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FORMULATION, DEVELOPMENT AND IN VITRO EVALUATION OF PULSATILE DRUG DELIVERY SYSTEM OF CANDESARTAN CILEXETIL FOR CARDIOVASCULAR DISEASES

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FORMULATION, DEVELOPMENT AND

IN VITRO

EVALUATION OF

PULSATILE DRUG DELIVERY SYSTEM OF CANDESARTAN

CILEXETIL FOR CARDIOVASCULAR DISEASES

S R Kawathe1*, K S Salunkhe1, S R Chaudhari1, M H Harwalkar2

Amrutvahini College of Pharmacy, Sangamner. Ahmednagar, Maharashtra, India.

2

Glenmark Pharma R and D Centre, Sinnar, Nashik

ABSTRACT

The chronomodulated drug delivery system is widely used for

treatment of diseases occurs due to circadian changes in the body the

body. This system is aims to release drugs at a programmed pattern

i.e.at appropriate time and/or at appropriate site of action. In this

research, formulation developed for the chronotherapy of

cardiovascular diseases to treat high blood pressure early in the

morning. For that purpose the compression coated tablet of candesartan

cilexetil was prepared by using different coating polymers like

hydroxy propyl methyl cellulose K4M, Eudragit L100-55 and Eudragit

S100. These polymers were gives the pulsatile drug delivery from the

formulation.

KEYWORDS: Pulsatile drug delivery system, Candesartan cilexetil, HPMC K4M, Eudragit L100-55, Eudragit S100, Compression coating.

INTRODUCTION

Pulsatile drug delivery systems are gaining importance because of their dependency on

circadian rhythm of the body. They provide scope for controlled release dosage form

formulation which has significant therapeutic importance.The principle rationale behind

designing these delivery systems is to release the drug at desired time as per the

pathophysiological need of disease, resulting in improved patient therapeutic efficacy and

compliance. As the name suggests, these systems are meant for chronopharmacotherapy,

treatment of those diseases that are caused due to circadian changes in body. These systems

are developed when zero order drug release is not desired. Pulsatile drug delivery systems are

Volume 3, Issue 4, 882-913. Research Article ISSN 2277 – 7105

Article Received on 15 April 2014,

Revised on 08 May 2014, Accepted on 01 June 2014

*Author for Correspondence

Sagar Kawathe

Amrutvahini College of

Pharmacy, Sangamner.

Ahmednagar, Maharashtra,

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designed to release certain amount of drug within a short period of time, immediately after a

predetermined lag time. Diseases in which these systems are promising include asthma,

peptic-ulcer, cardiovascular diseases, arthritis, attention-deficit syndrome in children and

hypercholestemia etc. (Table1)

Table 1.Diseases, chronological behaviour and drugs used for it

Diseases Chronological behaviour(category of drugs used)

Asthma Precipitation of attacks during night or at early morning hour (β2

agonist, Antihistaminics)

Arthritis Pain in the morning and more pain at night (NSAID, Glucocorticoids)

Cardiovascular disease

BP is at its lowest during the sleep cycle and

rise steeply during the early morning awakening period (Nitroglycerin, Calcium Channel blocker, ACE inhibitors etc )

Diabetes mellitus Increase in the blood sugar level after meal (sulfonylurea, Biguanide, insulin)

Hypercholestrolemia Cholesterol synthesis is generally higher during night than during day time (Statins)

Peptic ulcer Acid secretion is high (H2 blockers) Attention deficit

syndrome

Increase in DOPA level in afternoon (Increase in DOPA level in afternoon.)

Pulsatile system is also known as chronomodulated system or sigmoidal release system (fig.

1). The word chronomodulated is related with chronopharmaceutics and comes from

chronobiologic system. Chronobiology is the study of biological rhythms and their

mechanism. There are three types of mechanical rhythms in our body.

Circadian rhythm: The Oscillation in our body that are completed in 24 hrs. are termed as

circadian rhythm.

Ultradian rhythm: The oscillation that is completed in a shorter duration of less than 24 hrs.

are termed as ultradian rhythm.

Infradian rhythm: The oscillations that are completed in more than 24 hrs. are termed as

infradian rhythm.

The Circadian rhythm is the main rhythm in the body which maintains all the physiological,

chemical, biological and behavioural processes. Thus Circadian rhythms causes the changes

in the pathophysiology of certain disease states which may worsen the disease condition.

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which exactly matches the circadian changes in the body. Thus chronomodulated or pulsatile

drug delivery system is a novel system which can be used for treatment of such diseases.

Various approaches like capsular systems, systems with different type of barrier coatings,

[image:3.595.132.461.169.346.2]

stimuli sensitive pulsatile systems and externally regulated systems.[1,2,3,4]

Fig. 1: Drug release profile of PDDS [5] Cardiovascular diseases

Hypertension or Congestive Heart Failure mostly will comes after midnight or early in

mornings. So it is important to control the blood pressure at that particular time, if not control

may lead to increase in blood pressure and finally heart failure which may causes death also.

This can be done by using antihypertensive drugs, which can lowers the blood pressure at that

time. Candesartan cilexetil is an antihypertensive drug which is the angiotensin II receptor

blockers. It can blocks the angiotensin II receptor in vascular smooth muscles and adrenal

gland, producing decrease in blood pressure and avoids vasoconstriction and aldosterone

secretion.

The effect of drug is essential after some lag time, thus it can be achieved by using the time

and pH dependent polymer coating.

MATERIALS AND METHODS Materials

Candesartan cilexetil as an antihypertensive drug was gifted by Mylan laboratories, Nashik.

Crospovidone, Hydroxy propyl methyl cellulose K4M were gifted by Glenmark Pharma,

Nashik.Eudragit L100-55 and Eudragit S100 are gifted by Evonic Laboratories, Mumbai.

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procured from LobaChemie, Nashik and all other chemicals were used are of analytical

grade.

