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International Standard Serial Number (ISSN): 2319-8141 International Journal of Universal Pharmacy and Bio Sciences 2(5): September-October 2013
INTERNATIONAL JOURNAL OF UNIVERSAL
PHARMACY AND BIO SCIENCES IMPACT FACTOR 1.89***
ICV 3.00***
Pharmaceutical Sciences RESEARCH ARTICLE……!!!
Received: 17-09-2013; Accepted: 27-09-2013
FORMULATION AND IN-VITRO EVALUATION OF TOLTERODINE TARTRATE SUSTAINED
RELEASE PELLETS
M. Sirisha*1, Dr. C. Gopinath, C. Rajasree
1, H. Haripriya
2
1Department of Pharmaceutics, Annamacharya College of Pharmacy, New Boyanapalli, Rajampet,
2Y.S.R. Dist. - 516126, Andhra Pradesh, India.
KEYWORDS:
Conventional coating pan,
fluid bed coating, In-vitro
studies, stability studies.
For Correspondence:
M. Sirisha*
Address: 11-1-153,
Aravindh Nagar, 2nd
line,
near shivalayam, Anantapur,
Andhra Pradesh, India.
Email:sirimalavathu.47@gm
ail.com
ABSTRACT
The present invention concerns the development of sustained
release pellets of Tolterodine Tartrate, which are designed to
modify the drug release followed by sustained release action. There
are so many oral delivery systems in that one of the advance
techniques is Pelletization. The use of multiparticulate system to
provide modified release formulations is ever increasing and pellets
provide an ideal way of delivering unit dose of such formulations.
Sustained release pellets of Tolterodine Tartrate were formulated
by using the Pelletization process by drug layering on core pellets
by using binder in conventional coating pan. The drug-layered
pellets were coated by using coating materials such as ECN-50,
HPMCE-5 in fluid bed coating. The coated pellets was evaluated
for percentage yield, percentage of moisture content, friability,
Micromeritic, in-vitro dissolution studies stability studies and IR
analysis. Drug excipients interaction studies revealed that there is
no interaction between drugs and polymers. The results of in-vitro
evaluation showed that Tolterodine Tartrate drug release was slow
and sustained for 18hrs period. The formulations followed Zero
order kinetics and release mechanism was non-fickian. It is also
evident from the results that formulation GTT 6, better system for
once daily Sustained release of Tolterodine Tartrate having same
retardant release profile as marketed product (Innovator).
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International Standard Serial Number (ISSN): 2319-8141
INTRODUCTION:
There are so many oral delivery systems in that one of the advance techniques is Pelletization.
Pelletization is an agglomeration process that converts fine powders or granules of bulk drugs and
excipients into small, free-flowing, spherical units, referred to as pellets. The use of
multiparticulate system to provide modified release formulations is ever increasing and pellets
provide an ideal way of delivering unit dose of such formulations. It allows the combined delivery
of two or more bioactive agents, which may or may not be chemically compatible, at the same site
or at different sites within the gastrointestinal tract. It also permits the combination of pellets of
different release rates of the same drug in a single dosage form. The present invention concerns
the development of sustained release pellets of Tolterodine Tartrate, which are designed to modify
the drug release followed by sustained release action. Sustained release pellets of Tolterodine
Tartrate were formulated by using the two most common approaches to pellet formulation by
drug layering on core pellets by using binder in conventional coating pan and these drug layered
pellets can be film coated with a solution/suspension of coating materials by fluid bed coating
followed by modified-release coatings to obtain the release profile required.
Tolterodine Tartrate is a new drug that is classified as a muscarinic receptor antagonist. Both
bladder contraction and salivation (formation of saliva) are controlled by muscarinic receptors. It
is chemically designated as (R)-2-[3[bis (1-methylethyl)-amino] 1-phenylpropyl]-4- methyl
phenol [R(R*, R
*)] 2, 3 dihydroxybutanedioate (1:1) (salt). Tolterodine Tartrate is a white,
crystalline powder. Solubility in water is 12 mg/ml. It is soluble in methanol, slightly soluble in
ethanol, and practically insoluble in toluene. Tolterodine t ½ is approximately 2 to 4 h. The
typical dose of tolterodine tartrate is 1-2 mg, twice a day.
