Estimation of Montelukast Sodium

Table 5.1: Calibration curve for the estimation of Montelukast Sodium in water with 0.5% Sodiumlauryl suphate

Montelukast SodiumConcentration (µg/ml)

Absorbance(350 nm)

5

7.5

10

12.5

15

0.190

0.286

0.384

0.480

0.580

Figure 5.1: Calibration curve for the estimation of Montelukast Sodium in water containing 0.5%

Sodium lauryl suphate.

5.1.2 Analytical method for Estimation of Levoceterizine dihydrochloride

Table 5.2: Calibration curve for the estimation of Levoceterizine dihydrochloride in water with 0.5%


y = 0.038x - 0.002R² = 0.999

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16A

bsor

banc

e

Conc (µg/ml)

LevoceterizinedihydrochlorideConc (µg/ml)

Absorbance

(231 nm)

2 0.076

4 0.160

Fig. 5.2: Calibration curve for the estimation of Levoceterizine dihydrochloride in water with 0.5%


y = 0.037x + 0.003R² = 0.998

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0 2 4 6 8 10 12

Abs

orba

nce

Conc (µg/ml)

6 0.226

8 0.304

10 0.371

5.1.3 Analytical method for Estimation of Zafirlukast

Table 5.3: Calibration curve for the estimation of Zafirlukast in water with 1.0% Sodium lauryl suphate

Figure 5.3: Calibration curve for the estimation of Zafirlukast in water with 1.0% Sodium lauryl

suphate

Zafirlukast

Conc (µg/ml)

Absorbance

(238nm)

2 0.159

4 0.320

6 0.478

8 0.641

10 0.798

5.2 Solubility Studies

5.2.1 Solubility Studies of Montelukast Sodium

Table 5.4 Solubility studies of Montelukast Sodium

y = 0.079x - 0.000R² = 1

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

0 1 2 3 4 5 6 7 8 9 10 11 12

Abs

orba

nce

Conc (µg/ml)

Solvent Solubility (mg/ml)Water 0.15

Methanol 0.70pH 1.2 HCl 0.50

pH 3 Glycine buffer 0.53pH 4.5 Acetic acid buffer 0.33pH 6.8 Phosphate buffer 0.25pH 7.4 Phosphate buffer 0.47

5.2.2. Solubility studies of Levocetirizine Dihydrochloride

Table 5.5 Solubility studies of Levocetirizine Dihydrochloride

5.2. 3 Solubility studies of Zafirlukast

Table 5.6 Solubility studies of Zafirlukast

Solvent Solubility (mg/ml)

pH 9.2 Alkaline borate buffer 0.54Water with 0.5%SLS 0.96

Solvent Solubility (mg/ml)0.001N HCl 0.75

0.1N HCl 0.94

pH 4.5 Acetate buffer 0.60




Water 0.92

Water with 0.5%SLS 0.99

Water 0.007pH 1.2 HCl 0.45

pH 3.0 Glycine buffer 0.49pH 4.5 Acetic acid buffer 0.38pH 6.8 Phosphate buffer 0.42pH 7.4 Phosphate buffer 0.47

pH 9.2 Alkaline borate buffer 0.681.0% Sodium lauryl sulfate in water 0.92

5.3 Preformulation studies

5.3.1 Preformulation studies Montelukast Sodium

Table 5.7 Sieve analysis of Montelukast Sodium Bulk Drug

Name of Drug Montelukast sodium

Amplitude 60

Time 5 min


Sieve No. Initial Wt.(gm) Final Wt.(gm) Sample retained % Retained Cumm. %retained

40 183.69 190.64 6.95 17.38 17.3860 169.9 185.9 16 40.00 57.38

80 174.85 179.6 4.75 11.88 69.25100 174.73 184.62 9.89 24.73 93.98120 173.82 175.66 1.84 4.60 98.58

Fines collector 137.03 137.36 0.33 0.83 99.40Total 39.76 99.40 99.40

Table 5.8 : Illustration of all the physico - chemical characterization of Montelukast sodium

Parameter Result

Bulk density 0.59gm/mlTapped density 0.73gm/mlCompressibility Index 19%Angle of repose 36ºHauser’s ratio 1.22

5.3.2 Preformulation studies of Levocetirizine Dihydrochloride

Table 5.9 Sieve analysis of Levocetirizine Dihydrochloride Bulk Drug

Name of Drug Levocitirizine di hydrochloride

Amplitude 60

Time 5 min

Weight of sample taken in(g) 10.0

Sieve No. InitialWt.(gm)

FinalWt.(gm)

Sampleretained

%Retained

Cumm. %retained

40 190.75 191.5 0.75 7.50 30.4060 180.63 182.36 1.73 17.30 47.7080 176.93 178.22 1.29 12.90 60.60100 174.37 175.03 0.66 6.60 67.20120 173.8 176.3 2.5 25.00 78.10

fines collector 137.03 137.81 9.78 97.80 97.80Total 9.78 97.80 97.80

Table 5.10 : Illustration of all the physico - chemical characterization of Levocitirizine di

hydrochloride

Parameter Result






5.3.3 Preformulation studies Zafirlukast

Table 5.11 Sieve analysis of Zafirlukast Bulk Drug

Name of Drug Zafirlukast

Table 5.12 : Illustration of

all the physico -

chemical

characterization of Zafirlukast

Parameter Result





Amplitude 60

Time 5 min


Sieve No. Initial Wt.(gm) FinalWt.(gm)

Sampleretained

%Retained

Cumm. %retained

40 190.75 191.5 0.75 7.50 30.4060 180.63 182.56 1.93 19.30 49.7080 176.93 178.22 1.29 12.90 62.60100 174.37 175.03 0.66 6.60 69.20120 173.8 176.3 2.5 25.00 80.10fines

collector 137.03 137.81 9.98 99.80 99.80

Total 9.98 99.80 99.80


5.4. Drug – Excipient interaction study

Table 5.13 : Description of Drug – Excipient compatibility study

Ingredient Initial description Finaldescription

Montelukast sodium (D) White to off whitepowder No change

MS + Di calciumphosphate(1:5) White fine powder No change

MS + Lactose anhydrous (1:5) White fine powder No changeMS + Cross povidone (1:1) Off white fine powder No changeMS + Ac-di-sol (1:1) Off white fine powder No changeMS + β- CD (1:1) Off white fine powder No change

MS + SSG (1:1) White fine powder No change

MS + Pearlitol 200 (1:5) White fluffy crystals No changeMS + Acesulfame potassium(1:1) White fine powder No change

MS + Peppermint flavor (1:1) White fine powder No changeMS + aspartame (1:1) White fine powder No changeMS + Colloidal silicondioxide(1:1) White fine powder No change

MS + Magnesium stearate White fine powder No changeLevocetirizine Dihydrochloride White fine powder No changeLCH+Kyron 104 (1:1) White fine powder No changeLCH+Kyron 114(1:1) White fine powder No changeLCH+ Cross povidone(1:1) Off white fine powder No changeLCH+ Lactose anhydrous (1:5) White fine powder No changeLCH+ Mg.Sterate(1:1) White fine powder No changeZafirlukast White fine powder No changeZk + γ -cd (1:1) White fine powder No changeZk + Lactose Anhydrous (1:5) White fine powder No changeZk + Kyron T314 (1:1) White fine powder No changeZk + Citric acid (1:1) White fine powder No changeZk + Sodium bicarbonate(1:1) White fine powder No changeZk +Tartaric acid (1:1) White fine powder No changeZk +Malic acid (1:1) White fine powder No changeZk +Talc (1:1) White fine powder No changeZk +Magnesium stearate White fine powder No changeZk + Xanthan gum(1:3) White fine powder No changeZk + TSP(1:3) White fine powder No changeZk + HPC(1:3) White fine powder No changeZk + EC T-10(1:3) White fine powder No changeZk + Mannitol (1:5) White fine powder No change

ZK + aspartame (1:1) White fine powder No changeZK + strawberry (1:1) White fine powder No change

Table 5.14 : Drug content estimation

IngredientDrug content (%)

Initial After 15 days After 30 days

Montelukast sodium (MS) 99 ± 0.24 98 ± 0.59 98 ± 0.68MS+Di calcium phosphate(1:5) 96 ± 0.58 96 ± 0.56 96 ± 0.56MS + Lactose anhydrous (1:5) 98 ± 0.59 98 ± 0.58 98± 0.58MS + Cross povidone (1:1) 97 ± 0.54 96 ± 0.56 97± 0.68MS + Ac-di-sol (1:1) 98 ± 0.26 98 ± 0.28 98 ± 0.59MS + β-cd (1:1) 97 ± 0.54 97 ± 0.65 96 ± 0.54MS + SSG (1:1) 97± 0.26 96 ± 0.58 96 ± 0.65MS + Pearlitol 200 (1:5) 98 ± 0.59 98 ± 0.78 98± 0.88MS+Acesulfamepotassium(1:1) 98 ± 0.79 98 ± 0.58 99± 0.48MS + Peppermint flavor (1:1) 98 ± 0.59 98 ± 0.18 98± 0.28MS + aspartame (1:1) 99 ± 0.26 99 ± 0.28 98 ± 0.79MS+Colloidalsilicondioxide(1:1) 99 ± 0.26 99 ± 0.28 98 ± 0.79MS + Magnesium stearate(1:1) 99 ± 0.24 98 ± 0.59 98 ± 0.68Levocetirizine Dihydrochloride(LCH) 98 ± 0.79 98 ± 0.58 99± 0.48

LCH+Kyron 104 (1:1) 98 ± 0.59 98 ± 0.58 98± 0.58LCH+Kyron 114(1:1) 97 ± 0.54 96 ± 0.56 97± 0.68LCH+ Cross povidone(1:1) 98 ± 0.26 98 ± 0.28 98 ± 0.59LCH+ Lactose anhydrous(1:5) 97 ± 0.54 97 ± 0.65 96 ± 0.54LCH+ Mg.Sterate(1:1) 98 ± 0.59 98 ± 0.58 98± 0.58Zafirlukast (Zk) 97 ± 0.54 96 ± 0.56 97± 0.68

Zk + γ -cd (1:1) 98 ± 0.59 98 ± 0.78 98± 0.88Zk + Lactose Anhydrous (1:5) 98 ± 0.79 98 ± 0.58 99± 0.48Zk + Kyron T314 (1:1) 98 ± 0.59 98 ± 0.18 98± 0.28Zk + Citric acid (1:1) 99 ± 0.26 99 ± 0.28 98 ± 0.79Zk + Sodium bicarbonate(1:1) 99 ± 0.26 99 ± 0.28 98 ± 0.79Zk +Tartaric acid (1:1) 99 ± 0.24 98 ± 0.59 98 ± 0.68Zk +Malic acid (1:1) 99 ± 0.24 98 ± 0.59 98 ± 0.68Zk +Talc (1:1) 96 ± 0.58 96 ± 0.56 96 ± 0.56Zk +Magnesium stearate 98 ± 0.59 98 ± 0.58 98± 0.58Zk + Xanthan gum(1:3) 97 ± 0.54 96 ± 0.56 97± 0.68Zk + TSP(1:3) 98 ± 0.26 98 ± 0.28 98 ± 0.59Zk + HPC(1:3) 97 ± 0.54 97 ± 0.65 96 ± 0.54Zk + EC T-10(1:3) 97± 0.26 96 ± 0.58 96 ± 0.65Zk + Mannitol (1:5) 99 ± 0.24 98 ± 0.59 98 ± 0.68ZK + aspartame (1:1) 96 ± 0.58 96 ± 0.56 96 ± 0.56ZK + strawberry (1:1) 99 ± 0.54 98 ± 0.50 98 ± 0.68

5.5 Preparation of Inclusion Complexes of Montelukast sodium with β CyclodextrinTable5.15: Montelukast sodium with β-cyclodextin in different ratios

Ingredients(mg) Control A(1:0.5) B(1:0.75) C(1:1) D(1:2) E (1:3)

Montelukast sodium 10.4 10.4 10.4 10.4 10.4 10.4

β-cyclodextin -- 5.2 7.8 10.4 20.8 31.2

Total 10.4 15.6 18.2 20.8 31.2 41.6


Characterization of Montelukast Sodium- β-cyclodextrin Kneaded complexes: FTIR, DSC and XRD

studies were performed to detect the possible molecular interaction between Montelukast sodium and beta

cyclodextrin. The FTIR, DSC and XRD spectrums of Montelukast sodium and β-cyclodextrin individual

samples as well as kneaded system in 1:1 ratio were shown in Figures 5.4 -5.12.


Fig 5.4 : FTIR of Montelukast Sodium

(a)Montelukast Sodium pure drug; (b)β-cyclodextrin; (c)Montelukast sodium and β-cyclodextrin complex (1:1)



DSC Thermograms:





DSC Thermograms:





DSC Thermograms:












5.5.2 Determination of drug content in the complexes of Montelukast Sodium with β-CD:

Table 5.16: Drug content in the complexes of Montelukast Sodium and β-CD

Drug : β-CD (Inclusioncomplex)

Drug content inpercentage (%)

1:0.5 97

1:0.75 98

1:1 100

1:2 98.5

1:3 99

5.5.3 In-vitro drug release:

Table 5.17: Dissolution profile of the three ratio complexes and


Time(min)

% Drug released of Drug : β-CD (Inclusion complex)Control A(1:0.5) B(1:0.75) C(1:1) D(1:2) E(1:3)

5 21±0.07 62±0.12 70±0.15 77±0.71 75±0.63 76±0.17

10 35±0.10 69±0.39 76±0.77 80±0.49 78±0.52 79±0.19

15 50±0.35 73±0.49 81±0.69 85±0.35 83±0.15 84±0.32

20 58±0.49 78±0.13 85±0.33 93±0.32 91±0.29 92±0.22

30 68±0.52 81±0.66 90±0.22 100±0.19 98±0.31 99±0.16

45 91±0.11 93±0.76 94±0.14 100±0.16 98±0.41 99±0.19

Fig. 5.7 Dissolution profile of the Inclusion complexes and



5.5.4 Taste evaluation of Montelukast Sodium and β-CD complexes:

Table 5.18 : Rating for Taste evaluation

RatingInitial taste After taste

Mouth feel OverallacceptabilityBitterness Bitterness

1 Extremely Bitter Extremely bitter Very gritty Worst

2 Highly bitter Highly bitter Gritty Poor

0102030405060708090

100110

0 5 10 15 20 25 30 35 40 45

Cum

. % D

rug

diss

olve

d

Time (min)

Control

A(1:0.5)B(1:0.75)C (1:1)

3 Acceptable/Tolerable Acceptable/Tolerable Acceptable Acceptable

4 Very slightly bitter Very slightly bitter Creamy Good

5Not at all bitter

Not at all bitter Very creamy

Very good

(GoodPalatability)

Table 5.19: Taste evaluation of Inclusion complexes

Formulationcode

Vol

unte

er1

Vol

unte

er 2

Vol

unte

er 3

Vol

unte

er 4

Vol

unte

er 5

Overall

acceptability

Control 1 1 1 1 1 Worst

A(1:0.5) 3 2 2 2 2 Poor

B(1:0.75) 3 2 3 3 3 Acceptable

C(1:1) 5 5 4 5 5 Good Palatability

D(1:2) 5 5 4 5 5 Good Palatability

E(1:3) 5 4 5 5 5 Good Palatability

5.6 Preparation and Evaluation of Taste Masked complexes of Levocetirizine Di Hydrochloride – Resin(Kyron - T114) complexes:5.6.1 Selection of Resin

Adsorbate preparation:

Complexation between the drug and resin is essentially a process of diffusion of ions between the resin and

surrounding drug solution.