Methods

1. Preformulation study a. Drug characterization

Characterization of drug was done to check whether the obtained sample is in pure form or

not. Candesartan cilexetil sample was subjected for various tests like solubility, melting

point, UV, FTIR analysis.

b. Polymer characterization

Characterization of polymers were done to check whether the obtained sample is in pure form

or not. All polymer samples were subjected for various tests like solubility, melting point,

UV, FTIR analysis.

c. Compatibility study[6]

The compatibility study was carried out at 550C and for 14 days with moisture and without

moisture in hermetically sealed glass container of individual drug and Drug: Excipient was

taken [Table 12,13]. Individual IR graph were taken before placing the ingredient and drug

into the glass vials and these vials were kept for 14 days for 550C in duration of 14 days all

the vials were observed for any color change, gas formation, caking and liquification and

lastly after 14 days its IR was studied. The results are noted down in table 12 and 13.

2. Preparation of Candesartan cilexetil compression coated tablet [7] A] Preparation of core tablet

Core tablets were prepared by using 9 different formulae F1 to F9. Here 3 concentrations of

Crospovidone and Mannitol were used and 9 formulas were set and best was selected for

coating purpose. The excipients used here are CP, Mannitol, MCC, Magnesium stearate, and

Talc selected on basis of literature. While preparation of core tablet of Candesartan cilexetil

all the ingredients in formula were weighed and directly compressed by using 8 mm concave

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Table 2. Formula for core tablet Sr.

No. Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 1. Candesartan

Cilexetil[mg] 32 32 32 32 32 32 32 32 32 8 2. Crospovidone

[mg] 6 8 10 6 8 10 6 8 10 10

3. Mannitol[mg] 58 56 54 56 58 56 54 54 58 58

4. MCC [mg] 30 30 30 30 30 30 30 30 30 30

7. Mg. Stearate

[mg] 1 1 1 1 1 1 1 1 1 1

8. Talc [mg] 1 1 1 1 1 1 1 1 1 1

Total weight [mg] 128 128 128 126 130 130 124 126 132 100

B] Preparation of compression coated tablet of Candesartan cilexetil

After preparation of the core Tablet it was compressed coated with outer coating layer by

using 10mm concave punch. Eudragit L100-55, Eudragit S100, and HPMC K4M were used

as outer coating layer individually and in combination. In combination 50:50percent ratio of

Eudragit L100-55, Eudragit S100, and HPMC K4M were used in outer coating layer to

prepare compression coated tablet. Firstly the half quantity of outer layer was weighed and it

is placed at the bottom then core tablet was placed at the middle and again remaining outer

layer was placed and it was directly compressed by 10mm flat punch and thus compression

[image:5.595.80.511.82.272.2]

coated tablet was prepared. The formula for outer coating layer is given in table 3.

Table 3. Formula for outer coating layer Batches Percent

ratio Eudragit L100-55 Eudragit S100 HPMC

K4M Lactose

Total weight of coating

layer

F1 100 200 - - - 200

F2 100 - 200 - - 200

F3 100 - - 200 - 200

F4 50:50 100 - 100 - 200

F5 50:50 - 100 100 - 200

F6 40:40:20 100 - 100 50 250

F7 50:50 - - 100 100 200

F8 55:45 - - 110 90 200

F9 60:40 - - 120 80 200

F10 65:35 - - 130 70 200

F11 70:30 - - 140 60 200

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3. Evaluation study

a. Evaluation of Precompression Parameter for both core and coat material [8, 9] A] Bulk density

250 ml of measuring cylinder was taken and 100 gm of powder of all batches were weighed

and passed through the sieves and filled into the cylinder and their volumes were noted down

and bulk density was calculated. The formula used for calculation is as follow.

Bulk density = Mass / volume

The results for bulk density of core material and coat material were given in table 14 and 17

respectively.

B] Tapped density

250 ml of the measuring cylinder was taken and 100 gm of the powder of all batches were

weighed and filled into the cylinder, volume of powder measured and noted then that cylinder

was tapped about 300 times and again volume of powder measured and tapped density of

powder calculated by following formula.

Tapped density = Mass of powder / tapped volume

The results for tapped density of core material and coat material were given in table

14 and 17respectively.

C] Carr’s index

Carr’s index of the powder was determined for determination of flow of the powder, for the calculation of Carr’s index it requires tapped density and bulk density. Formula for the calculation of the Carr’s index is given below.

Carr’s index = [tapped density- bulk density / tapped density] × 100

Results for the Carr’s index of core and coat material were given in table 14 and

17respectively.

D] Hausner’s ratio

Hausner’s ratio gives information about flow ability of the powder, for the determination of the Hausner’s ratio it requires tapped density and bulk density.

Hausner’s ratio = tapped density / bulk density

The results for Hausner’s ratio of core material and coat material were given in table 14 and

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E] Angle of repose

Angle of repose was determined according to USP 2007 method, funnel was taken and it is

fixed at 1cm height on the stand. One cotton was placed at the orifice of the funnel and on

that cotton a constant powder weight was placed. The cotton was removed and the diameter

formed by powder and height formed by the pile of the powder was measured and angle of

repose was calculated from the following formula.

tan-1[θ] = h / r

Where h = height formed by the pile of the powder.

R = diameter formed by powder.

Results for angle of repose of core material and coat material were noted down in table 14

and 17respectively.

b. Evaluation of core tablet and compression coated tablet of Candesartan cilexetil[10] A] Friability testing

20 tablets were taken, it is weighed and initial weight was noted then it was placed into the

Roche friabilator and test was performed for 4 min by using 25 rpm after that tablets were

weighed and friability was calculated by using following formula and all results were noted

in table 15 and 18.

% loss = [Final wt. of tablets - Initial wt. of tablets/Initial wt. of tablets] x100

[image:7.595.179.419.530.656.2]

B] Weight variation

Table 4. Percentage weight variations allowed under weight variation

20 tablets were selected randomly and average weight was calculated, not more than 2 tablets

from this average weight should not be deviate shown in table 4. The test was performed

according to the Indian pharmacopoeia 2010 and results were recorded in table 15 and 18.

Weight variation was calculated by using following formula.