Materials and Methods
Tolterodine Tartrate was gifted by Zeon health care, Non peril seeds (20#30) in house,
microcrystalline cellulose was gifted by GR traders, Starch was gifted by Riddhi siddhi pharma,
PVPK-30 was gifted by Boanky pharmaceutical Ltd, ECN-50 and HPMC E-5 was gifted by
Headcel.
Formulation Steps Procedure:
Step I: Drug Loading:
All the materials as per manufacturing formulae (Table) were dispensed. Tolterodine Tartrate was
pulverized. PVPK-30 was added into IPA and stirred well till the clear solution was obtained.
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International Standard Serial Number (ISSN): 2319-8141
Basic Non-peril seeds were transferred into coating pan, and then sprayed with the binder solution
prepared. Over wetting of the core was avoided as it may cause agglomeration. Tolterodine
Tartrate was added slowly by spraying the binder. The pellets were then dried in a tray drier at
about 45ºc-55ºc. The dried pellets were sized on a sifter to remove agglomerates, broken pellets
and fine powder. After checking the weight of the pellets and noting down the yield they were
packed in a HDPE container lined with double polythene bags, labelled and securely tied. The
pellets were ready for coating.
Step II: S.R Coating of Tolterodine Tartrate Pellets:
Isopropyl alcohol was taken into a vessel and required quantity of ethyl cellulose N-50 (ECN-50)
and hydroxyl propyl methyl cellulose (HPMCE-5) as shown in table was slowly added till it was
dissolved. Stirring was continued till the clear solution was obtained. Drug loaded pellets were
transferred into the FBC and coated with the prepared coating solution. The spray rate, inlet air
temperature were adjusted in such a way that the drug coated pellets reached a temperature of
about 37ºc-42ºc. Over wetting of the drug coated pellets was avoided as it may cause
agglomeration. After complete quantity of the coating solution was consumed, the fluidization
was reduced for a brief post-drying period. The dried pellets were sieves. The weight of the
pellets was checked and the yield was noted, then the pellets were packed in double polythene
bags, and labelled.
Table no 1. Formula for Drug loading and their quantities as per percentage w/w
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S.No Ingredients Percentage (%)
1. API (Tolterodine Tartrate) 2
2. Sugar Core (24 # 30) 18
3. Sugar Powder 64.9
4. MCC 3.0
5. Starch 10
Binding Solution
6. PVPK-30 2
7. IPA Q.S
International Standard Serial Number (ISSN): 2319-8141 Table no 2. Sustained release coating solution composition
EVALUATION OF PELLETS:
Sieve Analysis (%)
The sieves were arranged according to their sieve number on a sieve shaker. The sieve numbers
used are 14, 16, 18, 20, 24, 30. The sieve number 14 was kept at the top & sieve number 30 was
kept at the bottom. Accurately weighed quantity of 100gms of Tolterodine Tartrate powder was
placed above the sieve no 14.The sieving was done with constant shaking for a period of 5mints.
All the sieves were removed carefully from the sieve shaker and the powder retained on the each
sieve was weighed by using the electronic balance. The obtained weights were given in the table
no 3.
