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Chetan et al. / Pharma Science Monitor 5(2), Sup-1, Apr-Jun 2014, 153-179

Pharma Science Monitor 5(2), Sup-1, Apr-Jun 2014

FORMULATION, EVALUATION AND OPTIMIZATION OF PRESS COATED

PULSATILE TABLET OF ZALTOPROFEN FOR THE TREATMENT OF

RHEUMATOID ARTHRITIS

Chetan G Kukadiya*, Kesha Desai, S. M. Vijayendra Swamy

Bhagwan Mahavir College of Pharmacy, Nr. Ashirwad Villa, New City Light Road, B/H Heena Bunglow’s, Vesu, Bharthana, Surat-395017

ABSTRACT The aim of the present study was to formulate, evaluate and optimize press coated pulsatile tablet of Zaltoprofen for the treatment of rheumatoid arthritis. The drug delivery system is based on the concept of chronotherapeutics. Dosage form provide delayed release up to 5 hour and after completion of lag time up to 5 hour dosage form provides burst release of drug therefore highest blood level of the drug coincide with peak pain and stiffness. Formulation comprising a core containing active ingredient, surrounded by the coating layer containing enteric pH dependent polymer eudragit L 100 and Ethyl cellulose. Core tablet was prepared by direct compression using crospovidone as a superdisintegrant and microcrystalline cellulose as a diluent. Core tablet was compression coated with barrier layer containing eudragit L 100 and ethyl cellulose using direct compression method. A 32 full factorial design was used to optimize barrier layer. The optimized check point formulation A1 was selected from overlay plot using Design expert 9.0. The press coated tablet with weight ratio of ethyl cellulose: eudragit L 100 76.48: 23.52 (%) with coating weight 356 mg is most satisfactory to provide desired pulsatile delivery of Zaltoprofen for effective treatment of rheumatoid arthritis. KEYWORDS: Zaltoprofen, Rheumatoid arthritis, Chronotherapy, Pulsatile release, Press coated tablet, Crospovidone, Eudragit L 100, Ethyl cellulose, Lag time. INTRODUCTION

For the treatment of various diseases oral route is the most preferred route and conventional

dosage forms are widely used for treatment. In conventional therapy drug is released

immediately after medication. So, the drug concentration in the plasma is raised and sometimes it

is more than the toxic level. The target of drug discovery is to obtain maximum drug efficacy and

minimum side effect. Although sustained and constant release systems have been developed

biological systems are not so responsive to these release systems. Several controlled release

preparation present numerous problems such as resistance and drug tolerance, and activation of

the physiological system due to long term constant drug concentrations in the blood and tissues.

The diseases currently targeted for chronopharmaceutical formulations are those for which have

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enough scientific backgrounds to justify their Chronopharmaceutical drug delivery compared to

the conventional drug administration approach. These include asthma, arthritis, duodenal ulcer,

cancer, diabetes, cardiovascular diseases, hypercholesterolemia, ulcer and neurological diseases.

The efficacy and side effect of many drugs vary depending on dosing time associated with

circadian rhythms of biochemical, physiological, and behavioral processes under the control of

circadian clock. It has been found out that circadian rhythm is useful for the treatment of various

pathophysiological conditions of human body. Rheumatoid arthritis (RA) is a chronic disease

that causes pain, stiffness, swelling and limited motion and function of many joints. The stiffness

seen in active RA is most often worst in the morning. These Symptoms closely follows the

circadian rhythms and mainly result of imbalance between anti-inflammatory effects of cortisol

and pro-inflammatory effect of melatonin (MLT) in RA during night and early morning.

Moreover, typical circadian rhythm of melatonin exhibits a maximum at 3.00 AM. The pulsatile

drug delivery system (PDDS) is intended to deliver a rapid, or transient, and quantified

medication release after a predetermined off-release period (lag time) . PDDS can deliver the

correct amount of medication at the desired location at the optimal time for maximum effect

against disease, thereby enhancing therapeutic efficacy and improving patient compliance.

