Presented byMr. Sumit A. Abnawe
Guided byProf. Vishnu P. Choudhary
In partial fulfillment of the degree of Master of Pharmacy in
Quality Assurance Techniques MAEER’s Maharashtra Institute of Pharmacy,
MIT campus, Kothrud, Pune - 411 038.
2009 - 20101
Development and Evaluation of Time – Based Rupturable Pulsatile Drug
Delivery System
CONTENTS
2
IntroductionLiterature ReviewResearch Envisaged and Plan of WorkDrug ProfileExcipients ProfileExperimental Work & ResultSummary and ConclusionIndustrial ApplicabilityAcknowledgementReferences
INTRODUCTION
3
Pulsatile Drug Delivery System It is the one type of drug delivery system, where the delivery device is capable of releasing drug after predetermined time delay (i.e. lag time).
4
Chronopharmaceutical Drug Delivery It is the delivery of drugs in accordance with the circadian rhythms of the disease.
Diseases and Chronological Behaviour
5
Disease Chronological behaviour Drugs used
Peptic ulcer Acid secretion is high in the afternoon and at night
H2 blockers
Asthma Precipitation of attacks during night or at morning hour
Early β2 agonist, Antihistaminics etc.
Cardiovascular diseases
BP is at its lowest during the sleep cycle and rises steeply during the early morning awakening period
Nitroglycerin, Calcium channel blocker, ACE inhibitors etc.
Arthritis Pain in the morning and more pain at night
NSAIDs, Glucocorticoids etc.
Diabetes mellitus Increase in the blood sugar level after meal
Sulfonylurea, Insulin, Biguanide etc.
Attention deficit syndrome
Increase in DOPA level in afternoon
Methylphenidate etc.
Hypercholesterolemia
Cholesterol synthesis is generally during night than during day time
Higher HMG CoA reductase inhibitors
6
PULSATILE DRUG
DELIVERY SYSTEM
Time controlled pulsatile drug
delivery
Single unit systems
1. Capsule based Capsular 2. Capsular system based on Osmosis3. System with erodible barrier coatings4.System with rupturable coating
Multiple unit systems
1. System with rupturable coating2. Osmotic based rupturable coating system3. Pulsatile delivery by change in membrane permeability
Stimuli induced
pulsatile drug delivery
1. Temperature induced systems2. Chemical stimuli induced pulsatile systems
Externally regulated
pulsatile drug delivery
Classification:
LITERATURE REVIEW
7
Journals and Articles review1. R. Bodmeier et al. investigated swelling characteristics
as follows: Croscarmellose sodium > Low-substituted
hydroxypropyl cellulose > sodium starch Glycolate > crospovidone > hydroxypropyl methylcellulose.
1. Andrei Dashevsky, Ahmad Mohamad studied and concluded that: For complete repture, amount of (Ac-Di-Sol®)
required was 48% (w/w). To use ethyl cellulose of lower molecular weight Addition of talc led to increase brittleness of
membrane
1. T.Y. Fan et al. studied and concluded that: DILTIAZIM atblet containing 8 mg SSG and coating
levels 5.7 %, 7.4 % and 9.5 % of Ethyl cellulose and Eudragit L (1:2) shows lag time of 1, 3 and 4 hours respectively.
8
4. Ahmad Mohamad and Andrei Dashevsky concluded that:
Rupturable top-coating was successfully performed using an aqueous dispersion of ethylcellulose.
A higher coating level was required, when aqueous dispersion was used, compared to organic coatings.
5. Raghavendra Rao N. G and Suryakar V. B prepared
Montelukast sodium buccal patches.
9
Patents Review Hrakovsky, Julia et al. has taken patent for:
“Stable pharmaceutical formulations of montelukast sodium.”
The invention encompasses stable pharmaceutical compositions in film coated tablet form comprising montelukast or salts thereof and methods of preparing the same. Preferably, the salt is the sodium salt.