Determination of Moisture Content (% w/w):
Take suitable quantity of Methanol in titration flask of Karl Fischer Titrator and titrate with Karl
Fischer reagent to end point. Grind the pellets to fine powder in a dry mortar, weigh accurately
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S.No Batch Code Percentage (%) IPA : MDC
(ml) ECN-50 HPMCE-5
1. GTT 1 -
- -
2. GTT 2 1
0.4 (4%DIL)80:20
3. GTT 3 2
0.8 80:20
4. GTT 4 3
1 80:20
5. GTT 5 3.5
1.2 80:20
6. GTT 6 4
1.4 80:20
7. GTT 7 4.5
1.6 80:20
% 𝑅𝑒𝑡𝑎𝑖𝑛𝑠 𝑜𝑛 14 =W 14 in g
weight of sample in g X 100
% 𝑃𝑎𝑠𝑠𝑖𝑛𝑔 𝑡ℎ𝑟𝑜𝑢𝑔ℎ 𝑜𝑛 30 =W 30in g
weight of sample in g X 100
International Standard Serial Number (ISSN): 2319-8141
about 1.0 g of the sample, transfer quickly to the titration flask, dissolve by stirring and titrate
with Karl Fischer reagent to end point.
Calculation:
Where,
F = Factor of Karl Fischer reagent
V = Volume in ml of Karl Fischer reagent consumed for sample titration.
Friability studies:
Friability studies of pellets are necessary to determine the strength of pellets, to withstand
transport, shipping, handling and storage.
IN-VITRO DRUG RELEASE BY HPLC (%W/W)
This is studied by using USP 1 dissolution test apparatus by using rotating basket at 37c=0.5c ,
100RPM and the buffer solution was prepared by dissolving 6.805g of potassium dihydrogen
orthophosphate in 1000ml water. Adjust with 2N Sodium hydroxide PH 6.8±0.05.
Standard preparation:
Weigh accurately about 4mg of Tolterodine Tartrate working standard in 100 ml volumetric flask,
dissolve and dilute to the volume with mobile phase. Take 5.0ml of this above solution in 25ml
volumetric flask and dilute to the volume with buffer solution.
Sample preparation:
Weigh accurately a quantity of pellets equivalent to 4mg of Tolterodine Tartrate individually in
each of the 6 dissolution flasks, containing 900ml of 6.8 PH buffer solutions which has been
equilibrated to the temperature of 37±0.5ºc. Immediately start the apparatus and run for 1st, 6
th,
18th
hours. After specified interval withdraw sample from a zone midway between the surface of
the medium and top of the rotating blade and not less than 1 cm from the vessel wall and filter
through 0.45µ membrane filter by discarding the first 5ml.
Chromatographic Conditions:
Column: Hypersil BDS-C18, 4.6 mm X 250 mm column that contains 5µm,
Flow Rate: 1.5 ml/min
Wave Length: 220nm
Injection Volume: 100µl
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𝒘𝒂𝒕𝒆𝒓 % =𝐕 𝐗𝐅 𝐗𝟏𝟎𝟎
𝐰𝐞𝐢𝐠𝐡𝐭 𝐨𝐟 𝐬𝐚𝐦𝐩𝐥𝐞 𝐢𝐧 𝐦𝐠
International Standard Serial Number (ISSN): 2319-8141
Buffer 7.4 pH Solution:
Dissolve 2.72 grams of potassium dihydrogen ortho phosphate and 0.525 grams of dipotassium
hydrogen phosphate in 1000 ml of water, and adjust PH to 7.4 with potassium hydroxide solution,
filter and degas.
Mobile phase: prepare a mixture of 7.4PH Buffer and Acetonitrile in the ratio of 40:60.
Standard solution preparation:
Weight accurately 50mg of Tolterodine Tartrate working standard in 100ml volumetric flask and
dissolve and dilute to the volume with mobile phase.
Sample solution preparation:
Weight accurately a quantity of pellets equivalent to about 50mg of Tolterodine Tartrate to a
100ml volumetric flask, dissolve and dilute the volume with mobile phase.
System solution: Inject 5 replicate injections of standard solution and the RSD is not more than
2.0%.
Injection sequins:
1. One injection of blank preparation solution (diluents)
2. Five injections of standard preparation solution
3. One injection of sample preparation solution
4. One injection of standard preparation solution (bracketing standard)
5. One injection of blank preparation solution.
Procedure:
Separately inject equal volume 100µl of the blank preparation, standard preparation and sample
preparation into the chromatogram, record chromatograms, and measure the peak responses and
calculated quantity of Tolterodine Tartrate taken by the formula.