Average tablet of the tablet [mg]

Percentage deviation

80 mg or less ±10

More than 80 mg but less than

250 mg ±7.5

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%weight variation = [Weight of single tablet – Average weight of tablet/Average weight of tablet] x 100

C] Hardness testing

The crushing strength kg/cm2 of prepared tablets was determined for tablets by using

Monsanto hardness tester. A tablet is placed between the anvils and the crushing strength,

which causes the tablet to break, is recorded. Average of three readings was taken and results

were tabulated. The average hardness was determined and results were noted down in table

15 and 18.

D] Diameter and thickness of core tablet [11]

The diameter and thickness of core tablet were measured by using Vernier caliper and results

were noted down in table 15 and 18.

E] Disintegration test for core tablet of Candesartan cilexetil

Disintegration test on core tablet of Candesartan cilexetil was performed by using distilled

water as media. 6 core tablets of Candesartan cilexetil were taken and placed in 6 respective

tubes of disintegration apparatus and disintegration time of core tablet was measured. The

result for disintegration test of core tablet of Candesartan cilexetil was given in table 15.

F] Dissolution testing of core tablet of Candesartan cilexetil [12, 13]

Dissolution testing of core tablet of Candesartan cilexetil was performed by using pH 6.8

phosphate buffers and 0.35% w/v Tween20 as dissolution medium. Dissolution study was

carried out for about 30 min. at 370 C and 50 rpm by using USP type II apparatus. 5ml sample

were removed from dissolution medium at every 5 min. and its absorbance was checked by

using UV [Labindia]. Drug release was calculated and noted down in table 16 and fig. 21.

G] In vitro dissolution testing of compression coated tablet of Candesartan cilexetil in phosphate buffer pH 1.2, 6.8, 7.4 [7]

Dissolution testing was carried out by using USP type II dissolution apparatus [Electro lab].

Dissolution medium used for the testing were 500ml phosphate buffer pH 1.2, pH 6.8, pH 7.4

each. Compression coated tablet was placed in pH 1.2 phosphate buffer for 2 hrs because

gastric emptying time is 2 hrs, then that medium was replaced with pH 6.8 phosphate buffer

and testing carried out for 3 hrs because intestinal emptying time is 3 hrs, after that pH 6.8

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withdrawn after every hour, filtered with Whatman’s filter paper and replaced with 5 ml of

fresh dissolution medium. The Temperature condition used for dissolution testing was 37.5 ±

0.50 C. The rotation speed was kept at 50rpm for dissolution testing. Each sample was tested

for its absorbance at 254 nm by using UV spectrophotometer. Drug release was calculated

and noted down in table 19 and 20.

H] Assay of the Candesartan cilexetil compression coated tablet [12, 14]

Ten tablets were weighed and powdered. An amount of powder equivalent to 8 mg of

candesartan cilexetil was dissolved in 100 ml of phosphate buffer [pH 6.8]. It was shaken by

mechanical means for 1 hr. Then it was filtered through a whatman filter paper. From this

resulted solution 1ml was taken, diluted to 100 ml with phosphate buffer of pH 6.8 and

absorbance was measured against blank at 255 nm using UV-Visible spectrophotometer.

From the absorbance values, amount of drug present in the given tablet was calculated using

calibration curve. Procedure was repeated by using two or more tablets from the same

formulation and the average value of all three tablets were calculated and noted down in table

24.

J] In vitro drug release kinetic of the Candesartan cilexetil compression coated tablet of batch F12 formulation [15, 16, 17]

The release kinetics of the F8 batch was taken out from the values obtained from in vitro

dissolution study. The values were fitted into various kinetic equations to find out the

mechanism of Candesartan cilexetil compression coated tablets. Release kinetic study was

done by using kinetics equations. The F12 batch was evaluated for Zero order, First order,

Higuchi model and Korsmeyer-peppas model. For zero order Time VS %Drug release, for

first order Time VS Log % drug remaining, for Higuchi model SQRT time VS % drug

release, for Korsmeyer-peppas model Log time VS Log % drug release in this way graphs of

all 5 models were plotted and from R2values the model was determined. The results are given

in table 25 and fig. 23.

K] Stability study [18, 19]

Stability of a drug has been defined as the ability of a particular formulation in a specific

container, to remain within its physical, chemical, therapeutic and toxicological

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The purpose of stability study is to provide evidence on the quality of a drug substance or

drug product which varies with time under the influence of a variety of environmental factors

such as temperature, humidity and light.

The best formulation was kept for stability study in stability chamber for period of 3 months

at temperature 45±20C and RH 75±5%. The changes in physical appearance, % drug release

and drug content were observed for an interval of 1 month to 3 months and results were noted

in table 26.

RESULT AND DISCUSSION 1. Preformulation study a. Drug characterization

Preformulation study of Candesartan cilexetil drug was carried out by using parameters like

[image:10.595.77.521.395.526.2]

solubility, loss on drying, melting point, IR, calibration curve.

Table 5. Preformulation study of Candesartan cilexetil

Parameter Observation Standard

Solubility study of Candesartan cilexetil

Practically insoluble in water,

sparingly soluble in methanol

Practically insoluble in water,

sparingly soluble in methanol

Loss on drying 0.3% NMT 0.5%

λmaxof Candesartan cilexetil 255nm 254 nm

Melting point of Candesartan cilexetil

161-1640C 1630C

λmax of Candesartan cilexetil drug was performed in three phosphate buffers that were pH 1.2,

6.8, 7.4.The λmax of Candesartan cilexetil was found to be 255 nm. The standard λmax of

Candesartan cilexetil was 254 nm. The λmax of Candesartan cilexetil is given in UV spectrum

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[image:11.595.92.504.64.650.2] [image:11.595.94.504.84.325.2]

Fig. 2.λmaxof Candesartan cilexetilin pH1.2

Fig. 3.λmaxof Candesartan cilexetilin pH6.8

Fig. 4. λmaxof Candesartan cilexetil in pH7.4

A) IR study of Candesartan cilexetil bulk drug

After physical characterization of Candesartan cilexetil the drug was subjected to FTIR to

check the structure and purity of Candesartan cilexetil. IR study of Candesartan cilexetil drug

[image:11.595.93.505.389.616.2]
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cilexetil of USP35–NF30.The IR graph is given in fig.5 and 6. Peak values for standard IR

[image:12.595.94.499.108.462.2]

and sample IR are given in table 6.