RESEARCH ENVISAGED AND PLAN OF WORK
10
In a large study involving 8,000 asthmatics, it is observed that,
1. 75% awakened one night per week,
2. 64% awakened 3 nights per week and
3. 39% had their sleep disturbed on a nightly basis.
The patients who self-characterized their asthma as mild,
1. 26% had nightly awakenings and
2. 53% of asthma deaths occurred during the night time hours.
3. Lung function is usually highest at 4 pm and lowest at 4 am the latter time is generally when asthma symptoms are most prevalent.
4. Based on these findings it was planned to modify drug delivery and therapy to achieve an effective drug level at the required time. This can be achieved by adapting a pulsatile drug delivery system of a suitable drug.
11
LiteratureSurvey
Selection of Drug &Excipients
Formulation development of trial batches (TD & TS)
Formulation Development
Preformulation Study
Evaluation of trial batches
Coating of trial batches
Results and Discussion
Evaluation of SA1 to SC4 batches
Formulation development of SA1 to
SC4 batches
Coating of SA1 to SC4 batches
Summary and Conclusion
LiteratureSurvey
DRUG PROFILE
12
Montelukast Sodium
Sr. no.
Parameter Comments
1 Mechanism of action
Selective leukotriene receptor antagonist of the cysteinyl leukotriene CysLT1 receptor.
2 Absorption Rapid absorption, BA is not affected by a standard meal
3 Half-life 2.7 to 5.5 hours
4 Tmax 3 to 4 hours
5 Dose >15 yrs, 10 mg daily
N
OCOO-Na+
HO
CH3
H3C
Cl
13
Marketing and Patent status
14
Innovetor
15
Patent Status
EXCIPIENTS PROFILE
16
Sr. no.
Excipient Use
1 Cellulose, microcrystalline
Diluent
2 sodium starch glycolate
Disintegrant.
3 Doshion P 544 C Disintegrant.
4 Colloidal silicon dioxide
Glidant
5 Magnesium stearate Lubricant
6 Sodium lauryl sulfate
Solubilizer in concentrations greater than critical micelle concentration
7 Ethylcellulose Sustained-release tablet coating
8 Talc To increase brittleness of coat
9 Titanium dioxide Opacifier
10 Castor oil Plasticizer
11 Dichloromethane Coating solvent
12 Isopropyl alcohol Coating solvent
EXPERIMENTAL WORK AND
RESULT
17
Preformulation Study
18
Sr. no.
Test Limit Result
1 Appearance Light yellow coloured powder,
hygroscopic in nature.
2 Identification by IR - -
3 Determination of BD & TD - 0.769 &
0.9094 Test for sodium
0.1 gm sample + 20 ml water + 2 ml 15 % Potassium carbonate + boil No ppt + 4 ml potassium pyroantimonate TS + boil + cool in ice water
Sodium is present.
5 Loss on drying (% w/w) 3 2.5
6 Determination of flow property -
7 Drug analysis by UV/Visible spectrophotometer
- 346 nm
8 Drug-excipient interaction - Compatible
9 Assay by HPLC (% w/w ) 98.0 - 102.0 99.78
Drug analysis by UV/Visible spectrophotometer
19
Sr. no.
Parameter Observation
1. Wavelength of detection (nm) 3462. Beer’s law limit (μg/ml) 6 - 163. Regression Equation (y = mx + c)4. Slope (m) 0.08535 Intercept (c) 0.16966 Correlation coefficient 0.9994
Preformulation Study
20
Sr. no.
Test Limit Result
1 Appearance Light yellow coloured powder,
hygroscopic in nature.
Light yellow coloured powder,
hygroscopic in nature.
2 Identification by IR - -
3 Determination of BD & TD - 0.769 & 0.9094 Test for sodium
0.1 gm sample + 20 ml water + 2 ml 15 % Potassium carbonate + boil No ppt + 4 ml potassium pyroantimonate TS + boil + cool in ice water
- Sodium is present.