Calculation:
Calculate the amount of Tolterodine Tartrate present in pellets, in %using the following formula:
Where,
At = Response due to sample preparation
As = Response due to standard preparation
Sw = Weight of Tolterodine Tartrate working standard taken in mg
Tw = Weight of sample taken in mg
P = (%) Purity of Tolterodine Tartrate working standard as is basis.
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A t
A s×𝑆 𝑤
100×
100
𝑇 𝑤×
𝑃
100× 100
International Standard Serial Number (ISSN): 2319-8141
STABILITY STUDY: Accelerated stability studies were performed at a temperature of 40±2o C
/ 75±5% RH over a period of three months (90 days) on the promising Tolterodine Tartrate
(formulations GTT6). Sufficient amount of pellets were packed in amber colored rubber
stoppered vials and kept in stability chamber maintained at 40±2o C / 75± 5% RH. Samples were
taken at one month interval for drug content estimation. At the end of three month period,
dissolution test was also performed to determine the drug release profiles.
Drug-Excipient Interaction Studies:
The IR spectra of Tolterodine Tartrate, Micro crystalline cellulose, Starch, PVPK-30, HPMC E-5,
ECN-50 and fprmulation (GTT6) were obtained by KBr pellet method.
DISCUSSION
In the present study 7 formulations with variable coating polymer concentration were prepared
and evaluated for physico-chemical, in-vitro dissolution studies. Preformulation studies for pure
drug was performed at first solubility study of pure Tolterodine Tartrate were performed and it
indicate that the pure drug was freely soluble in methanol, isopropyl alcohol, acetone, pH-6.8,
pH-7.4 and it is insoluble in chloroform, hydrochloric acid, sulphuric acid. The melting point of
pure drug was found to be 205-210c. The angle of repose for pure drug was found to be 16.62
indicating excellent flow properties. The bulk density and tapped density of pure drug was found
to be 0.66gm/ml and 0.76gm/ml respectively. The carr’s index for pure drug was 5.72%
respectively indicating excellent flow property. The sieve analysis for the pure drug was indicated
to be fairy flow. The pure drug Tolterodine Tartrate was pelletized by conventional coating pan
and fluid bed coating systems. The prepared pellets were evaluated for physical properties and the
results are tabulated in table. The angle of repose for pellets was in the range of 12.18 to 19.62
indicating excellent flow properties. The bulk density and tapped density of pellets was in the
range of 0.66gm/ml to 0.92gm/ml and 0.82gm/ml to 0.96gm/ml respectively. The carr’s index and
Hausner’s ratio for pellets was in the range of 2.32% to 6.02% and 0.70% to 1.07% respectively
indicating excellent flow property. The moisture content by KF should not be more than 3% and
the formulations were within the limit and ranges from 1.29% to 2.76%. The drug content should
not less than 1.8% and not more than 2.2% and the formulations were within the limit and ranges
from 1.8% to 2.1%. The friability of all the formulations was within 1% and was in the range of
0.052% to 0.53% indicates a good mechanical resistance of pellets.
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International Standard Serial Number (ISSN): 2319-8141
The dissolution rate studies for each of the formulation and the model innovator drug DETROL
LA studies were performed and the apparatus run for 1st, 3
rd, 6
th, 9
th, 12
th, 15
th and 18
th h,
maintaining at 100 rpm. Among all the seven formulations the GTT 6 was the optimized
formulation and releases the drug as per the specifications over a period of 18th h and comparisons
by model independent approach using a difference factor f1 was found to be 1.51 and similarity
factor f2 was found to be 89.96 for formulation GTT6. Based on the above dissolution values
GTT 6 was the optimized formulation, which was having the difference factor near to zero and
similarity factor near to 100. Optimized formulation GTT 6 was prepared by using 4.0% ECN-50
and HPMC E-5 1.4% as the polymer concentration. FTIR studies revealed the good compatibility
between the drug and the excipients. The mathematical modeling of the in-vitro drug release data
for the formulation GTT 6 was compiled and R2values are shown in Table 10. The drug release
from GTT 6 formulation was found to follow zero order kinetics, this is concentration dependent.