[image:12.595.93.503.523.710.2]

Fig. 5. IR of Candesartan cilexetil standard

Fig. 6. IR of Candesartan cilexetil sample

Table 6. Comparison of IR ranges of standard and sample Candesartan cilexetil IR ranges

of sample (cm-1)

Functional group IR ranges of Standard (cm-1)

Functional group

747.57 C-H (aromatics) 700-800 C-H (aromatics)

914.17 N-H wag

(primary & secondary amine)

900-1000 N-H wag

(primary & secondary amine)

1244.46 C-O str

(carboxylic acid, esters, ethers

1200-1300 C-O str

(carboxylic acid, esters, ethers

1449.42 C-C str (aromatic) 1400-1500 C-C str (aromatic) 1729.24 C-O str

(carboxylic acid)

1700-1800 C-O str

(carboxylic acid)

It was found that all the peaks in sample IR were in good agreement with standard IR of

[image:12.595.92.503.525.710.2]
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B) Solubility study of Candesartan cilexetil in phosphate buffer

Solubility study of Candesartan cilexetil was carried out in 3 different phosphate buffers i.e.;

[image:13.595.67.530.405.606.2]

pH 1.2, 6.8, 7.4. Solubility study of Candesartan cilexetil is shown in the table 7.

Table 7. Solubility of Candesartan cilexetil pure drug

pH Solubility found (mg/ml)

1.2 0.60

6.8 1.79

7.4 1.72

b. Polymer characterization

The above table gives different parameters for which polymers where characterized. Three

polymers where characterized namely Eudragit S100, Eudragit L100-55and HPMC K4M for

LOD, Solubility given in table 8.

Table 8. Preformulation study of Eudragit S100, L100 and HPMC K4M

Parameter Eudragit S100

Eudragit

L100-55 Standard HPMC K4M Standard

LOD 3.5% 2.8% NMT 5% 1.9% NMT 5%

Solubility Soluble in methanol and acetone Soluble in methanol and acetone soluble in Methanol, acetone Insoluble in ethanol, chloroformbut soluble in mixtures of ethanol and dichloromethane, mixtures of methanol and dichloromethane, and mixtures of water and alcohol

Insoluble in ethanol, chloroformbut soluble in mixtures of ethanol and dichloromethane, mixtures of methanol and dichloromethane, and mixtures of water and alcohol

IR study of polymers

The IR study of Eudragit S100, Eudragit L100-55 and HPMC K4M were performed by

Bruker instrument. IR study was performed to check the structure and purity of polymers. IR

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[image:14.595.116.478.73.228.2] [image:14.595.93.494.282.576.2]

Fig. 7. IR of Eudragit S100 Table 9. IR Observations of Eudragit S100 IR

IR ranges of Eudragit S100 Functional group

3744.77 cm-1 Broad peaks of free OH- group

2860.32-2918.09 cm-1 C-H stretching (aliphatic)

1457.80-1728.45 cm-1 C=O group

1017.58 cm-1 C-O group

Fig. 8. IR of Eudragit L100-55 Table 10. IR observations of Eudragit L100-55 IR

IR ranges of Eudragit L100-55 Functional group

3609-3744.59 cm-1 Broad peaks of free OH- group

2850.18-2917.81 cm-1 C-H stretching (aliphatic)

1467.71-1551.20 cm-1 C=O group

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[image:15.595.112.481.72.256.2] [image:15.595.134.471.322.378.2]

Fig. 9. IR of HPMC K4M Table 11. IR observations of HPMC K4M IR

IR ranges of HPMC K4M Functional group

3604cm-1 Broad peaks of free OH- group

2850.79-2918.87 cm-1 - CH2

101.92 cm-1 O-C=O

This IR study shows that all functional groups of sample polymers are in good agreement

with standard IR functional groups of polymer. Thus from above IR graph it is clear that

obtained polymers are pure.

c. Compatibility study

Table 12. Compatibility study without moisture Sr.

No. Physical mixture

Colour

Change Liquification

Gas

formation Caking 1 Candesartan cilexetil+

CP No No No No

2 Candesartan cilexetil+

MCC No No No No

3 Candesartan cilexetil+

Mannitol No No No No

4 Candesartan cilexetil+

Mg. stearate No No No No

5 Candesartan cilexetil+

talc No No No No

6 Physical mixture No No No No

7 PM + Eudragit L100-55 No No No No

8 PM + Eudragit S100 No No No No

9 PM + HPMC K4M No No No No

10 PM + Eudragit L100-55+

[image:15.595.96.505.498.761.2]
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11 PM + Eudragit S100 +

HPMC K4M No No No No

12 PM + HPMC K4M +

Lactose No No No No

Table 13. Compatibility study with moisture Sr.

No.

Physical mixture Colour

Change Liquification

Gas

formation Caking

1 Candesartan cilexetil + CP No No No No

2 Candesartan cilexetil +

MCC No No No No

3 Candesartan cilexetil +

Mannitol No No No No

4 Candesartan cilexetil +

Mg. stearate No No No No

5 Candesartan cilexetil + talc No No No No

6 Physical mixture No No No No

7 PM + Eudragit L100-55 No No No No

8 PM + Eudragit S100 No No No No

9 PM + HPMC K4M No No No No

10 PM + Eudragit L100-55 +

HPMC K4M No No No No

11 PM + Eudragit S100 +

HPMC K4M No No No No

12 PM + HPMC K4M +

Lactose No No No No

After observing all parameters like colour change, liquification, gas formation and caking it

was clear that drug is compatible with excipients and also all excipients used are compatible

with drug because there were no change in the colour, there was no gas formation or caking

in drug and excipients mixture even after storage for 14 days at 550C.

