5.experimental results montelukast sodium...
TRANSCRIPT
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%
Sodium lauryl suphate
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
pH 6.8 Phosphate buffer 0.95
pH 7.4 Phosphate buffer 0.55
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
Bulk density 0.54gm/ml
Tapped density 0.70gm/ml
Compressibility Index 22%
Angle of repose 35º
Amplitude 60
Time 5 min
Weight of sample taken in (g) 10.0
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
Hauser’s ratio 1.19
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)
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)
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)
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)
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)
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
Montelukast Sodium (pure drug)
(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
(n=3, Error bars indicate standard deviation)
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
(n=3, Error bars indicate standard deviation)
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)
(n=3, Error bars indicate standard deviation)
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
(n=3, Error bars indicate standard deviation)
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
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
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
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
(n=3, Error bars indicate standard deviation)
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)
5.7.4 Compatibility analysis:
Characterization of Zafirlukast and γ-CD inclusion complex:
Fourier transform infra-red spectroscopy:
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
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
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
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%
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%
Sodium lauryl suphate
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
pH 6.8 Phosphate buffer 0.95
pH 7.4 Phosphate buffer 0.55
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
Bulk density 0.54gm/ml
Tapped density 0.70gm/ml
Compressibility Index 22%
Angle of repose 35º
Amplitude 60
Time 5 min
Weight of sample taken in (g) 10.0
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
Hauser’s ratio 1.19
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)
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)
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)
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)
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)
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
Montelukast Sodium (pure drug)
(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
(n=3, Error bars indicate standard deviation)
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
(n=3, Error bars indicate standard deviation)
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)
(n=3, Error bars indicate standard deviation)
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
(n=3, Error bars indicate standard deviation)
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)
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
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
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
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
(n=3, Error bars indicate standard deviation)
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)
5.7.4 Compatibility analysis:
Characterization of Zafirlukast and γ-CD inclusion complex:
Fourier transform infra-red spectroscopy:
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.
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
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
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
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
M1 M2 M3 M4 M5 M6 M7 M8 M9 Control Marketed0 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.005 35±0.86 32±0.86 31±0.86 28±0.34 23±0.87 27±0.76 24±0.98 20±0.86 23±0.82 52±0.86 35±0.86
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
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
M1 M2 M3 M4 M5 M6 M7 M8 M9 Control Marketed0 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.005 35±0.86 32±0.86 31±0.86 28±0.34 23±0.87 27±0.76 24±0.98 20±0.86 23±0.82 52±0.86 35±0.86
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
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
M1 M2 M3 M4 M5 M6 M7 M8 M9 Control Marketed0 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.005 35±0.86 32±0.86 31±0.86 28±0.34 23±0.87 27±0.76 24±0.98 20±0.86 23±0.82 52±0.86 35±0.86
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 5.20 First order plots of M5, M6, M7 & M9 formulations
Fig 5.19 First order plots of M1, M2, M3 & M4 formulations
Fig 5.20 First order plots of M5, M6, M7 & M9 formulations
Fig 5.19 First order plots of M1, M2, M3 & M4 formulations
Fig 5.20 First order plots of M5, M6, M7 & M9 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
Fig 5.21 First order plots of M8 (Final), Control &
Marketed formulations
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)
Fig 5.21 First order plots of M8 (Final), Control &
Marketed formulations
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
(n=3, Error bars indicate standard deviation)
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
(M8)Marketed(Romilast)
0
10
20
30
40
50
60
70
80
90
100
110
0 5 10
Cum
mul
ativ
e %
Dru
g di
ssol
ved
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
(n=3, Error bars indicate standard deviation)
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
(M8)Marketed(Romilast)
10 15 20 25 30 35 40 45 50
Time (min)
Final (M8)
Control
Marketed (Romilast)
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
(n=3, Error bars indicate standard deviation)
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
(M8)Marketed(Romilast)
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
Media 0.5 % SLS in water
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
Media 0.5 % SLS in water
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
(n=3, Error bars indicate standard deviation)
Fig 5.27 (b) Levocetrizine
(n=3, Error bars indicate standard deviation)
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
Table 5.52: (a) Montelukast sodium
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
Table 5.53: (b) Levocetrizine
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
Table 5.54: (a) Montelukast sodium
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
Table 5.55: (b) Levocetrizine
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
Fig 5.29 (b) Levocetrizine
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)
Marketed (Montair lc)
Correlation Coefficient(R) Values of orally disintegrating formulations of Montelukast sodium withLevocetrizine: as per Zero Order and First Order Kinetics.
Table 5.56: (a) Montelukast sodium
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)
Marketed (Montair lc)
(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
P value summary ***Are means signif. different? (P < 0.05) Yes
One- or two-tailed P value? Two-tailedt, df t=19.95 df=4
5.9.4.2 Fit factor test (f1 and f2)
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
Fig 5.31 (b) Levocetrizine
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
(n=3, Error bars indicate standard deviation)
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
0=tasteless, 1=acceptable bitterness, 2=slight bitterness, 3=moderately bitterness and 4=strong bitterness
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)
Media 0.5 % SLS in water
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
(n=3, Error bars indicate standard deviation)
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
Media 0.5 % SLS in water
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
(n=3, Error bars indicate standard deviation)
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
5.11.4. In –vitro Dissolution kinetic parameters for all Orally Disintegrating Tablet formulations ofZafirlukast
10 15 20 25 30 35 40 45
Time (min)
S1
S2
S3
S4
S5
S6
S7
S8
S9
Control
Formulation code DP30 (%) DE30 (%) t90(min)S1 75.3 52.83 >45S2 78.2 58.23 45S3 77.6 55.44 45
5.11.4. In –vitro Dissolution kinetic parameters for all Orally Disintegrating Tablet formulations ofZafirlukast
S1
S2
S3
S4
S5
S6
S7
S8
S9
Control
Formulation code DP30 (%) DE30 (%) t90(min)S1 75.3 52.83 >45S2 78.2 58.23 45S3 77.6 55.44 45
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)
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 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)
Cum. % Drug dissolved
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)
(n=3, Error bars indicate standard deviation)
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
P value summary ***Are means signif. different? (P < 0.05) Yes
One- or two-tailed P value? Two-tailedt, df t=208.3 df=4
5.11.8.3 Fit factor test (f1 and f2)
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%RHObservations At
400C± 20C/75%± 5%RHObservations At
400C± 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 (%) 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
(n=3, Error bars indicate standard deviation)
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)
(n=3, Error bars indicate standard deviation)
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)
(n=3, Error bars indicate standard deviation)
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
(n=3, Error bars indicate standard deviation)
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)
(n=3, Error bars indicate standard deviation)
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
Time period Initial 1 month 3 month 6 month
Appearance Complies Complies Complies Complies
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 - -
Cr-Residual concentration; Ce-Extraploted concentration; Co–Original concentration
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 - -
Cr-Residual concentration; Ce-Extraploted concentration; Co–Original concentration
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