5 Loss on drying (% w/w) 3 2.5
6 Determination of flow property -
7 Drug analysis by UV/Visible spectrophotometer
- 346 nm
8 Drug-excipient interaction - -
9 Assay by HPLC (% w/w ) 98.0 - 102.0 99.78
21
VialNo. Drug + Excipients Ratio
Initial Observat
ion
Observation after 15 days under
following conditions
55°C
55°C, 5%
moisture
1. Pure Montelukast Sodium 1.0 White powder
Liquification
Liquification
2. Montelukast Sodium + Microcrystalline Sodium 1:1 White
powderNo
change
Brownish white cake
3.Montelukast Sodium + Microcrystalline Sodium + Doshion P 544 C
1:1:1 White powder
No change
Brownish white power
4.
Montelukast Sodium + Microcrystalline Sodium + Doshion P 544 C + Magnesium Stearate
1:1:1:1
White powder
No change
Brownish white power
5.
Montelukast Sodium + Microcrystalline Sodium + Doshion P 544 C + Magnesium Stearate + Hydrophobic Colloidal Anhydrous Silica
1:1:1:1:1
White powder
No change
No changeAbove observations shows that Montelukast Sodium is
compatible with selected excipients in presence and absence of 5 % moisture.
22
VialNo. Drug + Excipients Ratio
Initial Observati
on
Observation after 15 days under
following conditions
55°C 55°C, 5% moisture
1. Pure Montelukast Sodium 1.0 White powder
Liquification
Liquification
2. Montelukast Sodium + Microcrystalline Sodium 1:1 White
powderNo change
Brownish white cake
3.Montelukast Sodium + Microcrystalline Sodium + Sodium Starch Glycolate
1:1:1 White powder
No change
Brownish white cake
4.
Montelukast Sodium + Microcrystalline Sodium + Sodium Starch Glycolate + Magnesium Stearate
1:1:1:1 White powder
No change
Brownish white power
5.
Montelukast Sodium + Microcrystalline Sodium + Sodium Starch Glycolate + Magnesium Stearate + Hydrophobic Colloidal Anhydrous Silica
1:1:1:1:1
White powder
No change
No change
Above observations shows that Montelukast Sodium is compatible with selected excipients in presence and absence of 5 % moisture.
Preformulation Study
23
Sr. no.
Test Limit Result
1 Appearance Light yellow coloured powder,
hygroscopic in nature.
2 Identification by IR - -
3 Determination of BD & TD - 0.769 &
0.9094 Test for sodium
0.1 gm sample + 20 ml water + 2 ml 15 % Potassium carbonate + boil No ppt + 4 ml potassium pyroantimonate TS + boil + cool in ice water
Sodium is present.
5 Loss on drying (% w/w) 3 2.5
6 Determination of flow property -
7 Drug analysis by UV/Visible spectrophotometer
- 346 nm
8 Drug-excipient interaction - -
9 Assay by HPLC (% w/w ) 98.0 - 102.0 99.78
24
Assay of pure drug was carried out by ADL department of Elder pharmaceuticals using INH developed and validated HPLC method.
Montelukast sodium chromatogram by using optimized chromatographic conditions.
MO
NT
E -
6.2
50
AU
0.00
0.05
0.10
0.15
0.20
Minutes
0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00
Formulation design of core tablets
25
Formulation of Montelukast sodium core tablets of trial batches TD and TS
Sr. No.
IngredientWeight (mg) /
tablet Formulation code
TD TS
1.Montelukast Sodium (equivalent to 10 mg of Montelukast)
10.38 10.38
2. Microcrystalline Cellulose (PH 102) 102.47 102.07
3. Sodium Starch Glycolate - 10.4
4. Doshion P 544C 10 -
5. Hydrophobic Colloidal Anhydrous Silica 0.65 0.65
6. Magnesium Stearate 6.5 6.5
Final Weight 130 130
Manufacturing Process
26
1. All the ingredients were weighed accurately.
2. Weighed quantity of Montelukast sodium was passed through # 40 and mixed with microcrystalline cellulose PH 102 (previously passed through # 30) in geometrical proportion in dark room.