The mechanism of drug release is erosion as the value of n>1. The stability studies for GTT 6
were done at 40±2°C/75±5% RH for 3 months.
Table no 3. Sieve Analysis Values of Tolterodine Tartrate
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GTT 1 GTT 2 GTT 3 GTT 4 GTT 5 GTT 6 GTT 7
Sieve
No
%R %P %R %P %R %P %R %P %R %P %R %P %R %P
#14
0.66 99.34 1.33 98.67 1.66 98.34 2.53 97.47 2.06 97.94 1.5 98.5 1.96 98.04
# 16
6.66 93.34 9.33 90.67 8.56 91.44 14.33 85.67 15.46 84.54 17.73 82.27 14.96 85.04
# 18
35.33 64.67 71.33 28.67 62.13 37.87 61.06 38.94 64.33 35.67 62.66 37.34 63.33 36.67
# 20
86.33 13.67 86.66 13.34 71.26 28.74 74.66 25.34 72.2 22.8 80 20 84.4 15.6
# 24
90.66 9.43 93.33 6.67 85.46 14.54 88.93 11.07 87.1 12.9 88.4 11.6 89.26 10.74
# 30
99 1 98.06 1.94 96.13 3.7 97.1 2.9 96.3 3.7 96.86 3.14 97.8 2.2
International Standard Serial Number (ISSN): 2319-8141
Table no 4.Micromertictis studies for formulation GTT1 to GTT6
Table no 5. % Yield, % Moisture Content, Friability, Drug Content.
335 Full Text Available On www.ijupbs.com
Batch
Bulk
Density
(gm/ml)
Tapped
Density
(gm/ml)
Angle Of
Repose (Θ)
Carr’s
Index
Hausner’s
Ratio
GTT 1 0.77±0.015 0.82± 0.01 17.13 4.50 1.04
GTT 2 0.82 ±0.01 0.84± 0.01 12.18 2.38 1.02
GTT 3 0.66± 0.02 0.84± 0.01 16.35 5.21 1.05
GTT 4 0.91± 0.025 0.96± 0.02 19.62 4.51 1.04
GTT 5 0.92± 0.015 0.96± 0.01 15.80 3.82 0.70
GTT 6 0.87± 0.015 0.93± 0.02 16.62 5.72 1.05
GTT 7 0.78 ±0.020 0.85 ±0.035 16.85 6.02 1.07
Batch
No
% Yield % Moisture
Content
% Friability Drug content
(%)
GTT 1
96.14± 0.19 1.29 0.2 ± 0.02 1.80
GTT 2
96.43± 1.34 1.81 0.052 ± 0.011 1.92
GTT 3
95.65± 1.14 2.24 0.35 ± 0.032 1.96
GTT 4
96.22± 0.045 2.47 0.27 ± 0.0052 1.97
GTT 5
96.91± 0.56 1.90 0.53 ± 0.005 1.86
GTT 6
95.78± 0.42 2.76 0.11 ± 0.005 2.12
GTT 7
96.27± 0.96 1.67 0.23 ± 0.017 1.99
International Standard Serial Number (ISSN): 2319-8141
Table no 6. Dissolution Studies
336 Full Text Available On www.ijupbs.com
0
10
20
30
40
5060
70
80
90
100110
0 1 3 6 9 12 15 18
% D
rug
Rel
ease
Time (hrs)
Comparitive Dissolution profile from GTT1-GTT7 with Innovator
GTT1
GTT2
GTT3
GTT4
GTT5
GTT 6
GTT 7
Innovator
S.
No
Batch
name
1st h 3
rd h 6
th h 9
th h 12
th h 15
th h 18
th h
1.