Zaltoprofen is a novel NSAIDS with powerful anti inflammatory and analgesic effects on

inflammatory pain. Zaltoprofen is a drug with high efficacy contributing to the improvement of

daily activities in patient of chronic rheumatoid arthritis. Press coating is a novel, simple and less

time consuming technique of coating thereby Press coating technique is suitable to formulate

pulsatile release tablet. This system can be administered at night (before sleep) and gives drug

release in early morning that would be a promising chronopharmaceutic system1-8

MATERIALS AND METHODS

Materials: Materials used in the present investigation were obtained from the following sources:

Zaltoprofen was obtained from ZCL chemical, Mumbai. Crospovidone, Microcrystalline

cellulose, Eudragit L 100, Etheyl cellulose, Talc, Magnesium stearate were obtained from the

chemdyes corporation, Ahmedabad.

Methods:

1. Preformulation study

1.1) Organoleptic evaluation9

The color, odor, and taste of the drug were characterized and recorded using descriptive

terminology.



1.2) Drug excipients compatibility study

The drug excipients interaction studies were carried out using Fourier Transform Infrared

Spectrophotometer (FTIR).

1.3) Solubility study of Zaltoprofen10

Solubility of Zaltoprofen in phosphate buffer pH 7.4, pH 6.8 and in 0.1N HCL pH 1.2 was

determined by equilibrium solubility method. Sufficient excess amount of Zaltoprofen was added

to 5 ml stoppered glass vials containing pH 7.4, pH 6.8 and pH 1.2 buffer solutions separately.

The vials were shaken reciprocally for 72 h on mechanical shaker to reach equilibrium at R.T.

The solutions were transferred into tubes and centrifuged for 30 min at 2500 rpm. Solutions were

filtered using whatmann filter paper and the filtrate was analyzed for drug content by UV visible

spectrophotometer at 340nm and 338 nm after appropriate dilutions. The study was performed in

triplicate.

2. Preparation of press coated pulsatile tablet of zaltoprofen11

Two steps are involved in preparation of press coated pulsatile tablet of zaltoprofen:

2.1) Preparation of core tablet of zaltoprofen

The core tablets of Zaltoprofen were prepared by direct compression method. As shown in

below table. Core tablets of Zaltoprofen were prepared by using fixed concentration of

superdisintegrant crospovidone and diluent i.e. microcrystalline cellulose. Calculated quantities

of Zaltoprofen, super disintegrants, and diluents were accurately weighed and blended in a

mortar. All ingredients were passed through sieve no. 60 # and throughly mixed. Then the talc

and magnesium stearate were added to the mixture. The mixture was compressed into tablet on a

rotary tablet punching machine using 8 mm punch.

Table 1: Composition of core tablet

Ingredients Zaltoprofen Crospovidone Microcrystalline

cellulose

Magnesium

stearate

Talc

Quantity

(mg)

80 5 70 2 1

2.2) Preparation of Zaltoprofen press-coated tablet

The press-coated tablets of Zaltoprofen were prepared by direct compression method.

Calculated quantities of ethyl cellulose and eudragit L 100 were accurately weighed and blended

in a mortar. All ingredients were passed through sieve no. 60 # and thoroughly mixed. Then this

coating material was used as barrier layer to prepare press-coated tablet. Half the quantity of the



coating material was placed in the die cavity; the core tablet was carefully positioned in the

center of the die cavity and was filled with other half of the coating material. The coating

material was compressed using 12 mm punch on a rotary tablet compression machine.

3. Optimization by 32 full factorial design

In the present study, a 32 full factorial design by response surface methodology was used to

optimize press coated pulsatile tablet formulation of Zaltoprofen. In this design, two independent

variables were evaluated, each at three levels, and experimental trials were performed at all nine

possible combinations. Design-Expert 9.0 software (State-Ease Inc., USA) was used for

mathematical modeling, evaluation of the ability to fit to the model and response surface

modeling. Two independent variables, weight ratio of ethyl cellulose to eudragit L 100 (%) (X1)

and coating level (mg) (X2) were set at three different levels. High and low levels of each factor

were coded as 1 and -1 respectively and the medium level as zero. The levels of these

formulation variables were chosen on the basis of results obtained from the preliminary studies

and literature survey. In addition to factors and levels, dependent variables were also selected for

the evaluation of the factorial design batches. The dependent variables measured were lag time

(t10%) (min) (Y1), Cumulative percentage Drug release at 7 hour (Y2).