3. Weighed quantity of sodium starch glycolate or doshion P 544C was passed through # 30 and mixed with step 2.
4. Hydrophobic colloidal anhydrous silica was passed through # 60 and mixed with step 3 in polybag.
5. Magnesium stearate was passed through # 60 and mixed with step 4 in polybag for one minute.
6. The tablets were compress at average weight of 130 mg/tab.
7. Physical evaluation of tablets was carried out.
Evaluation of Montelukast sodium core tablets of TD and TS trial batches
27
Sr. No.
ParameterResult
LimitTD TS
1 Hardness (mm) 4.0 - 5.0 4.0 - 5.0 -
2 Thickness (mm) 3.85 3.86 -
3 Diameter (mm) 7.04 7.05 -
4 Friability (%) 0.437 0.537 < 1
5 Disintegration Time (min.) 2 - 4 10 - 12 < 15
min.
6 Weight variation (%) ±1.5 ±1.45 < 10
7 Content of active ingredient (%)
99.43 - 100.75
99.54 - 100.92
90 - 110
8 Uniformity of content (%)
99 - 10199 - 101 85 -
115
9 Dissolution Study (%) 100.02 98.21 NLT 70%
28
Dissolution Study
Experimental Conditions Apparatus - USP Dissolution Apparatus, Type
II (Paddle) Dissolution Medium - 0.5% SLS Volume - 900 ml Temperature - 37 ± 0.5ºC RPM - 50 Limit - NLT 70 % drug should be
dissolves in 30 minutes in 0.5 % SLS.
29
The tablets of batches TD and TS shows 98-101% drug dissolved in 30 min so it passes the dissolution test, as it is specified by FDA that NLT 70 % drug should be dissolves in 30 minutes in 0.5 % SLS.
Release profile of Montelukast sodium core tablets of TD and TS batches
Coating of Montelukast sodium tablets of TD and TS trial batches
30
Sr. No. Component Use Quantity
1.Ethyl cellulose 20 cps
Coating polymer 70 % w/v
2. TalcAnti-adherent 10 % w/v
3. Castor oil Plasticizer 15 % w/v
4. Titanium dioxide Opecifier 5 % w/v
5. Methylene chloride Solvent65 % of total
solvent
6. Isopropyl alcohol Solvent35 % of total
solvent
Coating parameters
31
Coating solution was prepared to have 5 % reconstitution level for ease of spray through the nozzle.Sr.
No.Parameter Quantity
1. Weight of tablets 100 gms
2. Coating level 20 %
3. Coating material 20 gm
4. Loss during process 2 %
5. Reconstitution level 5 %
6.Isopropyl alcohol (35 %)
(solvent)133 gm
7.Methylene chloride (65 %)
(solvent)247 gm
Total solvent 380 gm
Coating process conditions
32
Sr. No. Parameter Conditions
1. Inlet air temperature 400C
2. Product bed temperature 300C - 350C
3. Outlet temperature 360C - 380C
4. Pump RPM 1
5. Pan RPM 35
6. Spray rate 2.1 gm/min/gun
7. Process time 3 hrs.
Coating formula for trial batches
33
STAGE
FORMULA (mg)
TD TSI CORE TABLET PREPARATION
` Montelukast Sodium (equivalent to 10 mg of Montelukast) 10.38 10.38
2 Microcrystalline Cellulose (PH 102) 102.47 102.07
3 Sodium Starch Glycolate - 10.4
4 Doshion P 544C 10 -
5 Hydrophobic Colloidal Anhydrous Silica 0.65 0.65
6 Magnesium Stearate 6.5 6.5
Total weight 130 130II COATING OF ETHYL CELLULOSE
1 Ethyl cellulose 20 cps 9.1 13.65
2 Talc 1.3 1.95
3 Castor oil 1.95 2.9254 Titanium dioxide 0.65 0.975
Total weight 140.00 149.50
Weight gain on core tablets 10 % 15%
Evaluation of coated TD and TS batches
34
Sr. No.