Table 5.20: Selection of Resin

Resin Resin : Drug Percentage of drug boundto Resin

Kyron T 104 1:1 49.6

Kyron T 114 1:1 65.7

5.6.2 Effect of Resin Activation

Table 5.21: Effect of Resin Activation

Form of Resin Drug: Resin (%)Drug loading efficiency

Acid-activated resin 1:1 45.32

Alkali-activated resin 1:1 62.74

Without activation 1:1 77.36

5.6.3 Effect of Levocetirizine - Kyron T - 114 ratio on loading

Table 5.22: Effect of Drug: Resin ratio on drug loading

Resin Drug :Resin % of drug bound to Resin

Kyron T 114

1:1 65.711:1.5 73.331:2 78.62

1:2.5 80.121:3 82.51

5.6.4 Effect of volume of Distilled water on drug loading

Table 5.23: Effect of volume of Distilled water on drug loading

Resin Drug:Resin ratio Volume % of drug bound to Resin

KyronT 114

1:310 ml 91.1125 ml 96.2440 ml 88.12

60 ml 85.3475 ml 75.21

5.6.5 Effect of Kyron T-114 pH on Drug loading

Table 5.24 : Effect of Kyron T-114 pH on Drug loading

Resin Ratio pH % of Drug bound to Resin

Kyron T 114 1:3

2 83.13 85.34 87.6

4.5 89.25 93.5

5.5 96.96 94.2

7.5 93.88 88.3

Fig 5.8 Effect of Kyron T-114 pH on Drug Loading


5.6.6 Effect of Temperature on Drug loading

Table 5.25: Effect of Temperature on Drug loading

Resin Ratio Temperature(0C) % of Drug bound to Resin

Kyron T 114 1:3

27 96.79±0.2540 96.5±0.3750 96.2±0.2160 95.6±0.3770 95.2±0.7980 95.0±0.72

Fig 5.9: Effect of Temperature on Drug loading


0

20

40

60

80

100

120

0 2 4 6 8 10C

um. %

Dru

g bo

und

toR

esin

pH

5.6.7 Effect of soaking time of Resin on drug loading

Table 5.26: Effect of soaking time of Resin on drug loading

Resin Ratio Soaking time(min) % of drug bound to resin

KyronT 114

1:3

0 73.1±0.2210 78.3±0.2520 82.8±0.3430 91.3±0.2760 91.1±0.4290 91.0±0.52

Fig 5.10: Effect of soaking time of Resin on drug loading

0102030405060708090

100110

0 10 20 30 40 50 60 70 80 90

Cum

. % D

rug

boun

d to

Res

in

Temperature (0C)


5.6.8 Effect of Stirring time on drug loading

Table 5.27: Effect of Stirring time on drug loading

Resin Ratio Stirring time(min) % of drug bound to resin

30 60.4±0.41

60 67.3±0.39

0

20

40

60

80

100

0 10 20 30 40 50 60 70 80 90 100

Cum

. % D

rug

boun

d to

Res

in

Soaking time (min)

Kyron T 114 1:3

90 72.5±0.27

120 81.2±0.16

150 83.6±0.10

180 88.4±0.09

210 91.8±0.52

240 97.1±0.69

300 97.0±0.12

Fig 5.11: Effect of Stirring time on drug loading


5.6.9 Molecular properties of drug resin complexCharacterization of Levocetirizine-Kyron T114 complex:Fourier Transform Infra-red Spectroscopy (FTIR):

Fig 5.12: FT- IR spectra of Levocetirizine

(b) Levocetirizine pure drug; (b) Kyron T114; (c)DRC

0

20

40

60

80

100

120

0 50 100 150 200 250 300 350C

um. %

Dru

g bo

und

toR

esin

Stirring time (min)




0.1 N HCl 96.47






0.1 N HCl 96.47






0.1 N HCl 96.47



Time(min) % cumulative drug release5 52.41±1.4010 75.24±0.3215 86.64±0.1430 99.78±0.78

Fig 5.13 : Invitro release of Levocetirizine from the Drug-Resin complex in 0.1N HCl


5.6.12 Taste evaluation

Table 5.30: Bitterness evaluation by Taste panel

0102030405060708090

100110

0 5 10 15 20 25 30 35

Cum

. % D

rug

rele

ased

Time (min)

Formulation Volunteer Overall performance1 2 3 4 5 6

Pure drug 4.0 4.0 4.0 4.0 4.0 4.0 BitterDRC 1.0 0.0 0.0 1.0 1.0 0.0 Good palatability


5.7 Preparation and Evaluation Inclusion Complexes of Zafirlukast with γ- cyclodextrin

5.7.1 Phase solubility studies:

Table 5.31: Phase solubility of Zafirlukast in aqueous γ -cyclodextrin solution

Molar conc of γ- CD Absorbance (238 nm)0.002 0.0280.004 0.0440.006 0.0580.008 0.0720.01 0.089

control 0.007

Fig 5.14 : Phase solubility diagram of Zafirlukast

in aqueous γ -cyclodextrin solution

5.7.2 Preparation of Inclusion complex of Zafirlukast withγ – Cyclodextrin and Drug content analysis:

Table 5.32: Drug content of prepared Zafirlukast Inclusion complexes

5.7.3 In vitro dissolutionstudies:

Table 5.33(a) CumulativePercent Drug Released data of

Zafirlukast from Inclusioncomplexes in 1.0% Sodium lauryl sulfate in water

Time(min)

Puredrug

Physical mixtures Solvent evaporation Kneading mixturePM1 PM2 PM3 SE1 SE2 SE3 KM1 KM2 KM3

5 2±0.35 4.4±0.13 4.7±0.05 9.2±0.26 10.1±0.22 20.6±0.16 22.7±0.37 25.2±0.29 30.9±0.42 32±0.31

y = 0.007x + 0.01R² = 0.995

0

0.02

0.04

0.06

0.08

0.1

0 2 4 6 8 10 12Solu

bilit

y of

Zaf

irlu

kast

Conc of Gamma Cd (mM)

Zafirlukast: γ -CD Ratio Formulation code % drug Content

Physical Mixture1:0.51:0.75

1:1

PM1PM2PM3

97.2±1.0699.6±0.0896.9±0.03

Solvent evaporationmethod

1:0.51:0.75

1:1

SE1SE2SE3

99.5±0.0598.3±0.0595.0±0.07

Kneading method1:0.51:0.75

1:1

KM1KM2KM3

96.1±0.0498.4±0.0899.1±0.09

10 4.0±0.59 8.4±0.68 8.6±0.71 19.3±0.64 22.2±0.41 42±0.38 44.1±0.83 50±0.25 61.4±0.22 63±0.16

20 8.1±0.58 12±0.13 14±0.96 21.1±0.15 28.3±0.28 49.2±0.69 49.9±0.75 56.9±0.68 62.1±0.26 68.6±0.37

30 11.3±0.22 22±0.66 24.2±0.63 26.2±0.49 47±0.77 51.9±0.01 70.6±0.49 72.8±0.31 74.8±0.38 82±0.83

45 15.4±0.84 27.1±0.47 30.4±0.31 41.8±0.09 54.6±0.49 69.5±0.93 71.5±0.28 75.1±0.17 77.1±0.52 88.6±0.69

60 18.8±0.51 34.2±0.18 38.7±0.49 43.4±0.63 60.9±0.71 73±0.59 76.1±0.73 78.2±1.03 81±0.47 99±0.15

Table 5.33(b) ANOVA Table % DRUG RELEASED AFTER 60 min.Pure drug PM 1:1 SE 1:1 KM1:1

18 43 76 9920 45 78 10116 41 74 97

One-way analysis of varianceP value < 0.0001P value summary ***Are means signif. different? (P < 0.05) YesNumber of groups 4F 956.5R square 0.9972

ANOVA Table SS df MSTreatment (between columns) 11478 3 3826Residual (within columns) 32.00 8 4.000Total 11510 11

Dunnett's Multiple Comparison Test Mean Diff. q Significant? P < 0.05? Summarypure drug vs PM 1:1 -25.00 15.31 Yes ***pure drug vs SE 1:1 -58.00 35.52 Yes ***pure drug vs KM 1:1 -81.00 49.60 Yes ***

Fig 5.15 : Cumulative Percent Drug Release of Zafirlukast from Inclusion complexes(n=3, Error bars indicate standard deviation)


Characterization of Zafirlukast and γ-CD inclusion complex:


Fig 5.16 : FTIR Spectra of Zafirlukast

(b) Zafirlukast; (b) γ –cd; (c) Zafirlukast - γ cd (1:1) complex.

0102030405060708090

100110

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70C

um. %

Dru

g re

leas

ed

Time (min)

Pure Drug

PM - 1

PM - 2

PM - 3

SE - 1

SE - 2

SE - 3

KM - 1

Differential scanning calorimetry of Zafirlukast:

Fig 5.17: DSC thermogram of Zafirlukast

(b) Zafirlukast; (b) γ –CD; (c) Zafirlukast: γ- CD (1:1) complex.





Peppermint flavor.








Peppermint flavor.








Peppermint flavor.




Angle of repose(◦ ) 34 29Bulk density (g/ml) 0.58 0.56Tapped density (g/ml) 0.71 0.68% compressibility 19 15Haussner’s ratio 1.22 1.18low ability Good Good

Table 5.35: Evaluation of tablets

Formulationcode

Average weight oftablet(mg)

Thickness(mm)

Hardness(kg/cm2)

Friability(%) Drugcontent (%)

Disintegration Time

(sec)

Wettingtime (sec)

Mouthfeel

ContentUnifo

rmity (%)

D1 200.56±0.2 3.5±0.1 3.0±0.2 0.21 94 150 140 Palatable 99.86

D2 201.8±0.2 3.2±0.5 3.2±0.5 0.19 98 120 90 Palatable 101.10

5.8.2. Optimization of Superdisintegrants:

Table 5.36: Evaluation of directly compressible blends of Orally Disintegrating Tablets Montelukastsodium

Parameter Formulation Code

M1 M 2 M 3 M 4 M5 M6 M7 M 8 M 9 Control

Angle of repose(◦) 32 29 33 32 30 31 34 33 34 30

Bulk density(gm/ml) 0.54 0.58 0.54 0.58 0.55 0.53 0.59 0.57 0.58 0.55

Tapped density(gm/ml) 0.63 0.71 0.66 0.67 0.69 0.65 0.73 0.67 0.68 0.65

% Compressibility 13 18 14 12 18 11 19 14 17 15

Haussner’s ratio 1.16 1.21 1.20 1.13 1.17 1.15 1.22 1.18 1.19 1.20

Flow ability Good Good Good Good Good Good Good Good Good Good

5.8.3. Evaluation of Orally Disintegrating Tablets of Montelukast sodium

ParameterFormulation Code

M1 M 2 M 3 M 4 M5 M6 M7 M 8 M 9 Control Marketed

Averageweight(mg)±S.D

2201±0.2 203±0.32 202±0.32 202±0.32 201±0.36 203±0.36 202±0.34 202±0.32 201±0.24 203±0.24 205±0.36

Hardness(kg/cm2)±S.D 3±0.12 3.5±0.34 3.5±0.34 3±0.22 3±0.25 3±0.25 3±0.32 3.5±0.32 3±0.31 3±0.31 3±0.25

Friability (%) 0.19 0.21 0.18 0.17 0.20 0.19 0.18 0.16 0.16 0.16 0.20

InvitroDisintegration 21 19 20 18 17 18 14 11 15 72 62

Table 5.37 : Evaluation of Orally Disintegrating Tablet formulations of Montelukast sodium

5.8.4. Dissolution profile of Orally Disintegrating Tablets of Montelukast sodium:Table 5.38: Dissolution data of Orally Disintegrating Tablet formulations of Montelukast sodium

Time(min)

Cumulative % drug dissolved

M1 M2 M3 M4 M5 M6 M7 M8 M9 Control Marketed0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.005 65±0.86 68±0.86 69±0.86 72±0.34 77±0.87 73±0.76 76±0.98 80±0.86 77±0.82 48±0.86 65±0.87

10 70±0.54 73±0.86 73±0.86 76±0.76 83±0.43 78±0.45 86±0.98 95±0.54 87±0.85 67±0.54 82±0.8615 83±0.45 85±0.67 81±0.67 84±0.10 90±0.30 89±0.65 96±0.67 99±0.43 98±0.67 69±0.45 89±0.4630 98±0.48 99±0.48 99±0.28 97±0.84 99±0.57 99±0.48 99±0.34 99±0.23 99±0.67 82±0.48 99±0.2645 98±0.88 99±0.48 99±0.28 99±0.76 99±0.67 99±0.62 99±0.03 99±0.21 99±0.55 89±0.88 99±0.19