GTT 1 99.06±1.47 - - - - - -
2.
GTT 2 72.38± 1.03 97.5 ±0.62 99.30±0.70 - - - -
3.
GTT 3 51.23 ±1.01 77.12±0.98 97.56± 0.65 99.50±0.44 - - -
4.
GTT 4 32.52 ±0.65 57.50± 0.62 81.85± 0.99 95.32± 0.99 99.35±0.56 99.60±0.37 -
5.
GTT 5 27.93 ±0.86 50.59 ±1.02 82.74± 1.30 81.32± 0.20 94.03±0.53 98.90 ±0.56 98.95±0.86
6.
GTT 6 16.05 ±0.65 41.45± 0.98 53.37± 0.83 66.33± 1.06 77.64±1.01 88.85± 0.82 97.58± 1.04
7.
GTT 7 10.61 ±0.96 33.83 ±0.85 45.57± 0.63 56.73± 1.06 69.41±1.12 84.16± 0.74 90.68± 0.86
8. Innovator 25.6±0.83 44.73±0.67 58.31±0.82 69.24±0.19 78.11±0.18 86.87±0.65 95.23±1.02
International Standard Serial Number (ISSN): 2319-8141
MATHEMATICAL MODELS:
Table no 7. Mathematical model values for Innovator (DETROL LA ®)
S.No Zero order First order Korsmeyer
plot
Higuchi’s plot Hixson-Crowell
plot
T
(hr)
%
drug
release
T(hr) Log %
drug
release
Log
t
Log %
drug
release
√t % drug
release
3√t % drug
release
1.
1 25.60 1 1.48 0 1.48 1 25.60 4 25.60
2.
3 44.73 3 1.65 0.47 1.65 1.73 44.73 6.43 44.73
3.
6 58.31 6 1.76 0.77 1.76 2.44 58.31 7.3 58.31
4.
9 69.24 9 1.84 0.95 1.84 3 69.24 8.14 69.24
5.
12 78.11 12 1.89 1.07 1.89 3.46 78.11 8.81 78.11
6.
15 86.87 15 1.93 1.17 1.93 3.87 86.87 9.42 86.87
7.
18 95.23 18 1.97 1.25 1.97 4.24 95.23 9.87 95.23
Table no 8. Mathematical Zero Order model values for formulation GTT1-GTT7
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% Drug Release
S.No
Time
(hrs) GTT1 GTT2 GTT3 GTT4 GTT5 GTT6 GTT7
1.
1 99.06 72.38 51.23 32.52 27.93 16.05 10.61
2.
3 97.5 77.12 57.50 50.59 41.45 33.83
3.
6 99.30 97.56 81.85 82.74 53.37 45.57
4. 9
99.50 95.32 81.32 66.33 56.73
5. 12
99.35 94.03 77.64 69.41
6. 15
99.60 98.90 88.85 84.16
7. 18
98.95 97.58 90.68
International Standard Serial Number (ISSN): 2319-8141
Table no 9. Mathematical Higuchi’s model values for formulation GTT1-GTT7
338 Full Text Available On www.ijupbs.com
y = 4.618x + 20.31
R² = 0.8950
50
100
150
0 20% D
rug
Rel
ease
Time (h)
Zero order plot for Innovator
Series1
y = 99.06xR² = 1
0
50
100
150
0 1 2% D
rug
Rel
ease
Time (h)
Zero order plot for formulation GTT 1
Series1
Linear (Series1)
y = 4.856x + 10.02R² = 0.96
0
50
100
150
0 10 20
% D
rug
Re
leas
e
Time (h)
Zero order plot for formulation GTT 2
Linear (Series1)
y = 4.856x + 10.02R² = 0.96
0
50
100
150
0 5 10 15 20
% D
rug
Rel
eas
e
Time (h)
Zero order plot for formulation GTT 3
Series1
Linear (Series1)
% Drug Release
S.No
√T GTT1 GTT2 GTT3 GTT4 GTT5 GTT6 GTT7
1.