Parameter
Result
LimitTD TS
1 Hardness (mm) 6 - 8 9 - 10 -
2 Thickness (mm) 3.96 4.12 -
3 Diameter (mm) 7.32 7.48 -
4 Weight variation (%) ±1.0 ±1.0 < 10
5 Content of active ingredient (%)
99.38 -
101.20
99.46 -
100.83 90 - 110
6 Uniformity of content (%) 99 - 101 99 - 101 85 - 115
7 Dissolution Study (%) 100.02 98.21 NLT 70 %
35
According to release profile it was concluded that amount of resin required was not economic so it was planned to exclude Doshion P 544C and to use economic superdisintegrant, SSG and the changes had been made in to the formula of TS batch to get the required pulsatile profile.
Dissolution study
Drug release profile of coated Montelukast sodium tablets of TD and TS batches
Formulation of Montelukast sodium core tablets of SA, SB and SC batches
36
Sr.
No.Ingredient
Weight (mg) /
tablet
Formulation code
SA SB SC
1.Montelukast Sodium (equivalent to10 mg of Montelukast) 10.38 10.38 10.38
2. Microcrystalline Cellulose (PH 102) 109.87107.2
7
104.6
7
3. Sodium Starch Glycolate 2.6 5.2 7.8
4.Hydrophobic Colloidal Anhydrous
Silica0.65 0.65 0.65
5. Magnesium Stearate 6.5 6.5 6.5
Final Weight 130 130 130
Evaluation of Montelukast sodium core tablets of SA, SB and SC batches
37
Sr. No. Parameter
Result
LimitSA SB SC
1 Hardness (mm) 3.5 - 4.5 3.5 - 4.5 3.5 - 4.5 -
2 Thickness (mm) 3.65 3.69 3.7 -
3 Diameter (mm) 7.05 7.05 7.05 -
4 Friability (%) 0.217 0.253 0.221 < 1
5 Disintegration Time (min.) 3 - 4 5 - 6 6 - 8 < 15
min.
6 Weight variation (%) ±1.5 ±1.4 ±1.5 < 10
7 Content of active ingredient (%)
100.05 -101.00
100.19 -100.94
99.87 - 100.58 90 - 110
8 Uniformity of content (%) 99 - 101 99 - 101 99 - 101 85 -
115
9 Dissolution Study (%) 99.46 99.59 99.76 NLT 70%
Dissolution study
38
The tablets of batches SA, SB and SC shows 99-100% drug dissolved in 30 min so it passes the dissolution test, as it is specified by FDA that NLT 70 % drug should be dissolves in 30 minutes in 0.5 % SLS.