Fig 5.18 Dissolution profile of all Orally Disintegrating Tablets of montelukast sodium:(n=3, Error bars indicate standard deviation)

time(sec)

Drug content (%) 97 98 95 97 98 96 98 99 97 98 99

Wetting time(sec) 22 21 22 19 18 20 19 15 17 98 75

Drug dissolved in10min (%) 59 61 60 62 65 65 79 95 90.3 67 82

5.8.5. In –vitro Dissolution kinetic parameters for all Orally Disintegrating Tablet formulations ofMontelukast sodium

Table 5.39: Data of the %drug undissolved for all the formulations of Montelukast sodium

Time(min)

% drug undissolved


10 30±0.54 27±0.86 27±0.86 24±0.76 17±0.43 22±0.45 14±0.98 5±0.54 13±0.85 33±0.54 18±0.8615 17±0.45 15±0.67 19±0.67 16±0.10 10±0.30 11±0.65 4±0.67 1±0.43 2±0.67 31±0.45 11±0.4630 2±0.48 1±0.48 1±0.28 3±0.84 1±0.57 1±0.48 1±0.34 -- 1±0.67 18±0.48 1±0.26

0

20

40

60

80

100

120

0 5 10

Cum

mla

tive

% D

rug

diss

olve

d



Time(min)

% drug undissolved


10 30±0.54 27±0.86 27±0.86 24±0.76 17±0.43 22±0.45 14±0.98 5±0.54 13±0.85 33±0.54 18±0.8615 17±0.45 15±0.67 19±0.67 16±0.10 10±0.30 11±0.65 4±0.67 1±0.43 2±0.67 31±0.45 11±0.4630 2±0.48 1±0.48 1±0.28 3±0.84 1±0.57 1±0.48 1±0.34 -- 1±0.67 18±0.48 1±0.26

10 15 20 25 30 35 40 45

Time (min)

M1 M2 M3M4 M5 M6M7 M8 M9



Time(min)

% drug undissolved


10 30±0.54 27±0.86 27±0.86 24±0.76 17±0.43 22±0.45 14±0.98 5±0.54 13±0.85 33±0.54 18±0.8615 17±0.45 15±0.67 19±0.67 16±0.10 10±0.30 11±0.65 4±0.67 1±0.43 2±0.67 31±0.45 11±0.4630 2±0.48 1±0.48 1±0.28 3±0.84 1±0.57 1±0.48 1±0.34 -- 1±0.67 18±0.48 1±0.26

45 2±0.88 1±0.48 1±0.28 1±0.76 1±0.67 1±0.62 1.0±0.03 -- 1±0.55 11±0.88 -

Table 5.40: Data of the Log % drug undissolved for the first order plots of all the formulations ofMontelukast sodium

Time(min)

Log % drug undissolved

M1 M2 M3 M4 M5 M6 M7 M8 M9 Control Marketed0 2 2 2 2 2 2 2 2 2 2 2

5 1.544±0.32 1.505±0.17 1.491±0.06 1.447±0.37 1.361±0.18 1.431±0.35 1.380±0.62 1.301±0.86 1.361±0.23 1.716±0.64 1.544±0.2910 1.477±0.47 1.431±0.25 1.431±0.15 1.380±0.41 1.230±0.27 1.342±0.07 1.146±0.81 0.698±0.18 1.113±0.58 1.518±0.29 1.255±0.1715 1.230±0.07 1.176±0.34 1.278±0.09 1.204±0.52 1.000±0.05 1.041±0.13 0.60±0.03 0.000 0.301±0.45 1.491±0.26 1.041±0.5530 0.301±0.12 0.000 0.000 0.477±0.64 0.000 0.000 0.000 -- 0.000 1.255±0.03 0.00045 0.301±0.54 0.000 0.000 0.000 0.000 0.000 0.000 -- 0.000 1.041±0.57 -

Fig 5.19 First order plots of M1, M2, M3 & M4 formulations






Fig 5.21 First order plots of M8 (Final), Control &

Marketed formulations

00.25

0.50.75

11.25

1.51.75

22.25

0Log

% U

ndis

solv

ed



y = -0.019x + 1.839R² = 0.918

y = -0.132x + 1.990R² = 0.999

y = -0.064x + 1.942R² = 0.993

5 10 15 20 25 30 35 40 45

Time (min)

Control Final (M8) Marketed (Romilast)



45

Table 5.41: Correlation Coefficient(R) Values of all formulations of Montelukast sodium: as per Zero Orderand First Order Kinetics.

5.8.6 Comparative studyof Final formulation withmarket product.

5.8.6.1 ANOVATable 5.42 ANOVA

Table of Disintegration Time (Sec.)

Control Final formulation(M8)

Marketed product(Romilast)

72 11 6274 13 6471 10 60

Table 5.43 ANOVA Table

Let Null-hypothesis, H0 is that all the formulations are having same disintegration values.

One-way analysis of varianceP value < 0.0001

P value summary ***Are means signif. different? (P < 0.05) Yes

Number of groups 3F 1107

R square 0.9973

Parameter M1 M 2 M 3 M 4 M5 M6 M7 M 8 M 9 Control Marketed

Zero order

r2 0.5895 0.5635 0.5711 0.9362 0.9828 0.5014 0.4283 0.7538 0.41250.6467 0.5165

k0(µg/ml/min) 1.6522 1.6348 1.633 1.5283 1.4549 1.5583 1.4783 6.24 1.4609 1.5287 1.5722

First order

r2 0.9102 0.9131 0.9079 0.9727 0.8956 0.9063 0.8458 0.9992 0.7683 0.918 0.993

K1(min-1) 0.0902 0.1080 0.1082 0.0969 0.1020 0.1050 0.0999 0.3042 0.0978 0.0437 0.147

ANOVA Table SS df MSTreatment (between columns) 6395 2 3197

Residual (within columns) 17.33 6 2.889Total 6412 8

Dunnett's Multiple Comparison Test Mean Diff. q Significant? P < 0.05? Summarycontrol vs final 61.00 43.96 Yes ***

control vs marketed 10.33 7.446 Yes ***

Table 5.44: Comparision of dissolution profiles (cum. %drug dissolved data in 0.5%SLS in water) of Finalformulation (M8) Montelukast sodium with control & marketed product (Romilast)

Time (min) Control

Finalformulation

(M8)Marketed(Romilast)

0 0 0 0

5 48±0.86 80±0.86 65±0.86

10 67±1.54 95±1.54 82±1.86

15 69±0.45 99±1.43 89±1.46

30 82±0.48 -- 99±1.26

45 89±0.88 -- -

Fig 5.22 Comparison of dissolution profile (cum.% drug released data in 0.5% SLS in water) of finalODT MS with control and market product


Table 5.45 Comparision of dissolution profiles (log %drug undissolved data in 0.5%SLS in water) of Finalformulation (M8) Montelukast sodium with control & marketed product (Romilast)

Time (min) Control

Finalformulation


0

10

20

30

40

50

60

70

80

90

100

110

0 5 10

Cum

mul

ativ

e %

Dru

g di

ssol

ved




Time (min) Control

Finalformulation


10 15 20 25 30 35 40 45 50

Time (min)

Final (M8)

Control

Marketed (Romilast)




Time (min) Control

Finalformulation


0 2 2 2

5 1.716±0.86 1.301±0.86 1.544±0.54

10 1.518±1.54 0.698±1.54 1.255±

15 1.491±0.45 0 1.041±1.46

30 1.255±0.48 -- 0

45 1.041±0.88 -- -

Fig 5.23 LOG% drug unreleased in 0.5% SLS in water of final ODT MS with control and marketproduct

Table 5.46: Comparative study of final Formulation with marketed product

Parameter FinalFormulation(M8)

Marketedproduct(Romilast)

Average weight(mg)±S.D 202 299Hardness(kg/cm2) ±S.D 3.5 3.5

Friability (%) 0.19 0.21Invitro Disintegration time(sec) 11 62

y = -0.019x + 1.839R² = 0.918

y = -0.132x + 1.990R² = 0.999

y = -0.064x + 1.942R² = 0.993

0

0.25

0.5

0.75

1

1.25

1.5

1.75

2

2.25

0 5 10 15 20 25 30 35 40 45

Log

% U

ndis

solv

ed

Time (min)

Control

Final (M8)

Marketed (Romilast)

Drug content (%) 100 99.5Wetting time(sec) 15 75

Drug dissolved in 15 min (%) 99 89

5.8.6.2 Fit factor test (f1 and f2)

Fig 5.24 Dissolution Profile Comparison of orally disintegrating tablets of MontelukastDissolution Condition - Type-USP 2 (Paddle);

rpm - 50; Volume - 900 ml

Media 0.5 % SLS in water

Time(min) Final(M8) Marketed (Romilast)

0 0.0 0.0

5 80 65

10 95 82

15 99 89

30 99 99

45 99 99

0.015.030.045.060.075.090.0

105.0

0 10 20 30 40 50Cum

. % D

rug

Dis

solv

ed

Time (min)

Final(M8)

Marketed (Romilast)

Table 5.47: Drug release kinetics of Control, Final formulation (M8) and Marketed product (Romilast)

5.8.7Stabilitystudy

Table 5.48:Stability

studies forfinalized

orallyDisintegrati

ngformulations

ofMontelukast

sodium

f1 (Dissimilarity factor) = 8.05 f2 (Similarity factor) = 50.02

Formulation code

Time Vs %Drug unreleased Time Vs Log %Drug retained

t90 (min) DP15 (%) DE15 (%) DT (sec)Slope R2

KO

(µg/ml/min) Slope R2

K1

(min-1)

t1/2

(min)

Control 1.528 0.646 1.5287 0.019 0.918 0.043 15.8 45 69 55.99 72

Final formulation (M8) 6.24 0.753 6.24 0.132 0.999 0.304 2.2 10 99 75.59 11

Marketed product(Romilast) 1.572 0.516 1.5722 0.040 0.993 0.147 4.7 15 89 64.48 62

Fig 5.25 : Photographs showing disintegration of Final tablet (M8)

A: 0 time B: 2 sec C: 5 sec

Storage conditionObservations At

40oC± 20 C/75% ±5%RH

Observations At40oC± 2oC/75% ±

5%RH

Observations At40oC± 20C/75% ±

5%RH

Observations At 40oC± 20C/75%± 5%RH

Time period Initial 1 month 3 month 6 month

Appearance Complies Complies Complies Complies

Hardness(kg/cm2) 3.5±0.32 3.5±0.12 3.5±0.02 3.5±0.02

Drug content (%) 100.6 99.8 99.6 99.4

Invitro disintegration time (sec) 11 12 12 13% Drug dissolved in 15min 100.50 100 99.5 99.2

D: 8 sec E: 11 sec

5.9 Development of Orally Disintegrating Tablets of Montelukast plus Levocetrizine5.9.1 Evaluation of Orally Disintegrating Tablets of Montelukast plus Levocetrizine

Table 5.49: Evaluation of formulations of Orally Disintegrating Tablets of Montelukast plusLevocetrizine

Parameter Optimized Final MarketedAverage weight(mg)±S.D 203±0.24 202±0.24 205±0.36Hardness(kg/cm2) ±S.D 3.5±0.31 3.5±0.31 3±0.25

Friability (%) 0.16 0.14 0.20Invitro Disintegration time(sec) 11 16 57

Wetting time(sec) 15 27 78Drug content (%) Montelukast 99.6 100.10 98Drug content (%)Levocetrizine - 100.5 99

Drug dissolved in 15min(%)Montelukast 99 99 90

Drug dissolved in 15 min(%)Levocetrizine - 99

92

Mouth feel Palatable Palatable Bitter

5.9.2. Dissolution profile of Orally Disintegrating Tablets of Montelukast sodium with Levocetrizine.

Table 5.50: (a) Montelukast sodium


Time(min)Optimized

(M8)Final (M) Marketed

(montair lc)

0 0 0 0

5 80±0.86 75±0.26 72±0.47

10 95±0.54 94±0.41 85±0.83

15 99±0.43 99±0.28 90±0.92

30 99±0.23 99±0.20 96±0.05

45 99±0.21 99±0.15 98±0.57

Dissolution profile of Orally Disintegrating Tablets of montelukast sodium with Levocetrizine

Table 5.51: (b) Levocetrizine


Time(min) Final (L) Marketed (Montair lc)

0 0 0

5 80±0.62 75±0.39

10 95±0.89 85±0.52

15 99±0.37 92±0.92

30 99±0.22 95±0.27

45 99±0.16 98±0.37

Fig 5.26 (a) Montelukast sodium


Fig 5.27 (b) Levocetrizine


0102030405060708090

100110

0 5 10 15 20 25 30 35 40 45 50Cum

. % D

rug

diss

olve

d

Time (min)

Optimized (M8)

Final (M)

Marketed(montair lc)

5.9.3. In –vitro Dissolution kinetic parameters for all Orally Disintegrating Tablet formulations ofMontelukast sodium with Levocetrizine

Data of the %drug undissolved for all the formulations of Montelukast sodium with Levocetrizine


Time(min)

% drug Undissolved

Optimized(M8) Final (M) Marketed(montair lc)

0 100 100 100

0102030405060708090

100110

0 5 10 15 20 25 30 35 40 45

cum

m. %

Dru

g re

leas

ed

Time (min)

Final (L)

Marketed (Montair lc)

5 20±0.86 25±0.26 28±0.47

10 5±0.54 6±0.41 15±0.83

15 1±0.43 1±0.28 10±0.92

30 1±0.23 1±0.20 4±0.05

45 1±0.21 1±0.15 2±0.57


Time(min)% drug Undissolved

Final (L) Marketed (Montair lc)

0 100 100

5 20± 0.62 25±0.39

10 5±0.89 15±0.52

15 1±0.37 8±0.92

30 1±0.22 5±0.27

45 1±0.16 2±0.37

Data of the Log % drug undissolved for the first order plots of all the formulations of Montelukastsodium with Levocetrizine


Time(min)

Log % drug undissolved

Optimized

(M8)Final (M) Marketed

(montair lc)

0 2 2 2

5 1.301±0.86 1.397±0.26 1.447±0.47

10 0.698±0.54 0.778±0.41 1.176±0.83

15 0 0 1±0.92

30 0 0 0.602±0.05

45 0 0 0.301±0.57


Time(min)

Log % drug Undissolved

Final (L) Marketed(montair lc)

0 2 2

5 1.301±0.26 1.397±0.47

10 0.6989±0.41 1.176±0.83

15 0 0.903±0.92

30 0 0.698±0.05

45 0 0.301±0.57

First order plots of orally disintegrating formulations of Montelukast sodium with Levocetrizine:

Fig 5.28 (a) Montelukast sodium


y = -0.132x + 1.990R² = 0.999

y = -0.132x + 2.036R² = 0.996

y = -0.033x + 1.679R² = 0.897

00.25

0.50.75

11.25

1.51.75

22.25

2.52.75

3

0 5 10 15 20 25 30 35 40 45

Log

% U

ndis

solv

ed

Time (min)

Optimized (M8)

Final (M)


Correlation Coefficient(R) Values of orally disintegrating formulations of Montelukast sodium withLevocetrizine: as per Zero Order and First Order Kinetics.