1 99.06 72.38 51.23 32.52 27.93 16.05 10.61
2.
1.73 97.5 77.12 57.50 50.59 41.45 33.83
3.
2.44 99.30 97.56 81.85 82.74 53.37 45.57
4. 3
99.50 95.32 81.32 66.33 56.73
5. 3.46
99.35 94.03 77.64 69.41
6. 3.87
99.60 98.90 88.85 84.16
7. 4.24
98.95 97.58 90.68
International Standard Serial Number (ISSN): 2319-8141
y = 4.856x + 10.02R² = 0.96
0
50
100
150
0 10 20
% D
rug
Re
leas
e
Time (h)
Zero order plot for formulation GTT 4
Series1
y = 4.856x + 10.02R² = 0.96
0
50
100
150
0 10 20% D
rug
Re
leas
e
Time (h)
Zero order plot for formulation GTT 5
Series1Linear …
y = 5.026x + 14.94R² = 0.934
0
20
40
60
80
100
120
0 10 20
% D
rug
Rel
ease
Time (h)
Zero order plot for formulation GTT 6
Series1
Linear (Series1)
y = 4.856x + 10.02R² = 0.96
0
20
40
60
80
100
120
0 10 20
% D
rug
Rel
ease
Time (h)
Zero order plot for formulation GTT 7
Series1
Linear (Series1)
y = 21.95x + 3.097R² = 0.996
0
50
100
150
0 2 4 6
% D
rug
Rel
ease
Squre Root T
Higuchi's plot for Innovator
Series1
Linear (Series1)
y = 22.16x - 5.814R² = 0.984
-50
0
50
100
0 2 4 6% D
rug
Re
leas
e
Square Root T
Higuchi's plot for formulation GTT 1
Series1
Linear (Series1)
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International Standard Serial Number (ISSN): 2319-8141
340 Full Text Available On www.ijupbs.com
y = 22.16x - 5.814R² = 0.984
-50
0
50
100
0 5% D
rug
Re
leas
e
Square Root T
Higuchi's plot for formulation GTT 2
Series1
y = 22.16x - 5.814R² = 0.984
-50
0
50
100
0 2 4 6% D
rug
Re
leas
e
Square Root T
Higuchi's plot for formulation GTT 3
Series1
Linear (Series1)
y = 22.16x - 5.814R² = 0.984
-50
0
50
100
0 2 4 6% D
rug
Rel
ease
Square Root T
Higuchi's plot for formulation GTT 4
Series1
Linear (Series1)
y = 22.16x - 5.814R² = 0.984
-50
0
50
100
0 5% D
rug
Rel
ease
Square Root T
Higuchi's plot for formulation GTT 5
Series1
Linear (Series1)
y = 23.36x - 2.502R² = 0.994
-50
0
50
100
150
0 5% D
rug
Rel
ease
Square Root T
Higuchi's plot for formulation GTT 6
Series1
Linear (Series1)
y = 22.16x - 5.814R² = 0.984
-50
0
50
100
0 2 4 6
% D
rug
Rel
ease
Square Root T
Higuchi's plot for formulation GTT 7
Series1
Linear (Series1)
International Standard Serial Number (ISSN): 2319-8141
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y = 0.066x + 1.033R² = 0.456
0
0.5
1
1.5
2
2.5
0 10 20Log
% D
rug
Rel
ease
Time (h)
First order plot for Innovator
Series1
Linear (Series1)
y = 0.390x + 1.471R² = 0.998
0
0.5
1
1.5
2
2.5
0 0.5 1 1.5
Log
% D
rug
Re
leas
e
Log T
Korsemeyer plot for Innovator
Series1
y = 11.96x - 26.80R² = 0.979
0
20
40
60
80
100
0 5 10 15
% D
rug
Rel
ease
cube T
Hixson -Crowell plot for Innovator
Series1
Linear (Series1)
y = 5.026x + 14.94R² = 0.934
0
20
40
60
80
100
120
0 10 20
% D
rug
Rel
ease
Time (h)
Zero order plot for formulation GTT 6
Series1
Linear (Series1)
y = 0.074x + 0.928R² = 0.549
0
1
2
3
0 10 20
Log
% D
rug
Rel
ease
Time (h)