[image:16.595.86.512.561.729.2]

A) Without moisture B) With moisture

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A) Without moisture B) With moisture

Fig.11. IR of Candesartan cilexetil and MCC mixture A) Without moisture B) With moisture

Fig.12. IR of Candesartan cilexetil and mannitol mixture A) Without moisture B) With moisture

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A) Without moisture B) With moisture

Fig.14. IR of Candesartan cilexetil core tablet physical mixture

A) Without moisture B) With moisture

Fig.15. IR of Physical mixture and Eudragit L100-55 A) Without moisture B) With moisture

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A) Without moisture B) With moisture

Fig.17. IR of Physical mixture and HPMC K4M

A) Without moisture B) With moisture

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[image:20.595.83.515.76.264.2]

A) Without moisture B) With moisture

Fig.20. IR of Physical mixture+ HPMC K4M+Lactose

From above IR graphs it can be seen that there was no change in the graphs without moisture

and with moisture hence drug is compatible with all excipients used and also excipients are

compatible with drug and hence can be used for further study.

c. Evaluation of core tablet of Candesartan cilexetil

[image:20.595.116.480.445.634.2]

A) Evaluation of pre-compression parameters of core material given in table 14. Table 14. Pre-compression study of Candesartan cilexetil core material

Batch Bulk Density (gm/ml)

Tapped Density (gm/ml)

Hausner’s ratio

Carr’s Index

Angle of Repose(Ɵ)

F1 0.65 0.74 1.138 12.16 30.21

F2 0.64 0.72 1.125 11.11 32.47

F3 0.64 0.75 1.171 14.66 29.32

F4 0.63 0.72 1.142 12.5 37.66

F5 0.66 0.76 1.151 13.16 32.13

F6 0.68 0.73 1.074 6.85 29.49

F7 0.64 0.76 1.188 15.78 34.15

F8 0.65 0.73 1.123 10.96 28.54

F9 0.64 0.75 1.172 14.66 29.30

F10 0.64 0.75 1.172 14.66 28.69

Bulk density of all 10 batches were in the range of 0.63 to 0.68.

Tapped density of all10batches were in the range of 0.72 to 0.76.

Carr’s index of all 10 batches was in range of 6.85 to 15.78. Batch F6 shows Carr’s index

below 10 hence it shows excellent flow characteristics of core material. Carr’s index in the

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F8, F9 and F10 are in range of 11 to15. Hence these batches shows good flow properties. The

batch F7 shows Carr’s index within the range 16 to 20 hence it shows fair flow characteristics

of core material.

Hausner’s ratios for all 10 batches were within the 1.074 to 1.188.Hausner’sratio in the range

1.00 to 1.11 shows excellent flow properties. The batchF6 shows excellent flow property as

the value is within the range 1.00 to 1.11. Hausner’s ratio in the range 1.12 to 1.18 shows

good flow property. The batch F1, F2, F3, F4, F5, F7, F8, F9 and F10 shows good flow

property. Hausner’s ratio in the range 1.19 to 1.25 shows fair flow property.

The angle of repose of all 9 batches is within the range 28.540 to 37.660. Angle of repose in

the range 25 to 30 shows excellent flow. Batch F3, F6, F8, F9 and F10 shows excellent flow

ability. The batch F1, F2, F5 andF7 shows good flow as they are in the range 31 to 35. The

batch F4 shows fair flow as the value of angle of repose is within 36 to 40 according to

USP-NF27 2009.

d. Evaluation of post compression parameter of core tablet

Core tablet of Candesartan cilexetil were evaluated for Thickness, Diameter, Friability,

Hardness, Average weight, Disintegration testing and results are noted down in the table 15.

Table 15. Post-compression evaluation of core tablet

Batch Thickness (mm)

Diameter (mm)

Average weight(mg)

Friability (%)

Hardness Kg/cm2

Disintegration test (seconds)

F1 2.14 8.10 129 0.90 3.0 16

F2 2.20 8.12 130 0.65 3.5 21

F3 2.10 8.08 129 0.71 3.0 20

F4 2.15 8.01 128 0.77 3.5 19

F5 2.17 8.01 130 0.89 4.0 20

F6 2.17 8.05 130 0.92 3.5 15

F7 2.10 8.04 126 0.90 3.0 24

F8 2.14 8.06 126 0.75 3.0 22

F9 2.16 8.02 132 0.81 3.5 15

F10 2.14 8.04 100 0.53 3.0 15

According to IP 2010 the limit for friability is 1%. Friability of all batches F1-F10 were

below 1% thus these batches passes the test of friability according to IP 2010.

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The disintegration test was performed in phosphate buffer pH 6.8 to check the disintegrating

time of core tablet. The disintegration time of all batches F1-F10 was found 15 to 24 seconds.

Average weight was found to be within limit.

f. Dissolution testing of core tablet of Candesartan cilexetil

Dissolution test of core tablet of Candesartan cilexetil was performed to check that how much

time was actually required for maximum amount of drug release in phosphate buffer

pH6.8.The drug release data for core tablet of Candesartan cilexetil is given in table 16.

Table 16. Drug release of core tablet of Candesartan cilexetil Time

(min)

% Drug release

F1 F2 F3 F4 F5 F6 F7 F8 F9 F10

5 59.90 49.48 41.46 41.88 41.25 38.75 42.08 39.38 42.08 35.88

10 71.15 73.13 57.08 57.50 54.48 51.88 58.65 56.04 59.27 40.84

15 77.29 81.46 81.88 79.58 73.44 68.33 71.98 72.19 73.13 51.64

20 81.77 83.44 88.02 89.17 83.13 75.31 78.02 80.00 81.67 71.66

25 95.00 95.83 98.54 100.21 95.00 92.19 93.85 88.13 93.85 91.24

30 102.08 101.88 101.15 100.83 99.69 101.46 97.29 92.92 100.1 100.46 The core tablet dissolution test was carried out for about 30 minutes at 5 minutes time

interval. From above table it is clear that all batches shows good drug release in short time.