Formulation code

Time Vs %Drug unreleased(Zero order)

Time Vs Log %Drug retained(First order)

t90 (min) DP15 (%) DE15 (%) DT (sec)

Slope R2KO

(µg/ml/min)

Slope R2 K1(min-1)

t1/2(min)

Optimized (M8) 6.24 0.753 6.24 0.132 0.999 0.303 2.28 10 99 75.58 11Final (M) 6.22 0.798 6.22 0.132 0.996 0.303 2.28 10 99 73.56 16

Marketed (montair lc) 1.48 0.457 1.48 0.033 0.897 0.075 9.24 15 90 68.01 57

Table 5.57: (b) LevocetrizineFormulation code Time Vs %Drug unreleased Time Vs Log %Drug retained t90 (min) DP15 (%) DE15 (%) DT (sec)

y = -0.132x + 1.990R² = 0.999

y = -0.032x + 1.645R² = 0.865

00.25

0.50.75

11.25

1.51.75

22.25

2.52.75

3

0 5 10 15 20 25 30 35 40 45

Log

% U

ndis

solv

ed

Time (min)

Final (L)


(Zero order) (First order)

Slope R2KO(µg/ml/min) Slope R2

K1(min-1)

t1/2(min)

Final (L) 6.24 0.753 6.24 0.132 0.999 0.303 2.28 10 99 75.58 16Marketed (montairlc) 1.445 0.432 1.445 0.032 0.865 0.073 9.49 15 92 70.06 57

5.9.4 Comparative study of Final formulation with market product.5.9.4.1 Student t- test

Table 5.58 Student t- test (unpaired)Disintegration Time (Sec.)

Final formulation Marketed product (Montair lc)16 5718 5913 54

Mean± SEM = 15.67 ± 1.453 Mean± SEM = 56.67 ± 1.453Table 5.59 Unpaired t- test

Table Analyzed Data 1Column A Final formulation

vs vsColumn B Marketed product

Unpaired t testP value < 0.0001


One- or two-tailed P value? Two-tailedt, df t=19.95 df=4


Dissolution Profile Comparison of orally disintegrating tablets of Montelukast sodium with LevocetrizineFig 5.30 (a) Montelukast sodium

Media 0.5 % SLS in waterTime(min) Final (M) Marketed (Montair lc)

0 0 05 75 7210 94 8515 99 9030 99 9645 99 98


Media 0.5 % SLS in waterTime(min) Test Reference

0 0 05 80 7510 95 8515 99 9230 99 95

0153045607590

105

0 5 10 15 20 25 30 35 40 45 50

Cum

m.%

Dru

gD

isso

lved

Time (min)

Final (M)

f1 = 5.15 f2 = 60.79

45 99 98

f1 = 5.51 f2 = 60.225.9.5 Stability studyTable 5.60: Stability studies for finalized orally Disintegrating formulations of Montelukast sodiumwith Levocetrizine

5.10 Formulation and Evaluation of Montelukast Sodium Chewable Tablets by Different Techniques

0153045607590

105

0 5 10 15 20 25 30 35 40 45 50

Cum

m. %

dru

gdi

ssol

ved

Time (min)

Final (L)

Marketed(Montair lc)

Storage condition

Observations At40oC± 20 C/75%±

5%RH

Observations At40oC± 2oC/75%±

5%RH

Observations At40oC± 20C/75%±

5%RH

Observations At40oC± 20C/75%±

5%RH

Time period Initial 1 month 3 month 6 monthAppearance Complies Complies Complies Complies

Hardness(kg/cm2) 3.5±0.32 3.5±0.12 3.5±0.02 3.5±0.02Invitro disintegration time (sec) 16 18 20 18Drug content (%) Montelukast 99.6 98.6 98.8 98.9Drug content (%)Levocetrizine 100.3 99.9 100.1 99.9

Drug dissolved in 45min(%)Montelukast 100.00 99.60 99.40 100.1

Drug dissolved in 45 min(%)Levocetrizine 101 100 99.76 100

5.10 .1 Evaluation of Tablets

Table 5.61: Comparative Evaluation of Chewable tablets:

Parameters Formulation code

C1 C2 C3 Marketed

Weight of tablet (mg) 150±0.23 149±0.33 150±0.12 200±0.17

Hardness(kg/cm2) 3.5 3.5 4 4

Friability test (%) 0.19 0.18 0.16 0.17

Drug content (mg) 5.044 4.94 5.148 4.992

Assay (%) 97 95 99 99

Dissolution timecumulative % of drugdissolved in 45 min

95 96 99 98

C1- Non Aqueous granulation(NAG), C2- Aqueous granulation(AG), C3- Direct Compression(DC)

5.10.2 Dissolution test:

Table 5.62: Comparison of Dissolution profiles of Montelukast Sodium Chewable Tablets by DifferentTechniques

Time C1 (NAG) C2 (AG) C3 (DC) Marketed (emlucast)

0 0 0 0 0

5 48±0.36 62±0.61 63±0.27 50±0.38

10 65±0.75 67±0.17 78±0.14 70±0.72

15 89±0.42 70±0.42 91±0.02 90±0.82

30 94±0.98 90±0.64 99±0.49 96±0.16

45 98±0.82 96±0.02 100±0.15 99±0.37

C1- Non Aqueous granulation(NAG), C2- Aqueous granulation(AG), C3- Direct Compression(DC)

Fig 5.32 : Comparison of Dissolution profiles of Montelukast Sodium Chewable Tablets by DifferentTechniques


5.10.3 Taste Evaluation:

Table 5.63: Bitterness evaluation of prepared tablets by three methods

FormulationCode

volunteer Over allacceptability1 2 3 4 5 6 7 8 9

Directcompression (C3) 0 0 0 0 0 0 0 0 0

Goodpalatability

0

10

20

30

40

50

60

70

80

90

100

110

0 5 10 15 20 25 30 35 40 45

Cum

. % D

rug

diss

olve

d

Time (min)

C1 (NAG)

C2 (AG)

C3 (DC)

Marketed (emlucast)

Aqueousgranulation(C2) 2 1 2 1 1 1 2 1 1

acceptable

Non aqueousgranulation(C1) 1 1 1 1 1 1 1 1 0

acceptable


5.10.4 Comparison of Dissolution Profiles of Montelukast chewable tablet Final with Marketedformulation

Table 5.64 Dissolution Profile Comparison of Montelukast chewable tablet Final with Marketedformulation

Dissolution Profile Comparison of Montelukast chewable tablet

Dissolution Condition - Type-USP 2 (Paddle); RPM - 50; Volume -

900 ml(Montelukast)


Time(min) Final (C3) Marketed (emlucast )

0 0 0

5 63±0.27 50±0.38

10 78±0.14 70±0.72

15 91±0.02 90±0.82

30 99±0.49 96±0.16

45 100±0.15 99±0.37

Fig 5.33 Dissolution Profile Comparison of Montelukast chewable tablet Final with Marketedformulation


5.10.5. In –vitro Dissolution kinetic parameters of Montelukast chewable tablets

Table 5.65: Data of the %drug undissolved for all the formulations of Montelukast chewable tablets

Time(min)% Drug undissolved

C1 C2 Final (C3) Marketed (emlucast )

0 100 100 100 100

0102030405060708090

100110

0 5 10 15 20 25 30 35 40 45

% D

rug

diss

olve

d

Time (min)

Final (C3)

Marketed (emlucast)

5 52±0.36 38±0.61 37±0.27 50±0.38

10 35±0.75 33±0.17 32±0.14 30±0.72

15 11±0.42 30±0.42 9±0.02 10±0.82

30 6±0.98 10±0.64 1±0.49 4±0.16

45 2±0.82 4±0.02 0 1±0.37

Table 5.66: Data of the Log % drug undissolved for the first order plots of Montelukast chewabletablets

Time(min)Log % Drug undissolved

C1 C2 Final (C3) Marketed (emlucast)

0 2 2 2 2

5 1.716±0.62 1.579±0.47 1.568±0.69 1.698±0.38

10 1.544±0.43 1.518±0.69 1.342±0.18 1.477±0.17

15 1.041±0.74 1.477±0.16 0.954±0.63 1.000±0.85

30 0.778±0.18 1.000±0.38 0.000 0.602±0.14

45 0.301±0.27 0.602±0.15 - 0.000

Fig 5.34 First order plots of Montelukast chewable tablet formulations

Table 5.67: Correlation Coefficient(R) Values of chewable tablet formulations of montelukast sodium: as perZero Order and First Order Kinetics.

y = -0.032x + 1.69R² = 0.896

y = -0.028x + 1.858R² = 0.962

y = -0.065x + 1.964R² = 0.996

y = -0.043x + 1.887R² = 0.973

0

0.25

0.5

0.75

1

1.25

1.5

1.75

2

2.25

2.5

0 5 10 15 20 25 30 35 40 45

log

% D

rug

undo

ssol

ved

Time (min)

C1 (NAG)

C2 (AG)

Final - C3 (DC)

Marketed (emlucast)

Formulation code Time Vs %Drug unreleased(Zero order)

Time Vs Log %Drug retained(First order)

t90 (min) DP15 (%) DE15 (%) DP30 (%) DE30 (%)

Slope R2 KO(µg/ml/min)

Slope R2 K1(min-1)

t1/2(min)

C1 (NAG) 1.780 0.649 1.780 0.032 0.896 0.073 9.49 15 89 53.57 94 72.19C2 (AG) 1.493 0.509 1.493 0.028 0.962 0.064 10.8 30 70 56.94 90 70.13

Final - C3 (DC) 1.485 0.432 1.485 0.065 0.996 0.149 4.65 15 91 62.16 99 78.58

Marketed (emlucast) 1.540 0.503 1.540 0.043 0.973 0.099 7.0 15 90 55.55 96 74.74

5.10.6. Fit factor test (f1 and f2)

Fig 5.35 Dissolution Profile Comparison of chewable tablets of Montelukast


Time(min) Final(C3) Marketed (emlucast)

0 0.0 0.0

5 63 50

10 78 70

15 91 90

30 99 96

45 100 99

f1 = 6.03 f2 = 57.57

5.10.7. Stability study

Table 5.68: Stability studies for finalized chewable formulations of Montelukast sodium

0.0

15.0

30.0

45.0

60.0

75.0

90.0

105.0

0 10 20 30 40 50

Cum

m. %

Dru

g D

isso

lved

Time (min)

Final(C3)

Marketed (emlucast)

Storage condition

Observations At40oC± 20 C/75%± 5%RH

Observations At40oC± 2oC/75%± 5%RH

ObservationsAt

40oC±20C/75%±

5%RH

ObservationsAt

40oC±20C/75%±

5%RHTime period Initial 1 month 3 month 6 monthAppearance Complies Complies Complies Complies

Hardness(kg/cm2) 3.5±0.32 3.5±0.12 3.5±0.02 3.5±0.02

Drug content (%) Montelukast 99.6 98.6 98.8 98.9

5.11 Formulation and Evaluation of Orally Disintegrating Tablets of Zafirlukast

5.11.1 Selection and optimization of direct compressible diluentsTable 5.69: Evaluation tests for the prepared tablets

Formulationcode

Avg wtof

tablet(mg)

Weightvariation

±%

Thickness(mm)

HardnessKg/cm

Friability%

Contentuniformity

Disintegration time

(sec)

Wettingtime(sec)

A-1 98.6 1.42 3.5±0.12 3.0±0.22 0.35 97 132 130

A-2 100 1.0 3.0±0.5 3.0±0.5 0.28 99.9 75 122

A-3 99.8 2.5 3.5±0.17 3.5±0.17 0.38 98.6 180 200

Table 5.70: Powder flow properties of the selected formulation

Flow property A-2 FormulationAngle of repose(o) 26.24Bulk density(gm/cm 3) 0.481Tapped density(gm/cm 3) 0.562Carr’s compressibilityindex(%)

14.41

Hausner’s ratio 1.16Flow property Good

5.11.2 Selection and optimization of superdisintegrants

Drug dissolved in 45min (%)Montelukast 100.00 99.60 99.40 100.1

Table 5.71: Evaluation of blend and tablet parameters of Orally Disintegrating formulations ofZafirlukast

Blend parameters Formulation Code

S1 S2 S3 S4 S5 S6 S7 S8 S9 Control

Bulk density(gm/cm3) 0.404 0.421 0.418 0.429 0.401 0.417 0.424 0.412 0.431 0.401

Tappeddensity(gm/cm3) O.442 0.463 0.47 0.474 0.44 0.469 0.463 0.468 0.472 0.44

Hausner’s ratio 1.094 1.099 1.124 1.104 1.097 1.124 1.091 1.135 1.095 1.097

Compressibility index(%) 8.59 9.97 11.06 8.64 8.86 11.08 8.42 11.96 8.68 8.86Angle of repose (0) 25.44 26.21 25.43 26.18 24.22 26.32 24.9 26.19 23.48 24.22