Release profile of Montelukast sodium core tablets of SA, SB and SC batches
Coating of Montelukast Sodium tablets of SA, SB and SC batches Batch SA
39
STAGE FORMULA (Mg) BATCHE CODE
I CORE TABLET PREPARATION SA1 SA2 SA3 SA4
1Montelukast Sodium (equivalent to 10 mg of Montelukast)
10.38 10.38 10.38 10.38
2 Microcrystalline Cellulose (PH 102)109.8
7109.8
7109.8
7109.8
7
3 Sodium Starch Glycolate 2.6 2.6 2.6 2.6
4 Hydrophobic Colloidal Anhydrous Silica 0.65 0.65 0.65 0.65
5 Magnesium Stearate 6.5 6.5 6.5 6.5
Total weight 130 130 130 130
II COATING OF ETHYL CELLULOSE
1 Ethyl cellulose 20 cps 4.55 6.37 9.1 10.92
2 Talc 0.65 0.91 1.3 1.56
3 Castor oil 0.975 1.365 1.95 2.34
4 Titanium dioxide 0.325 0.455 0.65 0.78
Total weight136.50
139.10
143.00
145.60
Weight gain on core tablets (% w/w) 5 7 10 12
Batch SB
40
STAGE FORMULA (Mg) BATCH CODE
I CORE TABLET PREPARATION SB1 SB2 SB3 SB4
1Montelukast Sodium (equivalent to 10 mg of Montelukast)
10.38 10.38 10.38 10.38
2 Microcrystalline Cellulose (pH 102)107.2
7107.2
7107.2
7107.2
7
3 Sodium Starch Glycolate 5.2 5.2 5.2 5.2
4 Hydrophobic Colloidal Anhydrous Silica 0.65 0.65 0.65 0.65
5 Magnesium Stearate 6.5 6.5 6.5 6.5
Total weight 130 130 130 130
II COATING OF ETHYL CELLULOSE
1 Ethyl cellulose 20 cps 4.55 6.37 9.1 10.92
2 Talc 0.65 0.91 1.3 1.56
3 Castor oil 0.975 1.365 1.95 2.34
4 Titanium dioxide 0.325 0.455 0.65 0.78
Total weight136.50
139.10
143.00
145.60
Weight gain on core tablets (% w/w) 5 7 10 12
Batch SC
41
STAGE FORMULA (Mg) BATCH CODE
I CORE TABLET PREPARATION SC1 SC2 SC3 SC4
1Montelukast Sodium (equivalent to 10 mg of Montelukast)
10.38 10.38 10.38 10.38
2 Microcrystalline Cellulose (PH 102)104.6
7104.6
7104.6
7104.6
7
3 Sodium Starch Glycolate 7.8 7.8 7.8 7.8
4 Hydrophobic Colloidal Anhydrous Silica 0.65 0.65 0.65 0.65
5 Magnesium Stearate 6.5 6.5 6.5 6.5
Total weight 130 130 130 130
II COATING OF ETHYL CELLULOSE
1 Ethyl cellulose 20 cps 4.55 6.37 9.1 10.92
2 Talc 0.65 0.91 1.3 1.56
3 Castor oil 0.975 1.365 1.95 2.34
4 Titanium dioxide 0.325 0.455 0.65 0.78
Total weight136.50
139.10
143.00
145.60
Weight gain on core tablets (% w/w) 5 7 10 12
Evaluation of batches SA1 to SC4
42
Sr. No.
Formulation code
ParameterHardnes
s (kg/cm2)
Thickness (mm)
Diameter
(mm)
Weight variation
(%)1. SA1 5.2 3.85 7.20 ± 1
2. SA2 6.1 3.90 7.24 ± 1
3. SA3 6.3 3.95 7.33 ± 1
4. SA4 7.5 4.03 7.39 ± 1
5. SB1 5.1 3.85 7.21 ± 1
6. SB2 6.2 3.92 7.25 ± 1
7. SB3 6.3 3.96 7.31 ± 1
8. SB4 7.6 4.05 4.39 ± 1
9. SC1 5.2 3.84 7.20 ± 1
10. SC2 6.2 3.91 7.23 ± 1
11. SC3 6.4 3.96 7.32 ± 1
12. SC4 7.6 4.05 7.39 ± 1
43
Sr. No. Formulation code
Content of active ingredient (%)
1. SA1 99.83 - 100.86
2. SA2 99.89 - 100.53
3. SA3 99.93 - 100.32
4. SA4 99.23 - 100.10
5. SB1 99.53 - 99.98
6. SB2 99.91 - 100.98
7. SB3 99.84 - 100.64
8. SB4 99.96 - 100.82
9. SC1 99.79 - 100.90
10. SC2 99.76 - 100.11
11. SC3 99.78 - 100.20
12. SC4 99.79 - 100.78
Dissolution study: Batch SA
44
Montelukast release from tablet containing 2% (w/w) Sodium starch glycolate and coated with 5% (w/w) coating level shows the lag time of 1.5 hours then follow the sigmoidal release pattern with 100% drug release at 4.5 hours. As the concentration of coating level increases from 7 to 12 % (w/w) the lag time extended to 4 hours and then follows the delayed release profile with the 100 % drug release at the 5.5 to 6 hours.