But in that F9 and F10 batches which were have good binding property, good hardness, and

good friability hence F9 and F10 batches were selected for formulation of coated tablet of

[image:22.595.116.481.525.707.2]

Candesartan cilexetil.

(23)

From above drug release profile (fig.21) it is clear that F9and F10 batches gives100.10% and

100.46% drug release in phosphate buffer pH 6.8 as compared to other batches where batches

F1 gives 102.08%, F2 gives 101.88%, F3 gives 101.15%, F4 gives 100.83%, F5

gives99.69%, F6 gives 101.46%, F7 gives 97.29%, F8 gives 92.92% in 30min. The core

tablet of F9 batch dissolves in 30 minutes and about 100.10% drug was released. Hence from

above discussion it is clear that the F9 and F10 batches are best batches for the preparation of

the coated tablets.

g. Evaluation of compression coated tablet of Candesartan cilexetil A) Evaluation of pre-compression parameters of coating material

Coating material of compression coated tablet of Candesartan cilexetil was evaluated for

different pre-compression parameters like Bulk density, Tapped density, Carr’s index,

[image:23.595.81.518.364.590.2]

Hausner’s ratio and Angle of repose. All the results are noted in table 17.

Table 17. Pre-compression study of Candesartan cilexetil coating material Batch Bulk density Tapped density Carr’s index Hausner’s

ratio Angle repose

F1 0.50 0.62 18.03 1.22 31.38

F2 0.53 0.64 17.18 1.20 33.02

F3 0.55 0.60 8.33 1.09 26.56

F4 0.53 0.63 15.87 1.18 21.80

F5 0.54 0.61 11.47 1.12 30.96

F6 0.58 0.67 13.43 1.15 25.87

F7 0.53 0.62 14.51 1.16 22.78

F8 0.55 0.61 9.83 1.10 27.42

F9 0.58 0.66 12.12 1.13 29.24

F10 0.59 0.68 13.23 1.15 34.70

F11 0.52 0.62 16.12 1.19 28.38

F12 0.51 0.62 14.75 1.17 32.21

Bulk density of all 12 batches were in the range of 0.50 to 0.59.

Tapped density of all 12 batches were in the range of 0.61 to 0.68.

Carr’s index of all 12 batches was in range of 8.33 to 18.03. Batch F3, F8 shows Carr’s index

below 10 hence it shows excellent flow characteristics of coat material. Carr’s index in the

range 11 to 15 shows good flow properties and Carr’s index of batches F5, F6, F7, F9, F10,

F12 are in range of 11 to15 Hence these batches shows good flow properties. The batch F1,

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of coat material. Hausner’s ratios for all 12 batches were within the 1.09 to 1.22. Hausner’s

ratio in the range 1.00 to 1.11 shows excellent flow properties. The batch F3, F8 shows

excellent flow property as the value is within the range 1.00 to 1.11. Hausner’s ratio in the

range 1.12 to 1.18 shows good flow property. The batchF4, F5, F6, F7, F9, F10, and F12

shows good flow property. Hausner’s ratio in the range 1.19 to 1.25 shows fair flow

property. BatchF1, F2, F11 shows fair flow property as the value is within the range 1.19 to

1.25. The angles of repose of all 12 batches were within the range 210 to 340. Angle of

repose in the range 25 to 30 shows excellent flow. Batch F3, F4, F6, F7, F8, F9, F11 shows

excellent flow ability. The batch F1, F5, F10, F12 shows good flow as they are in the range

31 to 35.

B) Post compression evaluation of Candesartan cilexetil compression coated tablet

Compression coated tablet of Candesartan cilexetil were evaluated for thickness, diameter,

average weight, friability, hardness and results for all these parameters are noted down in

table 18.

Table 18. Post-compression evaluation of Candesartan cilexetil compression coated tablet

Hardness of all 12 batches is in range of 3.5 to 6.1 kg/cm2 and according to literature

hardness of compression coated tablet should be in the range 3 to 8 kg/cm2. Hence hardness

of all 12 batches is within the range.

According to IP 2010 the limit for friability is 1%. Friability of all 12 batches was found

below 1% thus these batches are within friability limit according to IP 2010. According to IP

Batch Thickness (mm)

Diameter (mm)

Average weight (mg)

Friability (%)

Hardness Kg/cm2

F1 4.98 10.07 333.5 0.082 3.5

F2 5.06 10.09 332.5 0.0943 3.5

F3 5.11 10.08 330 0.0956 4

F4 5.07 10.06 333 0.0973 4.4

F5 4.81 10.10 332 0.145 4.2

F6 4.24 10.09 380.5 0.579 5.5

F7 4.25 10.06 301 0.21 4.6

F8 4.21 10.04 300 0.125 5.2

F9 4.26 10.06 300.5 0.134 5.7

F10 4.23 10.08 298 0.278 4.2

F11 4.25 10.04 302 0.310 6.1

[image:24.595.115.482.419.626.2]
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2010 the weight variation limit for more than 250mg of tablet is ±5%. All tablets were within

limit. Average weight for all batches was found to be in the range 298 mg to 380.5 mg.

C) In vitro dissolution testing of compression coated tablet of Candesartan cilexetil

In vitro dissolution study was performed to check weather tablet releases maximum amount

of drug into the gastrointestinal environment within 5 hrs time. Dissolution testing of

compression coated tablet of Candesartan cilexetil in phosphate buffer pH 1.2, pH 6.8 and pH

7.4. Here dissolution testing of all 12 batches carried out by using USP type II dissolution

apparatus (Electrolab) at rotation speed of 50rpm and temperature of 37±0.5 0C and

absorbance was analysed spectrophotometrically at 254nm.The percentage drug release for

[image:25.595.131.465.524.673.2]

all batches in phosphate buffer pH 1.2, pH 6.8 and pH 7.4 are given in table 19 and 20.