Tablet parameters

Weight(mg) 101.02 99.78 99.21 98.02 101.08 99.75 99.24 100.07 100.05 98.02

Hardness(Kg/cm2 3.0 4.0 3.5 3.0 3.5 3.0 3.5 4.0 3.0 3.0

Friability (%) 0.45 0.32 0.37 0.4 0.38 0.43 0.36 0.12 0.39 0.4

Disintegration time(sec) 59 54 50 67 69 70 50 32 40 75

Wetting time (sec) 89 69 75 112 96 113 59 42 50 122

5.11.3. Dissolution profile of Orally Disintegrating Tablets of Zafirlukast:

Table 5.72: Dissolution data of Orally Disintegrating formulations of Zafirlukast

Time Sodium Starch Glycolate Croscarmellose Sodium Kyron T-314 Control

S1 S2 S3 S4 S5 S6 S7 S8 S9

0 0 0 0 0 0 0 0 0 0 0

5 40.5±0.42 49.5±0.51 43.8±0.39 22.6±0.06 34.8±0.51 27±0.57 54.8±0.36 55.1±0.52 59.6±0.15 20.6±0.59

10 49.5±0.31 59.6±0.32 52.8±0.71 43.8±0.35 46.1±0.37 45±0.71 60.7±0.42 69.6±0.72 63±0.71 39.8±0.79

15 54.2±0.12 61.6±0.47 59.8±0.27 54.0±0.22 55.0±0.09 59.0±0.02 65.5±0.71 75.5±0.36 74.5±0.57 48.20±0.21

20 65±0.76 67±0.39 66.3±0.25 63±0.39 64±0.19 62±0.07 68.6±0.06 79.2±0.52 77.8±0.16 54±0.11

30 75.3±0.19 78.2±0.46 77.6±0.32 69.7±0.21 74.2±0.76 70.8±0.18 82.1±0.07 85.2±0.31 84±0.35 60.7±0.56

45 87.7±0.27 91.4±0.51 90±0.52 84.3±0.09 88.8±0.35 86.6±0.21 92.2±0.17 100±0.17 93.3±0.49 74.3±0.47

Figure 5.36 : In vitro dissolution profiles of orally Disintegrating

formulations of Zafirlukast


5.11.4. In –vitro Dissolution kinetic parameters for all Orally Disintegrating Tablet formulations ofZafirlukast

0

10

20

30

40

50

60

70

80

90

100

110

0 5

Cum

. % D

rug

diss

olve

d

Formulation code DP30 (%) DE30 (%) t90(min)S1 75.3 52.83 >45S2 78.2 58.23 45S3 77.6 55.44 45


10 15 20 25 30 35 40 45

Time (min)

S1

S2

S3

S4

S5

S6

S7

S8

S9

Control



S1

S2

S3

S4

S5

S6

S7

S8

S9

Control


Table 5.73: In vitro Dissolution

parameters of the formulations

S4 69.7 47.43 >45S5 74.2 51.35 >45S6 70.8 49.13 >45S7 82.1 61.00 43S8 85.2 67.36 37S9 84 66.30 42

control 60.7 41.71 >45

5.11 .5 Selection and optimization of Effervescent agents

Table 5.74. Evaluation of Effervescent agents on Orally Disintegrating formulations of Zafirlukast

Formulation codeAverage weight

(mg) ±SD

Hardness

(Kg/cm2)

Thickness(m

m)

Friability

(%)

Percent drug

content ±SD

In vitro

Dispersion time (s) ±SD

E-1 98.5 ±0.20 3.0 2.59±0.05 0.18±0.17 98.42±1.01 20±0.68

E-2 99.5±0.24 3.5 2.67±0.06 0.18±0.12 99.74±0.88 18±0.45

E-3 99.8±0.36 3.0 2.87±0.05 0.18±0.17 98.44±0.62 16±1.32

E-4 96.5±0.42 3.5 2.65±0.67 0.12±0.15 100.06±0.68 28±0.36

E-5 98.5±0.21 4.0 2.74±0.02 0.18±0.08 98.25±0.58 25±0.68

E-6 101±0.12 3.5 2.76±0.01 0.12±0.21 97.49±0.88 22±1.54

E-7 97.8±0.26 4.0 2.68±0.14 0.14±0.11 99.96±0.62 18±0.91

E-8 97.6±0.21 4.0 2.49±0.17 0.18±0.16 100.08±049 15±0.62

E-9 99.8±0.10 3.5 2.69±0.04 0130±0.12 99.86±1.03 13±0.21

Control 98.5±0.21 3.0 2.64±0.02 0.18±0.08 98.25±0.58 45±0.68

5.11.6. Effect of effervescent agents on dissolution profile of Orally Disintegrating Tablets of

Zafirlukast

Table 5.75: Dissolution data of Orally Disintegrating Tablet formulations of Zafirlukast

Time

(min)

Cum. % Drug dissolved

Formulation

code

Malic acid +

Sodium bicarbonate(1:1)

Tartaric acid + Sodium

bicarbonate(1:1)

Citric acid +

Sodium

bicarbonate(1:1)

Marketed Control

E-1 E-2 E-3 E-4 E-5 E-6 E-7 E-8 E-90 0 0 0 0 0 0 0 0 0 0 0

5 51.7±1.19 56.2±0.74 57.3±0.8 41.6±0.91 46.1±1.14 48.3±1.09 61.1±0.75 64.1±0.84 70±0.25 62.2±0.25 20.6±0.36

10 70±1.0.6 72.0±1.06 76.5±0.7 55.5±0.82 56.2±1.32 69.7±1.01 75±0.69 78.0±0.81 88.8±0.65 70±0.15 39.8±0.41

15 74.2±1.56 77.6±1.82 79.8±0.5 63.0±0.67 65.0±1.19 72 ±0.75 81.5±0.81 85.5±1.02 95±1.05 77±0.05 48.20±0.28

20 79±1.04 85.5±0.81 87.7±0.9 66.4±0.75 75.3±0.64 77±0.67 89.1±0.64 91.1±1.08 100±1.19 80±0.25 54±0.37

30 92.2±0.85 94.5±0.64 99.0±1.5 84.3±0.82 87.7±0.91 88.8±0.35 91.0±0.92 95.0±0.90 100±1.10 89.20±0.15 60.7±0.19

45 97.8±0.90 98.2±0.89 99.0±1.1 95.6±1.06 96.7±0.19 97±0.65 98.0±0.91 99±0.74 100±1.05 90.0±0.25 74.3±0.26

Figure 5.37 : Dissolution profile of Orally Disintegrating Tablets of Zafirlukast(n=3, Error bars indicate standard deviation)

5.11.7. Effect of effervescent agents on In –vitro Dissolution kinetic parameters for all OrallyDisintegrating formulations of Zafirlukast

Table 5.76: Data of the %drug undissolved for all the formulations of ZafirlukastTime(min) % Drug undissolved

Formulationcode E-1 E-2 E-3 E-4 E-5 E-6 E-7 E-8 E-9 Marketed Control

0 100 100 100 100 100 100 100 100 100 100 1005 48.3±1.19 43.8±0.74 42.7±0.8 58.4±0.91 53.9±1.14 51.7±1.09 38.9±0.75 35.9±0.84 30±0.25 37.8±0.25 80.4±0.3610 30±1.0.6 28±1.06 23.5±0.7 44.5±0.82 43.8±1.32 30.3±1.01 25±0.69 22±0.81 11.2±0.65 30±0.15 60.2±0.4115 25.8±1.56 22.4±1.82 20.2±0.5 37±0.67 35±1.19 28±0.75 18.5±0.81 14.5±1.02 5±1.05 23±0.05 51.8±0.2820 21±1.04 14.5±0.81 12.3±0.9 33.6±0.75 24.7±0.64 23±0.67 10.9±0.64 8.9±1.08 0±1.19 20±0.25 46±0.3730 7.8±0.85 5.5±0.64 1±1.5 15.7±0.82 12.3±0.91 11.2±0.35 9±0.92 5±0.90 0±1.10 10.8±0.15 39.3±0.1945 2.2±0.90 1.8±0.89 1±1.1 4.4±1.06 3.3±0.19 3±0.65 2±0.91 1±0.74 0±1.05 10.0±0.25 25.7±0.26

0102030405060708090

100110

0 5 10 15 20 25 30 35 40 45 50

Cum

. % D

rug

diss

olve

d

Time (min)

E1

E2

E3

E4

E5

5.11 .5 Selection and optimization of Effervescent agents

Table 5.74. Evaluation of Effervescent agents on Orally Disintegrating formulations of Zafirlukast

Formulation codeAverage weight

(mg) ±SD

Hardness

(Kg/cm2)

Thickness(m

m)

Friability

(%)

Percent drug

content ±SD

In vitro

Dispersion time (s) ±SD

E-1 98.5 ±0.20 3.0 2.59±0.05 0.18±0.17 98.42±1.01 20±0.68

E-2 99.5±0.24 3.5 2.67±0.06 0.18±0.12 99.74±0.88 18±0.45

E-3 99.8±0.36 3.0 2.87±0.05 0.18±0.17 98.44±0.62 16±1.32

E-4 96.5±0.42 3.5 2.65±0.67 0.12±0.15 100.06±0.68 28±0.36

E-5 98.5±0.21 4.0 2.74±0.02 0.18±0.08 98.25±0.58 25±0.68

E-6 101±0.12 3.5 2.76±0.01 0.12±0.21 97.49±0.88 22±1.54

E-7 97.8±0.26 4.0 2.68±0.14 0.14±0.11 99.96±0.62 18±0.91

E-8 97.6±0.21 4.0 2.49±0.17 0.18±0.16 100.08±049 15±0.62

E-9 99.8±0.10 3.5 2.69±0.04 0130±0.12 99.86±1.03 13±0.21

Control 98.5±0.21 3.0 2.64±0.02 0.18±0.08 98.25±0.58 45±0.68

5.11.6. Effect of effervescent agents on dissolution profile of Orally Disintegrating Tablets of

Zafirlukast

Table 5.75: Dissolution data of Orally Disintegrating Tablet formulations of Zafirlukast

Time

(min)


Formulation

code

Malic acid +

Sodium bicarbonate(1:1)

Tartaric acid + Sodium

bicarbonate(1:1)

Citric acid +

Sodium

bicarbonate(1:1)

Marketed Control

E-1 E-2 E-3 E-4 E-5 E-6 E-7 E-8 E-90 0 0 0 0 0 0 0 0 0 0 0

5 51.7±1.19 56.2±0.74 57.3±0.8 41.6±0.91 46.1±1.14 48.3±1.09 61.1±0.75 64.1±0.84 70±0.25 62.2±0.25 20.6±0.36

10 70±1.0.6 72.0±1.06 76.5±0.7 55.5±0.82 56.2±1.32 69.7±1.01 75±0.69 78.0±0.81 88.8±0.65 70±0.15 39.8±0.41

15 74.2±1.56 77.6±1.82 79.8±0.5 63.0±0.67 65.0±1.19 72 ±0.75 81.5±0.81 85.5±1.02 95±1.05 77±0.05 48.20±0.28

20 79±1.04 85.5±0.81 87.7±0.9 66.4±0.75 75.3±0.64 77±0.67 89.1±0.64 91.1±1.08 100±1.19 80±0.25 54±0.37

30 92.2±0.85 94.5±0.64 99.0±1.5 84.3±0.82 87.7±0.91 88.8±0.35 91.0±0.92 95.0±0.90 100±1.10 89.20±0.15 60.7±0.19

45 97.8±0.90 98.2±0.89 99.0±1.1 95.6±1.06 96.7±0.19 97±0.65 98.0±0.91 99±0.74 100±1.05 90.0±0.25 74.3±0.26

Figure 5.37 : Dissolution profile of Orally Disintegrating Tablets of Zafirlukast(n=3, Error bars indicate standard deviation)

5.11.7. Effect of effervescent agents on In –vitro Dissolution kinetic parameters for all OrallyDisintegrating formulations of Zafirlukast

Table 5.76: Data of the %drug undissolved for all the formulations of Zafirlukast

0102030405060708090

100110

0 5 10 15 20 25 30 35 40 45 50

Cum

. % D

rug

diss

olve

d

Time (min)

E1

E2

E3

E4

E5

Time(min) % Drug undissolved

Formulationcode E-1 E-2 E-3 E-4 E-5 E-6 E-7 E-8 E-9 Marketed Control

0 100 100 100 100 100 100 100 100 100 100 1005 48.3±1.19 43.8±0.74 42.7±0.8 58.4±0.91 53.9±1.14 51.7±1.09 38.9±0.75 35.9±0.84 30±0.25 37.8±0.25 80.4±0.3610 30±1.0.6 28±1.06 23.5±0.7 44.5±0.82 43.8±1.32 30.3±1.01 25±0.69 22±0.81 11.2±0.65 30±0.15 60.2±0.41

15 25.8±1.56 22.4±1.82 20.2±0.5 37±0.67 35±1.19 28±0.75 18.5±0.81 14.5±1.02 5±1.05 23±0.05 51.8±0.2820 21±1.04 14.5±0.81 12.3±0.9 33.6±0.75 24.7±0.64 23±0.67 10.9±0.64 8.9±1.08 0±1.19 20±0.25 46±0.3730 7.8±0.85 5.5±0.64 1±1.5 15.7±0.82 12.3±0.91 11.2±0.35 9±0.92 5±0.90 0±1.10 10.8±0.15 39.3±0.1945 2.2±0.90 1.8±0.89 1±1.1 4.4±1.06 3.3±0.19 3±0.65 2±0.91 1±0.74 0±1.05 10.0±0.25 25.7±0.26

Time

(min)

Log % Drug undissolved

Table 5.77: Data of the Log % drug undissolved for the first order plots of all the formulations ofZafirlukast

Formulation

code

Marketed Control

E-1 E-2 E-3 E-4 E-5 E-6 E-7 E-8 E-90 2 2 2 2 2 2 2 2 2 2 2

5 1.683±1.19 1.641±0.74 1.630±0.83 1.766±0.91 1.731±1.14 1.713±1.09 1.589±0.75 1.555±0.84 1.477±0.25 1.577±0.25 1.905±0.36

