International Standard Serial Number (ISSN): 2319-8141 …. RPA131400206014...pdf · 2018. 7....

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).

327 Full Text Available On www.ijupbs.com

http://www.ijupbs.com/

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.




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


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


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



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


𝒘𝒂𝒕𝒆𝒓 % =𝐕 𝐗𝐅 𝐗𝟏𝟎𝟎

𝐰𝐞𝐢𝐠𝐡𝐭 𝐨𝐟 𝐬𝐚𝐦𝐩𝐥𝐞 𝐢𝐧 𝐦𝐠



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.


A t

A s×𝑆 𝑤

100×

100

𝑇 𝑤×

𝑃

100× 100



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.




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


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



Table no 4.Micromertictis studies for formulation GTT1 to GTT6

Table no 5. % Yield, % Moisture Content, Friability, Drug Content.


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



Table no 6. Dissolution Studies


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



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


% 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



Table no 9. Mathematical Higuchi’s model values for formulation GTT1-GTT7


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)


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)


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



y = 4.856x + 10.02R² = 0.96

0

50

100

150

0 10 20

% D

rug

Re

leas

e

Time (h)


Series1

y = 4.856x + 10.02R² = 0.96

0

50

100

150

0 10 20% D

rug

Re

leas

e

Time (h)


Series1Linear …

y = 5.026x + 14.94R² = 0.934

0

20

40

60

80

100

120

0 10 20

% D

rug

Rel

ease

Time (h)


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)


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)





y = 22.16x - 5.814R² = 0.984

-50

0

50

100

0 5% D

rug

Re

leas

e

Square Root T


Series1

y = 22.16x - 5.814R² = 0.984

-50

0

50

100

0 2 4 6% D

rug

Re

leas

e

Square Root T


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


Series1

Linear (Series1)

y = 22.16x - 5.814R² = 0.984

-50

0

50

100

0 5% D

rug

Rel

ease

Square Root T


Series1

Linear (Series1)

y = 23.36x - 2.502R² = 0.994

-50

0

50

100

150

0 5% D

rug

Rel

ease

Square Root T


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


Series1

Linear (Series1)




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)


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)



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


y = 23.36x - 2.502R² = 0.994

-50

0

50

100

150

0 2 4 6% D

rug

Re

leas

e

Square Root T


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



Table no 12. Diffusion exponent drug release mechanism

Table no 13.Comparative Dissolution Profile of GTT 6 before and After Stability Studies


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



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).

REFERENCES:

1. Chine YW. Novel drug delivery system. 2nd edition revised and expanded. New

York: Informa health care; 2009. P. 1-50.

2. Paul B, Gupta PK, Ara HD, John EH. Remington the science and practice of

pharmacy.21st edition. New York: Wolter kluwer, Lippincott Williams and Wilkins;

2006.P.939-962.

3. Edith M. Encyclopedia of controlled drug delivery.1st edition. New York: A Wiley Inter

science publication; 2009.P.381-385.

4. Gilbert SB, Christopher TR. Modern Pharmaceutics. 3rd

edition revised and expanded.

New York: Marcel Dekker Inc; 1995.P.575-608.

5. Donald LW. Handbook of pharmaceutical controlled release technology. 1stedition. New

York: Marcel Dekker Inc; 2000.P.431-460.

6. Yvonne P, Thomas R. Pharmaceutics-Drug delivering targeting.1stedition Pharmaceutical

press; 2010.P.85-115, 117-139.

7. James S. Encyclopaedia of Pharmaceutical technology.3rd

edition. New York: Informa

health care; 2007.P.1082-1103.

8. Khan GM. Controlled release oral dosage forms: Some recent advances in matrix type

drug delivery system: A Review article. Asian network for scientific information.2001

sept-oct; 1(5); 350-354.

9. Patel H, Dhrupesh R, Patel PU, Suthar M. Matrix type drug delivery system: A Review.

Journal of pharmaceutical science and bio scientific res. 2011 Nov-Dec; 1(3); 143-51.




10. Sakr AM, Elsabbagh HM. Correlation of water absorption with the disintegration

Effectiveness of guar gum. Pharma Ind. 1975; 37; 457-459.

11. Altaf SA, Yu AL, Parasrampuria J, Friend DR. Guar gum based sustained Release

diltiazem pharma Res. 1998; 15; 1196-1201.

12. Paulo C, Lobo JMS. Modelling and comparison of dissolution profiles. European Journal

of Pharmaceutical Sciences.2001; 13; 123-133.

13. Kalam MA, Humayun M, Parvez N. Release kinetics of modified pharmaceutical Dosage

forms: A review. J. Pharmaceutical Sciences. 2007; 1; 30-35.

14. Dash S, Murthy P, and Chowdhury P. Kinetic modelling on drug release from controlled

drug delivery systems: A review. Acta Poloniae Pharmaceutical - Drug

Research.2010;679(3);217-223.

15. Paul B, Gupta PK, Ara HD, John EH. Remington the science and practice of

pharmacy.21st edition. New York: Wolterkluwer, Lippincott Williams and Wilkins; 2006.

P. 939-962.



International Standard Serial Number (ISSN): 2319-8141 …. RPA131400206014...pdf · 2018. 7....

Documents

Transcript of International Standard Serial Number (ISSN): 2319-8141 …. RPA131400206014...pdf · 2018. 7....