Table 19. % drug release of Candesartan cilexetil compression coated tablet

Batches F1 F2 F3 F4 F5 F6

Lag time

(hrs) 2.30 5.15

More than

8 hrs 5.30 6.30 5.00

% Drug Release After Lag time

5 min 38.75 39.38 - 43.12 46.12 40.01

10 min 51.88 56.04 - 59.27 61.24 56.78

15 min 68.33 72.19 - 73.13 70.52 69.94

20 min 83.44 84.58 - 87.71 86.46 84.56

25 min 92.19 88.13 - 93.85 94.62 95.29

30 min 101.46 99.92 - 101.20 100.02 100.34

Table 20. % drug release of Candesartan cilexetil compression coated tablet

Batches F7 F8 F9 F10 F11 F12

Lag time

(hrs) 3.30 3.30 3.35 3.45 4.0 4.30

% Drug Release After Lag time

5 min 24 21.88 27.63 23.5 30.25 24.25

10 min 53.13 68.75 67.5 45.37 52.87 52.38

15 min 69.94 77.13 80.25 65.81 53.87 63.44

20 min 74.5 82.69 90.81 85.15 62 75

25 min 82.19 93.44 95.19 94 72.56 91.56

30 min 100.44 98.5 99.75 101.87 96.62 100.43

From above table it is clear that none of the batch gives drug release in buffer pH1.2, but

there are some batches which give drug release in the phosphate buffer 6.8. Because our basic

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h. Evaluation of best batch F12

1. Evaluation of pre-compression parameters of best batch F12

The pre-compression parameters like bulk density, tapped density, Carr’s index, Hausner’s

[image:26.595.118.475.187.311.2]

ratio and angle of repose were evaluated, given in table 21.

Table 21. Evaluation of pre-compression parameters of F12 batch Formulation Bulk

density Tapped density Carr’s index Hausner’s ratio

Angle of repose

CCT1 0.59 0.65 9.23 1.101 28.520

CCT2 0.56 0.62 9.67 1.107 27.300

CCT3 0.57 0.61 9.83. 1.07 28.700

Average 0.573 0.626 9.576 1.092 28.350

SD ± 0.015 ±0.020 ±0.310 ±0.0199 ±0.763

The average bulk density of F12 batch was found to be 0.573± 0.015.

The average tapped density of F12 batch was found to be 0.626±0.020.

The average Carr’s index of F12 was found to be 9.576±0.310. This shows Carr’s index

below 10 hence it shows excellent flow characteristics of coat material.

The average Hausner’s ratios of F12 was found to be 1.092±0.0199. Hausner’s ratio in the

range 1.00 to 1.11 shows excellent flow properties.

The average angle of repose of F12 was found to be 28.350±0.763. Angle of repose in the

range 25 to 30 shows excellent flow.

2. Evaluation of Post compression parameters of best batch F12

The large scale production of F12 batch was done and it was evaluated for hardness,

friability, average weight, thickness, diameter and results were noted down in table 22.

Table 22. Evaluation of post compression parameters of F12 batch Batch Friability

% Average weight (mg) Thickness (mm) Diameter (mm) Hardness (kg/cm2)

CCT1 0.312 300 4.98 10.05 6.5

CCT2 0.161 300 5.12 10.04 6.0

CCT3 0.644 301 4.87 10.08 6.5

Average 0.372 300.33 4.99 10.05 6.33

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The average hardness of batch F12 formulation was found to be 6.33±0.288 kg/cm2. The

average friability was found to be 0.372±0.202% which is below 1% hence it indicates that

tablets had good mechanical strength. The batch F12 formulation passes the test of weight

variation. The average thickness of tablet was found to be 4.99±0.125 mm and average

diameter of tablet was found to be 10.05±0.0208 mm.

3. In vitro drug release of best batch F12

The in vitro dissolution study was also performed in phosphate buffers that is pH1.2, 6.8, and

[image:27.595.76.483.254.637.2]

results were noted down in table 23.

Table 23. Percentage drug release study of F12 batch

Batches CCT1 CCT2 CCT3 Average SD

Lag time

(hrs) 4.30 4.35 4.30 4.316 ±0.0288

% Drug release after lag time

5 min 27.40 30.29 16.83 24.84 ±7.085

10 min 61.78 59.38 40.38 53.84 ±11.724

15 min 82.45 72.36 60.58 71.79 ±10.945

20 min 88.70 80.77 68.99 79.48 ±9.917

25 min 95.67 92.31 82.45 90.14 ±6.871

[image:27.595.117.480.445.632.2]

30 min 99.76 98.56 95.91 98.08 ±1.196

Fig.22. % Drug Release of CCT1, CCT2, CCT3 (a, b, c)

Thus from above table 23 and fig.22, it is clear that batch F12 gives drug release in the buffer

of pH 6.8. From above table it can be concluded that result which we obtained are

(28)

4. Assay of Candesartan cilexetil compression coated tablet

Table 24. Drug content of Candesartan cilexetil compression coated tablet

Drug content Limit

98.85% NLT 95.0% and NMT 105.0%

[image:28.595.67.517.209.271.2]

5. Drug release kinetics of F12 batch

Table 25. Drug release kinetics of Batch F12 compression coated tablet Batch Zero order

(R2)

First order (R2)

Higuchi Model (R2)

Korsmeyer- Peppas model

(R2)

Hixoncrowell (R2)

F12 0.8258 0.5467 0.8072 0.9809 0.815

The drug release kinetics was studied to check drug release pattern of formulation. Above

table 25 shows all R2values of the F12 batch. From above R2 values it is Korsmeyer peppas

model shows highest R2value 0.845 as compared to other orders and models. Hence batch

F12 follows Korsmeyer-peppas model. The graph of Korsmeyer- peppas was plotted as log

[image:28.595.126.471.402.588.2]

time VS log % drug release. The graph is shown in the fig.23.

Fig.23.Graph of Korsmeyer-peppas model 6. Stability study

The stability study was performed to see weather selected formulation undergoes any

significant changes in different parameters like appearance, drug content and %drug release.

We need formulation to remain stable at temperature 45±2 0C and RH 75±5% the results

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[image:29.595.136.465.90.223.2]

Table 26. Result of stability study Sr.