10 1.477±1.0.6 1.447±1.06 1.371±0.7 1.648±0.82 1.641±1.32 1.481±1.01 1.397±0.69 1.342±0.81 1.049±0.65 1.477±0.15 1.779±0.41

15 1.411±1.56 1.350±1.82 1.305±0.5 1.568±0.67 1.544±1.19 1.447±0.75 1.267±0.81 1.161±1.02 0.698±1.05 1.361±0.05 1.714±0.28

20 1.322±1.04 1.161±0.81 1.089±0.9 1.526±0.75 1.392±0.64 1.361±0.67 1.037±0.64 0.949±1.08 - 1.301±0.25 1.66±0.37

30 0.892±0.85 0.740±0.64 0±1.53 1.195±0.82 1.089±0.91 1.049±0.35 0.954±0.92 0.698±0.90 - 1.033±0.15 1.594±0.19

45 0.342±0.90 0.255±0.89 - 0.643±1.06 0.518±0.19 0.477±0.65 0.301±0.91 0±0.74 - 1±0.25 1.409±0.26

Fig 5.38 First order plots of E1, E2, E3, E4 & E5 formulations

Fig 5.39 First order plots of E6, E7 & E8 formulations

y = -0.034x + 1.923R² = 0.983

y = -0.037x + 1.891R² = 0.988y = -0.060x + 2.041R² = 0.928

y = -0.028x + 1.980R² = 0.975y = -0.031x + 1.973R² = 0.987

00.25

0.50.75

11.25

1.51.75

22.25

2.5

0 5 10 15 20 25 30 35 40 45

Log

% D

rug

undi

ssol

ved

Time (min)

E1

E2

E3

E4

E5

Fig 5.40 First order plots of Final (E9), Control & Marketed (Zuvair) formulations

y = -0.031x + 1.916R² = 0.975

y = -0.033x + 1.824R² = 0.954

y = -0.040x + 1.831R² = 0.977

00.25

0.50.75

11.25

1.51.75

22.25

2.5

0 5 10 15 20 25 30 35 40 45

Log

% D

rug

undi

ssol

ved

Time (min)

E6

E7

E8

y = -0.086x + 1.956R² = 0.992 y = -0.020x + 1.751

R² = 0.829y = -0.012x + 1.944

R² = 0.958

00.25

0.50.75

11.25

1.51.75

22.25

2.5

0 5 10 15 20 25 30 35 40 45

Log

% D

rug

undi

ssol

ved

Time (min)

Final (E9) Marketed (Zuvair) Control

Table 5.78: Correlation Coefficient(R) Values of all formulations of Zafirlukast: as per Zero Order and FirstOrder Kinetics.

Table 5.79: Drug releasekinetics of Control, Final

formulation (E9) and Marketed product (Zuvair)

Formulation code

Time Vs %Drug unreleased Time Vs Log %Drug retained

t90 (min) DP20 (%) DE20 (%) DT (sec)Slope R2

KO

(µg/ml/min) Slope R2

K1

(min-1)

t1/2

(min)

Control 1.501 0.846 0.027 0.012 0.958 0.043 25.6 >45 54 33.9 -

Final (E9) 1.575 0.448 0.198 0.020 0.992 0.304 3.5 12 100 77.2 13

Parameter E1 E 2 E 3 E 4 E5 E6 E7 E 8 E 9 Marketed control

Zero

order

r2 1.671 0.631 0.728 0.808 0.777 0.687 0.568 0.543 0.448 0.539 0.846

k0(µg/ml/min) 1.742 1.723 2.803 1.808 1.823 1.735 1.627 1.631 1.575 1.474 1.501

First

order

r2 0.983 0.988 0.928 0.975 0.987 0.975 0.954 0.977 0.992 0.829 0.958

K1(min-1) 0.078 0.085 0.138 0.064 0.071 0.071 0.075 0.092 0.198 0.046 0.027

Marketed (Zuvair) 1.474 0.539 0.046 0.086 0.829 0.147 15.0 45 80 62.3 400

5.11.8 Comparative study of Final formulation with market product.5.11.8.1 Comparision of dissolution profile of Final formulation (E9) with control and Marketed product

(Zuvair)

Table 5.80: Comparision of dissolution data of Final formulation (E9) with control and Marketed product

(Zuvair)

Time(min)


Final (E-9) Marketed (Zuvair) Control

0 0 0 0

5 70±0.25 62.2±0.25 20.6±0.36

10 88.8±0.65 70±0.15 39.8±0.41

15 95±1.05 77±0.05 48.20±0.28

20 100±1.19 80±0.25 54±0.37

30 - 89.20±0.15 60.7±0.19

45 - 90.0±0.25 74.3±0.26

Fig 5.41 Comparison of dissolution profiles of Final formulation (E9)with control and Marketed product (Zuvair)


5.11.8.2 Student t - testTable 5.81 Student t - test (Unpaired)

Disintegration Time (Sec.)Final formulation(E9) Marketed product (Zuvair)

13 40015 40211 397

0

10

20

30

40

50

60

70

80

90

100

110

0 5 10 15 20 25 30 35 40 45

Cum

. % D

rug

diss

olve

d

Time (min)

Control

Final (E9)

Marketed (Zuvair)

13.00 ± 1.155 399.7 ± 1.453Table 5.82 Student t - test

Table Analyzed Data 1Column A Final formulation

vs vsColumn B Marketed product

Unpaired t testP value < 0.0001


One- or two-tailed P value? Two-tailedt, df t=208.3 df=4


Fig 5.42 Dissolution Profile Comparison of orally disintegrating tablets of Zafirlukast

Media 1.0 % SLS in waterTime(min) Final (E9) Marketed (Zuvair)

0 0.0 0.05 70.0 62.2010 88.8 70.0015 95.0 77.0020 100.0 80.0030 100.0 89.2045 100.0 90.00

f1 =7.94 f2=51.40Table 5.83: Final Formulation ODT of Zafirlukast

Name of ingredients Qty/unit in mg

Zafirlukast and γ -CD (1:1) complexequivalent to10mg Zafirlukast 20

Mannitol (Pearlitol 200) 63.5

Polacrilin Potassium(Kyron T314) 5

Citric acid + Sodium bicarbonate(1:1) 8

Talc 1

Magnesium stearate 1

Colloidal Silicon Dioxide (Aerosil 200) 0.75

Ferric oxide red 0.25

0.015.030.045.060.075.090.0

105.0

0 10 20 30 40

Cum

m. %

Dru

gD

isso

lved

Time (min)

Final (E9) Marketed (Zuvair)

Aspartame 1.5

Strawberry flavor 0.25

5.11.9 Stability studies for finalized formulation Orally Disintegrating Tablets of Zafirlukast

Table 5.84: Stability data of Orally Disintegrating Tablets of Zafirlukast

5.12DevelopmentandOptimizationofcoreand

press coated tablets of Zafirlukast5.12.1. Evaluation of directly compressible blends of barrier layer and press coated tablets of Zafirlukast

Table 5.85: Evaluation of directly compressible blends of barrier layer and press coated tablets ofZafirlukast

Storage conditionObservations At

400C± 20C/75%± 5%RHObservations At



400C± 20C/75%± 5%RH



Hardness(kg/cm2) 3.5±0.32 3.5±0.12 3.5±0.02 3.5±0.02

Drug content (%) 99.6 98.6 99.6 99.0

Invitro disintegration time (sec) 13 16 14 15

Drug dissolved in 45 min (%) 99.5 99.2 98.75 98.75

Formulation Code Angle of

repose(◦)

Bulk density

(gm/cm3)

Tapped

density(gm/cm3

)

%

Compressibilit

y

Haussner’s

ratio

Flow ability Average weight(mg)±S.D Hardness(kg/cm2)

±S.D

Friability (%) Swelling index

(%)

X1 38 0.50 0.60 18 1.21 Fair 399.8±0.21 5±0.12 0.21 3.2

X2 37 0.52 0.61 16 1.19 Fair 399.1±0.32 5±0.34 0.11 3.3

X3 32 0.54 0.62 14 1.15 Good 399.8±0.21 5±0.34 0.11 3.5

X4 33 0.58 0.65 12 1.13 Good 399.5±0.23 5±0.22 0.14 3.3

X5 30 0.56 0.65 13 1.17 Good 399.1±0.33 5±0.26 0.12 3.7

X6 31 0.56 0.64 12 1.15 Good 399.1±0.32 5±0.25 0.13 3.8

X7 34 0.57 0.67 14 1.18 Good 399.16±0.31 5±0.32 0.10 5.2

X8 33 0.55 0.64 14 1.18 Good 399.56±0.22 5±0.32 0.10 4.2

X9 32 0.55 0.63 15 1.15 Good 399.16±0.33 5±0.34 0.11 4.3

X10 32 0.54 0.62 15 1.16 Good 399.4±0.24 5±0.34 0.12 4.6

X11 33 0.53 0.62 14 1.17 Good 399.1±0.34 5±0.26 0.16 4.7

X12 34 0.54 0.63 15 1.17 Good 399.8±0.21 5±0.26 0.12 4.8

H1 39 0.50 0.61 18 1.22 Fair 399.8±0.21 5±0.12 0.21 2.97

H2 38 0.50 0.60 18 1.21 Fair 399.56±0.22 5±0.32 0.10 2.9

H3 34 0.54 0.63 15 1.17 Good 399.8±0.21 5±0.34 0.11 2.5

H4 33 0.54 0.62 14 1.15 Good 399.5±0.23 5±0.22 0.14 2.6

Table 5.86: Viscosity determination of polymers

Polymer Viscosity (CPs)Xanthan gum 15000HPC 600EC10 30000

5.12.2. Dissolution profiles of press coated tablets:

Table 5.87: Dissolution profile of Formulations of I set of Press coated tablets (Xanthan gum and EC)

H5 32 0.58 0.65 12 1.13 Good 399.1±0.33 5±0.26 0.12 2.8

Time (hrs) X1 X2 X3 X4 X5 X6 X7 X8 X9 X10 X11 X12

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Time(hrs)

% dr

ug d

issol

ved

X1X2X3X4X5X6X7X8X9X10X11X12

Figure 5.43 : Dissolution profilesof I set of Press coated tablets

(Xanthan gum and EC)(n=3, Error bars indicate standard

deviation)

Table 5.88: Dissolution profile of X12 Formulation at

0 0 0 0 0 0 0±0 0±0 0±0 0±0 0±0 0±0 0±0

1 0 0 0 0 0 0±0 0±0 0±0 0±0 0±0 0±0 0±0

2 0 0 0 0 0 0±0 0±0 0±0 0±0 0±0 0±0 0±0

3 0 0 0 0 0 0±0 0±0 0±0 0±0 0±0 0±0 0±0

4 0 0 0 0 0 0±0 29±1.2 0±0 0±0 0±0 0±0 0±0

5 0 0 0 0 0 0±0 49±1.75 0±0 0±0 0±0 0±0 0±0.11

6 0 0 0 0 0 0±0 95±2.3 0±0 0±0 0±0 0±0 47±2.3

7 0 0 0 0 0 0±0 99±2.5 0±0 0±0 0±0.24 0±0.13 64±3.1

8 0 0 0 0 0 0±0 0±0.24 0±0.23 49±2.3 59±3.6 79±3.6

9 0 0 0 0 0 0±0 0±0.15 63±2.5 60±3.5 75±4.2 99±4.2

10 0 0 0 0 0 0±0 68±3.3 81±3.5 94±4.1 96±3.9

11 0 0 0 0 0 0±0 91±3.6 99±4.4 99±3.6

12 0 0 0 0 0 2±1.5 98±4.2

13 0 0 0 0 0 25±1.7

14 0 0 0 0 0 60±0.5

15 0 0 48 0 0 95±0.6

X12

-200

20406080

100120

0 1 2 3 4 5 6 7 8

Time(hrs)

%d

rug

dis

solv

ed

50rpm

75rpm

100rpm

different rpm and media

Figure 5.44 : Dissolution

profiles of optimized

formula X12 at different rpm

(n=3, Error bars indicate

deviation)standard

Time(hrs)

50rpm 75rpm 100rpm Time(hrs)

Waterwith

1.0%SLS

1.2PH

HCl6.8Phosphatebuffer

Time(min)

SimulatedGI Fluid(pepsin)

SimulatedIntestinalfluid(pancreatin)

0 0±0 0±0 0±0 0 0±0 0±0 0±0 5 0 0

1 0±0 0±0 0±0 1 0±0 0±0 0±0 10 0 0

2 0±0 0±0 0±0 2 0±0 0±0 0±0 15 0 0

3 0±0 0±0 0±0 3 0±0 0±0 0±0 20 0 4

4 0±0 0±0 5±1.3 4 0±1.1 0±0 13±1.7 25 2 17

5 2±0 2±0 21±1.8 5 10±1.6 14±1.4 56±1.6 30 19 35.9

5.5 42±1.2 54±0 59±1.8 5.5 56±1.7 59±1.9 83±1.9 35 34 56

6 60±1.5 78±1.5 83±1.6 6 80.6±1.9 85±1.7 94±1.7 40 49 67

6.5 79±2.1 94±1.3 98±1.4 6.5 92.3±1.8 95±1.6 45 62 82.3

7 98±2.1 98±1.7 50 76 98

55 85

60 93

X12

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7 8

Time(hrs)

%dr

ug d

isso

lved 0.5%SLS

1.2PH Hcl

6.8Phosphatebuffer

Figure 5.45 : Dissolution profile of X12 of Zafirlukast in different media


Figure 5.46 : Dissolution profile of X12 in Simulated GI fluids (USP)

Fig 2(k)

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40 45 50 55 60

Time(min)

%dr

ug d

isso

lved (X12)Simulated GI

fluid(pepsin)

(X12)Simulatedintestinalfluid(pancreatin)


Table 5.89: Dissolution data ofFormulations of II set of Press coated tablets

(HPC and EC)