Drug release profile of coated Montelukast sodium tablets of SA1 to SA4 batches
Batch SB
45
Montelukast release from tablet containing 4 % (w/w) Sodium starch glycolate and coated with 5% (w/w) coating level shows the lag time of 1.5 hours then follow the sigmoidal release pattern with 100% drug release at 3.5 hours. As the concentration of coating level increases from 7 to 12 % (w/w) the lag time extended to 4.25 hours and then follows the delayed release profile with the 100 % drug release at the 4 to 6 hours.
Release profile of coated Montelukast sodium tablets of batches SB1 to SB4
Batch SC
46
Montelukast release from tablet containing 6 % (w/w) Sodium starch glycolate and coated with 5% (w/w) coating level shows the lag time of 1.5 hours then follow the sigmoidal release pattern with 100% drug release at 4th hours. As the concentration of coating level increases from 7 to 12 % (w/w) the lag time extended to 4 hours and then follows the delayed release profile with the 100 % drug release at the 3.5 to 6 hours.
Release profile of coated Montelukast sodium tablets of batches SC1 to SC4
Stability study of selected batch
47
INTERMEDIATE STABILITY:Storage conditions: 30 ± 2o C and RH 65 % ± 5%
Product: Pulsatile drug system of Montelukast sodium tablets
Batch no. – SC2
Pack Size - 10 tablets packed in alu-alu pouch
Batch size - 400 tabs
Kept for stability on - April 2010
Label claim - Each coated tablet contains:
Montelukast sodium equivalent to Montelukast..........10 mg
Colour - Titanium dioxide
48
Sr. No.
Parameter
Specification Initial 1 M 2M 3M
1. Description
Pale yellow, circular, biconvex
Pale yellow, circular, biconve
x
Pale yellow, circular, biconve
x
Pale yellow, circular, biconve
x
Pale yellow, circular, biconve
x
2. Assay 90 - 110 % 99.76 - 100.11
99.74 - 99.99
98.52 - 100.07
98.62 - 99.91
3. Dissolution NLT 70% 99.72 99.70 99.71 99.68
49
Montelukast release from batch C tablets after 1st and 2nd months does not shows significant change in lag time and cumulative % drug release but after 3rd month it shows drastic change in lag time from initial value 2 hrs to 1.5 hrs and shows 100 % drug release at 4th hr showing instability of coat after 3 months.
Drug release profile of coated Montelukast sodium tablets of SC2 batch after 1, 2 and 3 monthswhich were kept for Intermediate Stability study
50
ACCELARATED STABILITY Storage conditions: 30 ± 2o C and RH 65 % ± 5% Product: Pulsatile drug system of Montelukast sodium tabletsBatch no. – SC2Pack Size - 10 tablets packed in alu-alu pouchBatch size - 400 tabsKept for stability on - April 2010Label claim - Each coated tablet contains:Montelukast sodium equivalent to Montelukast..........10 mgColour - Titanium dioxide
51
Sr.
No.
Paramet
er
Specificat
ion
Initial 1 M 2M 3M
1 Descriptio
n
Pale
yellow,
circular,
biconvex
Pale
yellow,
circular,
biconve
x
Pale
yellow,
circular,
biconve
x
Pale
yellow,
circular,
biconve
x
Pale
yellow,
circular,
biconve
x
2 Assay 90 - 110 % 99.76 -
100.11
99.63 -
99.97
98.32 -
99.51
98.11 -
99.28
3 Dissolutio
n
NLT 70%99.72 99.73 99.68 99.64
52
Montelukast release from batch C tablets after 1st month does not shows significant change in lag time and but shows 100 % drug release after 4th hr but after 2nd and 3rd month it shows drastic change in lag time from initial value 2 hrs to 1.5 hrs and shows 100 % drug release after 4th hr showing instability of coat after 2 months.