First order plot of formulation GTT6
Series1
Linear (Series1)
y = 0.597x + 1.256R² = 0.976
0
1
2
3
0 1 2
Log
% D
rug
Re
leas
e
Log T
Korsemeyer plot for formulation GTT 6
Series1
Linear (Series1)
International Standard Serial Number (ISSN): 2319-8141
Table no 9. Mathematical model values for Innovator
Table no 10. Mathematical model values formulation GTT 6
Table no 11. Diffusion characteristics of Tolterodine Tartrate pellets GTT 1-GTT 7
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y = 23.36x - 2.502R² = 0.994
-50
0
50
100
150
0 2 4 6% D
rug
Re
leas
e
Square Root T
Higuchi's plot for formulation GTT 6
Series1
Linear (Series1)
y = 0.914x + 14.78R² = 0.888
0
10
20
30
40
0 10 20
% D
rug
Re
leas
e
3√T
Hixson-crowell plot for formulation GTT 6
Series1
Linear (Series1)
Formulation code
Correlation coefficient values(r2)
Diffusion
Exponent values
(n)
Zero order Higuchi’s model
GTT 1 0.99 0.98 0.706
GTT 2 0.96 0.98 0.762
GTT 3 0.96 0.98 0.860
GTT 4 0.96 0.98 0.935
GTT 5 0.96 0.98 1.002
GTT 6 0.93 0.99 1.232
GTT 7 0.96 0.98 1.478
S.
NO
BATCH
CODE
ZERO
ORDER (R2)
FIRST
ORDER (R2)
HIGUCH
MODEL (R2)
KORSEMEYER
MODEL (R2)
HIXSON MODEL
(R2)
1.
GTT 6 0.89 0.45 0.99 0.99 0.97
S. NO
BATCH
CODE
ZERO
ORDER (R2)
FIRST
ORDER (R2)
HIGUCH
MODEL (R2)
KORSEMEYER
MODEL (R2)
HIXSON MODEL
(R2)
1.
GTT 7 0.93 0.54 0.99 0.97 0.75
International Standard Serial Number (ISSN): 2319-8141
Table no 12. Diffusion exponent drug release mechanism
Table no 13.Comparative Dissolution Profile of GTT 6 before and After Stability Studies
343 Full Text Available On www.ijupbs.com
0
20
40
60
80
100
120
0 5 10 15 20
% D
rug
Rel
ease
Time (hrs)
GTT 6
GTT 6 After 3 Months
S.NO Diffusion exponent
value(n)
Drug release mechanism
1 <0.45 Fickian release
2 0.45-0.89 Non fickian release
3 0.89 Case II Transport
4 >0.89 Super case II Transport
Time (h)
GTT 6 Before stability studies GTT 6 After Stability Studies (3 Months)
1
16.05 15.34
3
41.45 40.28
6
53.37 52.69
9
66.33 67.84
12
77.64 76.32
15
88.85 85.75
18
97.58 96.85
International Standard Serial Number (ISSN): 2319-8141
CONCLUSION
In this study, pellets containing Tolterodine Tartrate were prepared successfully using powder
layering technique in coating pan. Coating was done in fluid bed coating system using Ethyl
cellulose N-50 as rate retarding polymer. It may be concluded from the present study that
sustained release pellets of Tolterodine Tartrate over a period of 18th
h was obtained from
sustained release pellets of formulation GTT 6 employing polymer as 4.0%. The release
mechanism was followed with Zero order kinetics, and erosion from polymeric system. It is also
evident from the results that formulation GTT 6, better system for once daily Sustained release of
Tolterodine Tartrate having same retardant release profile as marketed product (Innovator).
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