Time(hrs) H1 H2 H3 H4 H5

0 0±2.3 0±0.35 0±0.12 0±0.12 0±0.12

1 97±3.4 0±4.3 0±0.13 0±0.32 0±0.14

2 0±3.5 0±0.15 0±0.15 0±0.15

3 25±4.2 0±0.12 0±0.14 3±2.4

4 73.7±4.3 0±0.21 29±2.5 56±3.5

HPC

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7 8

Time(hrs

%d

rug

dis

so

lved H1

H2H3H4H5

5 94±2.3 6±2.5 75±3.5 82.3±4.5

6 75±3.4 93±4.5 92±3.4

7 95±4.5

Figure 5.47 : Dissolution profiles of II set of Press coated tablets

(HPC and EC)


H3

-20

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7 8

Time(hrs)

%dr

ug d

isso

lved

50rpm75rpm100rpm

Table 5.90: Dissolution data of H3 Formulation different rpm and mediaTime

(hrs) 50rpm 75rpm 100rpm Time(hrs) 1%SLS 1.2pH HCl 6.8 Phosphate buffer Simulated GI fluid(pepsin)

0 0±0 0±0 0±0 0 0±0 0±0 0±0 0±0

1 0±0 0±0 0±0 1 0±0 0±0 0±0 0±0

2 0±0 0±0 0±0 2 0±0 0±0 0±0 0±0

3 0±0 0±0 0±0 3 0±0 0±0 0±0 0±0.02

4 0±0.13 0±0.23 2±1.25 4 0±0.05 0±0.03 0±0.12 23±1.5

5 6±0.32 10±0.43 24±1.45 5 6±1.8 4±1.4 8±3.2 49±3.2

6 75±0.43 68±0.35 79±3.42 6 75±2.2 25±2.5 69±3.4 95±4.3

7 95±0.45 96±0.51 97±2.34 7 95±3.4 65±3.5 96±4.1

8 93±4.1

Figure 5.48 : Dissolution profile of H3 atdifferent rpm


H3

0

20

40

60

80

100

120

0 2 4 6 8 10

Time(hrs)

%dr

ug d

isso

lved 0.5%SLS

1.2PH Hcl

6.8PhosphatebufferSimulated GIfluid(pepsin)

Figure 5.49 : Dissolution profile of H3 in different dissolution media and Simulated GI fluids (USP)


Figure 5.50 : Optimized Press coated tablet H3 showing drug release after lag time

a b c d e

(a): 1 hr (b): 2 hr (c): 3 hr (d): 4 hr (e):5 hr

Fig5(a) y = -0.015x + 6.524R2 = 0.9948

0

0.5

1

1.5

2

2.5

300 330 360 390

Time(min)

Log%

undi

ssol

ved

X12

Fig 5(c)y = -0.0107x + 5.1933

R2 = 0.996

00.5

11.5

22.5

300 360 420

Time(min)

Log%

undi

ssol

ved

H3

5.12.3. First order plots of press coated tablets:

Figure 5.51 : First order plot of X12 formulation

Figure 5.52 : First order plot of H3

formulation

5.12.4. In-vitro release kinetic parameters for press coated tablets:Table 5.91: In-vitro release kinetic parameters for press coated tablets

Formulation code Lag time (hrs) Zero - order model First-Order Modelr2 k0(µg/mL/hr) r2 k1(hr-1)

X1 >15 NA NA NA NAX2 >15 NA NA NA NAX3 14 NA NA NA NAX4 >15 NA NA NA NAX5 12 0.8973 0.530 0.8990 0.010X6 10 0.9044 0.420 0.9601 0.011

X7 <5 0.9343 0.801 0.9503 0.030X8 9 0.9045 0.471 0.9847 0.013X9 8 ½ 0.9117 0.480 0.9861 0.014X10 8 0.9164 0.470 0.9880 0.014X11 7 0.9226 0.930 0.9899 0.032X12 5 ½ 0.9361 0.931 0.9948 0.034H1 <1 - - - -H2 2 1/2 0.9465 0.575 0.989 0.021H3 5 0.9082 0.741 0.996 0.024H4 3 1/2 0.9400 0.533 0.996 0.019H5 3 0.9330 0.300 0.997 0.014

Table 5.92: Final Formulation of Press Coated Zafirlukast tablet

Ingredient Qty/unit (mg)Core tablet 100mg

Zafirlukast and γ -CD (1:1) complexequivalent to10mg Zafirlukast 20Mannitol (perlitol 200) 64Polacrilin Potassium(Kyron T314) 5Citric acid + Sodium bicarbonate(1:1) 8Talc 1Magnesium stearate 1Colloidal Silicon Dioxide (Aerosil 200) 0.75Ferric oxide red 0.25

Barrier layer(H3)300mglayer-I 150mg

HPC(Klucel HXF) 75Ethyl cellulose T10 75

layer-II 150mg

HPC(Klucel HXF) 75Ethyl cellulose T10 75

Total weight of the tablet 400mg

Table 5.93: Physical and kinetic parameters of Optimized Formulation (H3)

Table 5.94: Stability studies forpress coated tablets of ZafirlukastFormulation

code

Averageweight(mg)

±S.D

Hardness(kg/cm2)

±S.D

Friability(%)

Swellingindex(%)

Lagtime(hrs)

Zero - order modelFirst-Order

Model

r2 k0(µg/mL/hr) r2k1

(hr-1)

H3 399.8±0.21 5±0.34 0.11 2.5 5 0.908 0.741 0.996 0.024Storage condition

Observations At

400C± 20C/75%±

5%RH

Observations At

400C± 20C/75%±

5%RH

Observations At

400C± 20C/75%±

5%RH

Observations At

400C± 20C/75%±

5%RH



Drug content (%) 99.6 99.8 98.6 99.0

Hardness(kg/cm2) 5.5±0.32 4.5±0.12 5.0±0.02 5.0±0.02

5.13 IN – VIVO STUDIES

5.13.1 Plasma concentrations of Montelukast sodium

Table5.95. Plasma concentrations of Montelukast sodium following its orally administration as formulation M8

in Animal models

Final (M8) Plasma concentration (ng/ml)

Time(hrs)1 2 3 4 5 6 ±s.d

0 0 0 0 0 0 0 0

0.1 55 45 56 47 60 55 53±5.2

0.25 80 74 78 92 96 88 84.7±7.9

(PDDS)

Lag time(hrs) 5 5 5 5

0.5 220 260 230 200 280 225 235.8±26.5

0.75 510 452 486 525 440 460 478.8±30.9

1 780 692 726 760 672 690 720±39.2

1.5 595 645 670 705 630 610 654.2±35.7

2 550 570 620 590 600 540 578.3±27.9

4 440 390 380 425 445 370 408.3±29.5

6 260 290 275 255 285 270 272.5±12.5

10 120 140 135 132 145 142 135.7±8.2

15 50 45 60 53 65 53 54.3±6.5

20 20 28 24 30 21 28 25.2±3.8

24 10 19 14 13 16 12 14±2.9

Table5.96 Plasma concentrations of Montelukast sodium following its orally administration as Marketed

formulation (Romilast) in Animal models

Marketed (Romilast) Plasma concentration (ng/ml)

Time(hrs) 1 2 3 4 5 6 ±s.d

0 0 0 0 0 0 0 00.1 20 23 29 25 28 26 25.2±30.25 41 57 52 45 53 58 51±6.10.5 85 122 106 110 90 104 102.8±12.30.75 180 243 192 200 260 235 218.3±29.2

1 383 462 423 392 470 440 428.3±32.71.5 582 635 540 590 645 610 600.3±352 560 540 530 568 576 568 554±31.54 420 484 442 428 505 478 459.5±31.36 272 358 336 332 308 314 320±26.710 114 149 125 138 110 142 149.7±14.415 48 73 53 64 50 65 68.8±9.120 24 38 33 39 20 29 33.1±5.324 9 15 8 17 9 10 11.3±3.3

Fig 5.53 Plasma concentrations of Montelukast sodium following its orally administration as Final formulation

(M8) and Marketed formulation (Romilast)

5.13.2 Determination of Residual concentrations of Montelukast sodium

Table5.97 Determining Residual concentrations to various times by the application of Method ofResiduals (Final formulation M8)

Time(hrs)

1 2 3 4 5 6 Cr ± s.d

Co Ce Cr Co Ce Cr Co Ce Cr Co Ce Cr Co Ce Cr Co Ce Cr

0 - - - - - - - - - - - - - - - - - - -

0.1 1.74 2.88 1.14 1.653 2.9 1.247 1.748 2.91 1.162 1.672 2.9 1.228 1.778 2.91 1.132 1.74 2.88 1.14 1.174±0.045

0.25 1.903 2.87 0.967 1.869 2.89 1.021 1.892 2.9 1.008 1.963 2.88 0.917 1.982 2.9 0.918 1.944 2.87 0.926 0.959±0.042

0.5 2.342 2.85 0.508 2.414 2.87 0.456 2.361 2.88 0.519 2.301 2.87 0.569 2.447 2.88 0.433 2.406 2.85 0.444 0.488±0.048

0

200

400

600

800

0 5 10 15 20 25 30

Mea

n pl

asm

aco

ncen

trat

ion

(ng/

ml)

Time (Hrs)

Final (M8) Marketed (Romilast)

0.75 2.707 2.83 0.123 2.655 2.85 0.195 2.686 2.86 0.174 2.72 2.84 0.12 2.643 2.86 0.217 2.662 2.83 0.168 0.166±0.035

1 2.892 2.892 - 2.84 2.84 - 2.86 2.86 - 2.88 2.88 - 2.827 2.827 - 2.838 2.838 - -

1.5 2.774 2.774 - 2.809 2.809 - 2.826 2.826 - 2.848 2.848 - 2.799 2.799 - 2.785 2.785 - -

2 2.74 2.74 - 2.755 2.755 - 2.792 2.792 - 2.77 2.77 - 2.778 2.778 - 2.732 2.732 - -

4 2.643 2.643 - 2.591 2.591 - 2.579 2.579 - 2.628 2.628 - 2.648 2.648 - 2.568 2.568 - -

6 2.414 2.414 - 2.462 2.462 - 2.439 2.439 - 2.406 2.406 - 2.454 2.454 - 2.431 2.431 - -

10 2.079 2.079 - 2.146 2.146 - 2.13 2.13 - 2.12 2.12 - 2.161 2.161 - 2.152 2.152 - -

15 1.698 1.698 - 1.653 1.653 - 1.778 1.778 - 1.724 1.724 - 1.812 1.812 - 1.724 1.724 - -

20 1.301 1.301 - 1.447 1.447 - 1.38 1.38 - 1.477 1.477 - 1.322 1.322 - 1.447 1.447 - -

24 1 1 - 1.278 1.278 - 1.146 1.146 - 1.113 1.113 - 1.204 1.204 - 1.079 1.071 - -

Cr-Residual concentration; Ce-Extraploted concentration; Co–Original concentrationFig 5.54 Semi logarithmic plots of Residual concentration Vs Time following the orally administration of Final

formulation (M8)

1 2

y = -1.604x + 1.326R² = 0.995

00.20.40.60.8

11.21.4

0 0.2 0.4 0.6 0.8

Log

resi

dual

conc

entr

atio

n

Time (hrs)

3

4

5

6

y = -1.687x + 1.404R² = 0.978

0

0.5

1

1.5

0 0.5 1

Log

resi

dual

conc

entr

atio

n

Time (hrs)

y = -1.579x + 1.347R² = 0.991

00.20.40.60.8

11.21.4

0 0.5 1

Log

resi

dual

conc

entr

atio

n

Time (hrs)

y = -1.661x + 1.373R² = 0.995

0

0.5

1

1.5

0 0.5 1

Log

resi

dual

conc

entr

atio

n

Time (hrs)

y = -1.461x + 1.259R² = 0.975

00.20.40.60.8

11.2

0 0.5 1

Log

resi

dual

conc

entr

atio

n

Time (hrs)

y = -1.541x + 1.286R² = 0.987

00.20.40.60.8

11.2

0 0.5 1

Log

resi

dual

conc

entr

atio

n

Time (hrs)

Table5.98 Determination of Residual concentrations to various times by the application of Method of Residuals

(Marketed formulation - Romilast)

Time(hrs)

1 2 3 4 5 6 Cr ± s.d

Co Ce Cr Co Ce Cr Co Ce Cr Co Ce Cr Co Ce Cr Co Ce Cr

0 - - - - - - - - - - - - - - - - - - -

0.1 1.301 2.94 1.639 1.361 2.90 1.539 1.462 2.86 1.434 1.397 2.900 1.503 1.477 3.030 1.553 1.414 2.990 1.576 1.54±0.063

0.25 1.612 2.92 1.308 1.755 2.88 1.125 1.716 2.84 1.124 1.653 2.89 1.237 1.724 3.02 1.296 1.763 2.98 1.217 1.217±0.07

0.5 1.929 2.90 0.971 2.086 2.86 0.774 2.025 2.83 0.805 2.041 2.87 0.829 1.954 3.00 1.046 2.017 2.96 0.943 0.894±0.09

0.75 2.255 2.87 0.615 2.385 2.84 0.455 2.283 2.82 0.537 2.301 2.86 0.559 2.414 2.98 0.566 2.371 2.94 0.569 0.55±0.048

1 2.583 2.84 0.257 2.664 2.815 0.151 2.626 2.80 0.174 2.593 2.84 0.247 2.672 2.96 0.288 2.643 2.92 0.277 0.236±0.05

1.5 2.764 2.764 - 2.802 2.802 - 2.732 2.732 - 2.770 2.770 - 2.809 2.809 - 2.785 2.785 - -

2 2.748 2.748 - 2.732 2.732 - 2.724 2.724 - 2.754 2.754 - 2.76 2.76 - 2.754 2.754 - -

3 2.623 2.623 - 2.684 2.684 - 2.645 2.645 - 2.631 2.631 - 2.703 2.703 - 2.679 2.679 - -

4 2.434 2.434 - 2.553 2.553 - 2.526 2.526 - 2.521 2.521 - 2.488 2.488 - 2.496 2.496 - -

6 2.056 2.056 - 2.173 2.173 - 2.096 2.096 - 2.198 2.198 - 2.041 2.041 - 2.152 2.152 - -