Drug release profile of coated Montelukast sodium tablets of SC2 batch, after 1, 2 and 3 months which were kept for Accelerated Stability study
SUMMARY AND CONCLUSION
53
The main objective of the study was to develop rupturable pulsatile drug delivery system to treat asthma. Lung function (e.g., peak expiratory flow rate or FEV1) is usually highest at 4 pm and lowest at 4 am the latter time is generally when asthma symptoms are most prevalent. So, the intension was that the formulation should be administered in the evening at 10.00 pm which will rupture after 2 hours and will reach to its C max at around 3.00 pm to around 3.30 pm and will be available at the site of action for at least 4 to 5 hours.
54
For batch TD, The release profile of batch TD containing 10 mg Doshion P 544 C and coated with 10 % Ethyl cellulose shows lag time of 3.5 hours and 100% drug release at 4.25 hour. According to release profile it was concluded that amount of resin required was not economic so it was planned to exclude Doshion P 544 C and to use economic superdisintegrant.
For batch TS, Montelukast sodium release from batch TS containing 8 % Sodium starch glycolate and coated with 15 % coating level showed lag time of 4 hours and 56 % drug release at 4.5 hour. According to the release profile of control batch, the changes were done in the formula to required pulsatile release profile.
55
Montelukast sodium release from batches A1 to A4 containing 2% (w/w) Sodium starch glycolate and coated with 5% (w/w) coating level shows the lag time of 1.5 hours and 100% drug release at 4.5 hours. As the concentration of coating level increases from 7 to 12 % (w/w) the lag time extended to 4 hours and then follows the delayed release profile with the 100 % drug release at the 5.5 to 6 hours.
Montelukast sodium release from batches B1 to B4 containing 4% (w/w) Sodium starch glycolate and coated with 5% (w/w) coating level shows the lag time of 1.5 hours and 100% drug release at 3.5 hours. As the concentration of coating level increases from 7 to 12% (w/w) the lag time extended to 4.25 hours and then follows the delayed release profile with the 100% drug release at the 4 to 6 hours.
56
Montelukast sodium release from batches C1 to C4 containing 6% (w/w) Sodium starch glycolate and coated with 5% (w/w) coating level shows the lag time of 1.5 hours and 100% drug release at 4th hours. As the concentration of coating level increases from 7 to 12 % (w/w) the lag time extended to 4 hours and then follows the delayed release profile with the 100 % drug release at the 3.5 to 6 hours.
Therefore the present study indicates that, to get pulsatile drug release profile, Montelukast sodium core tablets with average weight of 130 mg containing 6 % of sodium starch glycolate with minimum coating level of 7 % Ethyl cellulose with addition of 15 % castor oil and 10 % talc, showing lag time of 2 hours and 100% drug release, was achieved.
INDUSTRIAL APPLICABILITY
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Not a single pulsatile release tablet of Montelukast Sodium is available in the domestic, regulated and non regulated market.
Patent expiration date is Aug. 13, 2013.After expiration of the drug exclusivity and
patents of innovator or before that the pulsatile formation can be commercialized in the choice of market.
ACKNOWLEDGEMENT
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I would like to acknowledge here Proff. V. P. Choudhari, my Research
guide Dr. Prof. B. S. Kuchekar for giving me a
chance to be a part of this prestigious institute.
Dr. Miss. Swati Jagdale for helping me during the project work
Elder Pharmaceuticals Ltd for giving me a valuable training and
last but not the least, my Friends.....
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THANK YOU
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