No. Time

Evaluation parameter Physical

appearance

% Drug

release Drug content

1 0 days No change 99.05±0.45 99.62±0.130

2 30 days No change 98.71±0.065 98.89±0.070

3 60 days No change 98.77±0.204 99.12±0.658

4 90 days No change 98.94±0.155 99.37±0.466

From above table it is clear that best batch F12 do not show any significant variation in the

physical appearance, Drug content and % drug release when kept at temperature 40±20C and

RH 75±5% in stability chamber for 3 months. Hence formulation is stable.

7. Study of marketed tablet of Candesartan cilexetil and its comparison with prepared tablet

There are various marketed products of Candesartan cilexetil like tablets. Here marketed tablet of Candesartan cilexetil was evaluated for hardness, friability, disintegration time and% drug release.

Name of tablet: CANDESAR 8 mg tablets

Manufactured By: Ranbaxy Laboratories Ltd.

Strength: Candesartan cilexetil 8 mg

[image:29.595.105.488.532.643.2]

Type: Uncoated tablet

Table 27. Study of marketed tablet

Sr.no. Parameters Result

1 Hardness 4.5 kg/cm2

2 Friability 0.563%

3 DT (min) 2.03 min

4 %drug release 98.09% in 60 min

The above table shows that marketed tablet has good hardness of 4.5 kg/cm2, friability up to

0.563%, disintegration time is 2.03 min and releases maximum amount of drug 98.09% in the

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Fig.24. Comparison of % drug release between prepared and marketed preparation

CONCLUSION

In the present work pulsatile tablets of Candesartan cilexetil were prepared by compression

coating technique by using Eudragit L100-55, Eudragit S100 and HPMC K4M. These

polymers are used in combination and individually. F12 batch which gives best results and

also economically best. All tablets were subjected to hardness, friability, weight variation,

drug content, In vitro drug release study and short term stability study. This prepared

formulation produced desired lag time i.e. 4.30 hours which is hypothetically essential to treat

the hypertension at early in the morning hours. After lag time the formulation was released

the complete drug immediately in 30 minutes and shows pulsatile release. As compared with

marketed preparation, the prepared formulation shows desired lag time to treat hypertension

in the early mornings. As the prepared formulation gives drug release upto 98.08% in 5 hrs

and marketed preparation gives drug release upto 98.09% in 1 hrs.

ACKNOWLEDGEMENT

I sincerely thanks to Amrutvahini College of Pharmacy, Sangamner to provide me

laboratories and instrumental facilities for doing my research work. I also thanks to Mylan

laboratories, Glenmark Pharma R and D Centre, Sinnar, Nashik and Evonic Industries,

Mumbai to provide me API and other ingredients.

REFERENCES

1. Kulkarni U, Sampada HC and Hariprasanna RC: Pulsatile drug delivery systems: current

(31)

2. Jain V, Jain D, Raturi R, Bansal P and Singh R: Recent technologies in pulsatile drug

delivery systems. Biomatter, Landes Bioscience 2011; 1(1):55-65.

3. Kalantzi LE, KaravasE ,Koutris EX and Bikiaris DN: Recent advances in oral pulsatile

drug delivery & formulation. Bentham science publishers Ltd. 2009; 3(1):49-63.

4. Gupta NB, Sharma P, Bhandari N, Singh K and Kumari A: Pulsatile drug delivery as

modified release dosage form: a review. Journal of Drug Delivery & Therapeutics 2012;

2(6): 102-110.

5. Modasiya MK and Patel VM: Pulsatile Drug Delivery System for Colon – A Review.

International Journal of Research in Pharmaceutical and Biomedical Sciences 2011; 2

(3):934-941.

6. Cartestensen JT, Rhodes CT: Drug Stability Principle and Practices, 2010; 3rd edition,

107:225-255.

7. Malik D, Singh I: Formulation and evaluation of press coated tablets of esomeprazole for

colonic delivery. Asian Journal of Pharmaceutics 2012; 6(4):252-258. [cited 2014 Mar

19] Available from: http://www.asiapharmaceutics.info/text.asp?2012/6/4/252/107560

8. USP32-NF27, The United States of Pharmacopoeial Convention, Rockville MD, 2009;

1:227,689.

9. Hadkar UB: A Handbook of Practical Physical Pharmacy and Physical Pharmaceutics,

NiraliPrakashan, 85-88.

10.Indian pharmacopoeia, Government of India, ministry of health and family welfare, The

Indian pharmacopoeia commission, Ghaziabad, 2010; I:56-63, 150.

11.Niazi SK: Handbook of Preformulation, Informa healthcare, 2007; 241-276.

12.Jasem AM, Ghareeb MM: Preparation and characterization of orodispersible tablets of

candesartan cilexetil by direct compression method. International Journal of Pharmacy

and Pharmaceutical Sciences 2013; 5(1):328-333.

13.Available online from: USFDA dissolution methods

www.accessdata.fda.gov/scripts/cder/dissolution/dsp_searchResults_Dissolution.cfm?Pri

ntAll=/ [cited on: 27 march 2014].

14.USP35–NF30, The United States of Pharmacopoeial Convention, Rockville MD, 2012;

36(6):1506.

15.Costa P: Modeling and comparison of dissolution profiles. European Journal of

(32)

16.Ugurlu T, Turkoglu M: Colonic delivery of compression coated nisin tablets using

Pectin/HPMC polymer mixture. European Journal of Pharmaceutics and

Biopharmaceutics, 2007; 67:202–210.

17.Brahmankar D, Jaiswal S: Biopharmaceutics and Pharmacokinetics- A Treatise, 2nd

edition, 2009; 431-440.

18.Malik A, Kumar V: World Health Organization’s Guidelines for Stability Testing of

Pharmaceutical Products. Journal of Chemical and Pharmaceutical Research, 2011;

3(2):892-898.

Figure

Fig. 1: Drug release profile of PDDS [5]
Table 3. Formula for outer coating layer
Table 4. Percentage weight variations allowed under weight variation
Table 5. Preformulation study of Candesartan cilexetil
+7

References

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