8 1.681 1.681 - 1.863 1.863 - 1.724 1.724 - 1.869 1.869 - 1.698 1.698 - 1.812 1.812 - -

10 1.38 1.38 - 1.579 1.579 - 1.518 1.518 - 1.591 1.591 - 1.301 1.301 - 1.462 1.462 - -

12 0.954 0.954 - 1.176 1.176 - 0.903 0.903 - 1.230 1.230 - 0.954 0.954 - 1 1 - -

Cr-Residual concentration; Ce-Extraploted concentration; Co–Original concentration

Fig 5.55 Semi logarithmic plots of Residual concentration Vs Time following the orally administration ofMarketed formulation (Romilast)

1

2

3

4

5

6

y = -1.493x + 1.734R² = 0.994

0

0.5

1

1.5

2

0 0.5 1 1.5

Log

Resi

dual

con

cent

rati

on

Time (min)

y = -1.479x + 1.578R² = 0.978

0

0.5

1

1.5

2

0 0.5 1 1.5

Log

resi

dual

conc

entr

atio

n

Time (hrs)

y = -1.341x + 1.512R² = 0.991

0

0.5

1

1.5

2

0 0.5 1 1.5

Log

resi

dual

conc

entr

atio

n

Time (hrs)

y = -1.378x + 1.591R² = 0.991

0

0.5

1

1.5

2

0 0.5 1 1.5

Log

resi

dual

conc

entr

atio

n

Time (hrs)

y = -1.415x + 1.686R² = 0.991

0

1

2

3

4

0 0.5 1 1.5

Log

resi

dual

conc

entr

atio

n

Time (hrs)

y = -1.398x + 1.643R² = 0.987

0

0.5

1

1.5

2

0 0.5 1 1.5

Log

resi

dual

conc

entr

atio

n

Time (hrs)

5.13.3 Estimation of Pharmacokinetic parameters of Montelukast sodium

Table5.99 Summary of Pharmacokinetic parameters estimated following the orally administration ofMontelukast sodium formulations, Final (M8) and Marketed (Romilast) in Animal models

S.No. Parameter Product Significance ofdifferenceFinal(M8) Marketed (Romilast)

1 Cmax (ng/ml) 720±39.2 600.3±35*** Significant***

2 Tmax (h) 1±0.00 1.5±0.00* Significant*

3 AUC0-24 (ng.h/ml) 4179.808±107.95 4171.179±241.311 Not significant

4 AUC24-∞ (ng.h/ml) 81.736±19.566 66.513±23.068 Not significant

5 Ka (h-1) 3.658±0.173 3.263±0.123** Significant**

6 Ke (h-1) 0.172±0.006 0.174±0.011 Not significant

7 t1/2(h) 4.018±0.155 3.987±0.260 Not significant

*** = p < 0.001; ** = p < 0.01; * = p < 0.05

5.13.4 Plasma concentrations of ZafirlukastTable5.100 Plasma concentrations of Zafirlukast following its orally administration as Final formulation (E9) in

Animal modelsFinal (E9) Plasma concentration (ng/ml)

Time(hrs) 1 2 3 4 5 6 ±s.d

0 0 0 0 0 0 0 00.1 14 16 17.5 15 16 19 15±10.25 28 27 29 32 29 31 30±1.40.5 66 60 75 71 68 70 104.7±5.30.75 175 160 180 165 150 160 170±13.2

1 308 270 365 305 283 264 225.8±12.71.5 325 390 405 335 350 345 358.3±29.12 295 310 370 315 297 315 313.7±15.63 245 260 310 260 250 280 292.5±14.94 180 195 225 200 180 215 199.2±16.76 115 110 95 130 90 135 112.5±16.58 66 70 80 69 73 84 73.7±6.310 37 42 39 40 44 35 39.5±3.112 19 21 22 18 21 18 19.8±1.6

Table 5.101 Plasma concentrations of Zafirlukast following its orally administration as Marketed formulation(Zuvair) in Animal models

Marketed

(Zuvair)

Plasma concentration (ng/ml)

Time(hrs) 1 2 3 4 5 6 ±s.d

0 0 0 0 0 0 0 00.1 11 13 25 17 10 9 9.67±1.1

0.25 18 19 34 20 15 14 29.8±2.30.5 31 30 55.5 34 24 25 69±5.6

0.75 44 46 62 49 45 34 114.17±9.61 68 74 90 78 57 54 170.8±10.6

1.5 167 148 190 136 135 129 227.5±13.12 290 270 305 290 250 287 286.67±16.2

3 345 355 360 320 310 350 340±18.54 245 250 275 245 230 260 260.83±16.76 110 105 110 125 110 115 120±8.78 31 40 38 53 49 33 50.83±2.410 8 12 11 18 17 12 10±1.712 5 5 6 7 7 6 6±1

Fig 5.56 Plasma concentrations of Zafirlukast following its orally administration as Final formulation (E9) and

Marketed formulation (Zuvair)

5.13.5 Determination of Residual concentrations of Zafirlukast

0

50

100

150

200

250

300

350

400

450

0 2 4 6 8 10 12 14Mea

n pl

asm

a co

ncen

trat

ion

(ng/

ml)

Time (Hrs)

Final formulation (E9) Marketed (Zuvair)

Table5.102 Determination of Residual concentrations to various times by the application of Method of

Residuals (Final formulation-E9)

Time (hrs)1 2 3 4 5 6 Cr ± s.d

Co Ce CrCo Ce Cr

Co Ce CrCo Ce Cr

Co Ce CrCo Ce Cr

0 - - - - - - - - - - - - - - - - - - -

0.1 1.146 2.68 1.534 1.204 2.73 1.526 1.246 2.81 1.564 1.176 2.77 1.594 1.204 2.69 1.486 1.273 2.78 1.507 1.535±0.03

0.25 1.447 2.66 1.213 1.432 2.72 1.288 1.462 2.79 1.328 1.505 2.75 1.245 1.462 2.675 1.213 1.491 2.755 1.264 1.258±0.04

0.5 1.819 2.62 0.799 1.78 2.7 0.92 1.874 2.76 0.886 1.853 2.72 0.867 1.831 2.65 0.819 1.841 2.73 0.889 0.863±0.04

0.75 2.243 2.60 0.357 2.204 2.67 0.645 2.255 2.73 0.475 2.217 2.69 0.473 2.178 2.625 0.447 2.204 2.695 0.491 0.481±0.08

1 2.488 2.56 0.071 2.432 2.642 0.21 2.562 2.7 0.138 2.484 2.66 0.176 2.452 2.59 0.138 2.422 2.668 0.246 0.163±0.05

1.5 2.511 2.511 - 2.591 2.591 - 2.653 2.653 - 2.525 2.525 - 2.544 2.544 - 2.537 2.537 - -

2 2.469 2.469 - 2.491 2.491 - 2.568 2.568 - 2.498 2.511 - 2.472 2.472 - 2.498 2.498 - -

3 2.423 2.389 - 2.414 2.414 - 2.462 2.491 - 2.447 2.447 - 2.397 2.397 - 2.447 2.447 - -

4 2.255 2.255 - 2.29 2.29 - 2.352 2.352 - 2.301 2.301 - 2.255 2.255 - 2.332 2.332 - -

6 2.06 2.06 - 2.041 2.041 - 1.977 1.977 - 2.113 2.113 - 1.954 1.954 - 2.13 2.13 - -

8 1.819 1.819 - 1.845 1.845 - 1.903 1.903 - 1.838 1.838 - 1.863 1.863 - 1.924 1.924 - -

10 1.568 1.568 - 1.623 1.623 - 1.591 1.591 - 1.602 1.602 - 1.643 1.643 - 1.544 1.544 - -

12 1.278 1.278 - 1.322 1.322 - 1.342 1.342 - 1.255 1.255 - 1.322 1.322 - 1.255 1.255 - -


Fig 5.57 Semi logarithmic plots of Residual concentration Vs Time following the orally administration of Finalformulation (E9)

1

2

3

4

Subject – 5

Subject – 6

y = -1.634x + 1.645R² = 0.991

00.5

11.5

2

0 0.5 1 1.5Log

resi

dual

conc

entr

atio

n

Time (hrs)

y = -1.499x + 1.661R² = 0.993

0

0.5

1

1.5

2

0 0.5 1 1.5

Log

resi

dual

coce

ntra

tion

Time (hrs)

y = -1.609x + 1.715R² = 0.997

00.5

11.5

2

0 0.5 1 1.5Log

resi

dual

conc

entr

atio

n

Time (hrs)

y = -1.556x + 1.680R² = 0.990

0

0.5

1

1.5

2

0 0.5 1 1.5

Log

resi

dual

conc

entr

atio

n

Time (hrs)

y = -1.499x + 1.600R² = 0.996

00.5

11.5

2

0 0.5 1 1.5Log

resi

dual

conc

entr

atio

n

Time (hrs)

y = -1.427x + 1.621R² = 0.993

0

0.5

1

1.5

2

0 0.5 1 1.5

Log

resi

dual

conc

entr

atio

n

Time (hrs)

Table5.103 Determination of Residual concentrations to various times by the application of Method of

Residuals (Marketed formulation-Zuvair)

Time (hrs)1 2 3 4 5 6 Cr ± s.d

Co Ce CrCo Ce Cr

Co Ce CrCo Ce Cr

Co Ce CrCo Ce Cr

0 - - - - - - - - - - - - - - - - - - -

0.1 1.054 3.18 2.126 1.141 3.21 2.069 1.403 3.22 1.817 1.24 3.125 1.885 1 3.142 2.142 0.954 3.19 2.236 2.04±0.153

0.25 1.258 3.15 1.892 1.291 3.184 1.893 1.531 3.184 1.653 1.291 3.096 1.805 1.177 3.11 1.933 1.167 3.162 1.995 1.861±0.10

0.5 1.492 3.1 1.608 1.479 3.125 1.646 1.745 3.134 1.389 1.532 3.048 1.516 1.379 3.062 1.683 1.393 3.108 1.715 1.592±0.11

0.75 1.645 3.05 1.405 1.66 3.078 1.418 1.796 3.082 1.285 1.689 3.005 1.316 1.657 3.038 1.381 1.536 3.058 1.522 1.387±0.07

1 1.83 2.995 1.165 1.867 3.022 1.155 1.953 3.018 1.065 1.89 2.954 1.064 1.755 2.948 1.193 1.729 3.005 1.276 1.153±0.07

1.5 2.222 2.893 0.671 2.171 2.918 0.747 2.28 2.937 0.657 2.135 2.862 0.727 2.133 2.866 0.733 2.11 2.902 0.792 0.721±0.04

2 2.462 2.788 0.316 2.431 2.812 0.381 2.484 2.82 0.336 2.477 2.77 0.303 2.397 2.776 0.307 2.458 2.8 0.342 0.320±0.01

3 2.537 2.537 - 2.55 2.55 - 2.556 2.556 - 2.505 2.505 - 2.491 2.491 - 2.544 2.544 - -

4 2.389 2.389 - 2.397 2.397 - 2.439 2.439 - 2.389 2.389 - 2.462 2.462 - 2.414 2.414 - -

6 2.041 2.041 - 2.021 2.021 - 2.041 2.041 - 2.096 2.096 - 2.041 2.041 - 2.06 2.06 - -

8 1.491 1.491 - 1.602 1.602 - 1.579 1.579 - 1.724 1.724 - 1.69 1.69 - 1.518 1.518 - -

10 1.176 1.176 - 1.079 1.079 - 1.041 1.041 - 1.255 1.255 - 1.23 1.23 - 1.079 1.079 - -

12 0.698 0.698 - 0.698 0.698 - 0.778 0.778 - 0.845 0.845 - 0.845 0.845 - 0.778 0.778 - -


Fig.5.58 Semi logarithmic plots of Residual concentration Vs Time following the orally administration

of Marketed formulation (Zuvair)

1

2

3

4

5

6

y = -0.941x + 2.132R² = 0.992

0

0.5

1

1.5

2

2.5

0 1 2 3

Log

resi

dual

conc

entr

atio

n

Time (hrs)

y = -0.889x + 2.105R² = 0.995

0

0.5

1

1.5

2

2.5

0 1 2 3

Log

resi

dual

conc

entr

atio

n

Time (hrs)

y = -0.838x + 1.961R² = 0.995

0

0.5

1

1.5

2

0 1 2 3Lo

g re

sidu

alco

cent

rati

onTime (hrs)

y = -0.838x + 1.961R² = 0.995

0

0.5

1

1.5

2

0 1 2 3

Log

resi

dual

coce

ntra

tion

Time (hrs)

y = -0.917x + 2.142R² = 0.990

0

0.5

1

1.5

2

2.5

0 1 2 3

Log

resi

dual

conc

entr

atio

n

Time (hrs)

y = -0.971x + 2.257R² = 0.996

0

0.5

1

1.5

2

2.5

0 1 2

Log

resi

dual

conc

entr

atio

n

Time (hrs)

5.13.6 Estimation of Pharmacokinetic parameters of Zafirlukast

Table 5.104 Summary of Pharmacokinetic parameters estimated followingthe orally administration of Zafirlukast formulations, Final (E9) and

Marketed (Zuvair) in Animal models

S.No. Parameter

ProductSignificance of

differenceFinal(E9)

Marketed(Zuvair)

1 Cmax (ng/ml) 358.333±29.107 340±18.484 Not significant

2 Tmax (h) 1.5±0.00 3±0.00 Significant***

3 AUC0-t

(ng.h/ml) 1638.063±64.387 1544.696±31.897 Significant**

4 AUCt-∞

(ng.h/ml) 73.302±6.634 13.126±2.462 Significant***

5 Ka (h-1) 1.537±0.070 0.887±0.067 Significant***

6 Ke (h-1) 0.270±0.009 0.461±0.024 Significant***

7 t1/2(h) 2.562±0.086 1.501±0.086 Significant***

* = p < 0.05; ** = p < 0.01; *** = p < 0.001

Documents

5.EXPERIMENTAL RESULTS Montelukast Sodium …shodhganga.inflibnet.ac.in/bitstream/10603/8378/12/13_chapter 5.pdf · 5.2.1 Solubility Studies of Montelukast Sodium ... Levocetirizine