Table 2: Coded and decoded values for all the formulations

Batch code Coded value for

X1 factor

Coded value for

X2 factor

Decoded value for

X1 factor (%)

Decoded value for

X2 factor (mg)

F1 -1 -1 75:25 300

F2 -1 0 75:25 350

F3 -1 1 75:25 400

F4 0 -1 80:20 300

F5 0 0 80:20 350

F6 0 1 80:20 400

F7 1 -1 85:15 300

F8 1 0 85:15 350

F9 1 1 85:15 400



Table 3: Composition of factorial batches press coated tablet

Ingredients

(mg)

F1 F2 F3 F4 F5 F6 F7 F8 F9

Zaltoprofen 80 80 80 80 80 80 80 80 80

Crospovidone 5 5 5 5 5 5 5 5 5

Microcrystalline cellulose 70 70 70 70 70 70 70 70 70

Mg. Stearate 2 2 2 2 2 2 2 2 2

Talc 1 1 1 1 1 1 1 1 1

Ethyl cellulose 225 262.5 300 240 280 320 255 297.5 340

Eudragit L 100 75 87.5 100 60 70 80 45 52.5 60

Total 458 508 558 458 508 558 458 508 558

4. Evaluation of tablets

All the prepared press coated tablets were evaluated for pre compression and post compression

parameters

4.1) Pre compression evaluation parameters12

Angle of repose ():

The angle of repose of powder blend was determined by the funnel method. The accurately

weight powder blend was taken in the funnel. The height of the funnel was adjusted in such a

way the tip of the funnel just touched the apex of the powder blend. The powder blend was

allowed to flow through the funnel freely on to the surface. The diameter of the powder cone was

measured and angle of repose was calculated using the following equation.

tan = h/r

Where, h and r are the height and radius of the powder cone.

Bulk density

It is the ratio of total mass of powder to the bulk volume of powder. It was measured by pouring

the weighed powder into a measuring cylinder and initial weight was noted. This initial volume

was called the bulk volume. From this the bulk density was calculated according to the formula

mentioned below. It is expressed in gm/ml and is given by

Weight of powder

Bulk density =

Volume of bulk powder in cylinder



Tapped density:

It is the ratio of total mass of the powder to the tapped volume of the powder. Volume was

measured by tapping the powder for 100 times and the tapped volume was noted. It is

expressed in gm/ml and is given by

Compressibility index (Carr’s index):

It indicates powder flow properties. It is expressed in percentage and is given by

Hausner’s Ratio:

It was calculated by the following formula.

4.2) Post compression evaluation parameters

Uniformity of weight13

Weigh individually 20 units selected at random and calculate the average weight. Not more than

two of the individual weights deviate from the average weight by more than the percentage

shown in the table and none deviates by more than twice that percentage.

Table 4: Uniformity of Weight

Average weight of tablet % deviation

80 mg or less 10

More than 80 mg but less than 250 mg 7.5

250 or more 5

Mass of powder

Tapped Density =

Tapped volume of the powder

Tapped density – Bulk density

Carr’s consolidation index = 100

Tapped density

Tapped density

Hausner’s ratio =

Bulk density



Thickness and diameter11

Thickness and diameter of tablets was determined using vernier caliper. Three tablets were

evaluated and an average value was calculated. The thickness and diameter were measured in

mm.

Hardness test11

Hardness was measured using Monsanto hardness tester. The force required to break the tablet is

recorded. The hardness of tablets of each batch was measured in kg/cm2

Friability test11

Tablets require certain amount of strength or hardness and resistance to withstand mechanical

shock of handling in manufacturing, packaging, and shipping. A pre weighed tablets were placed

in the Roche friabilator and apparatus was rotated at 25 rpm for 4 minutes. After revolutions the

tablets were dedusted and weighed again. The percentage friability was measured using the

formula,

Drug content14

Five tablets were taken and powdered. Tablet powder equivalent to 100 mg of Zaltoprofen was

weighed, sufficient volume of phosphate buffer was added and volume was made up to 100 ml

with phosphate buffer pH 6.8. Then the solution was filtered and the filtrate was further diluted

with phosphate buffer pH 6.8 to get require concentration. The absorbance of resulting solution

was measured by UV spectrophotometer at 340 nm.

In vitro disintegration time for core tablet15

Disintegration time was determined using USP disintegration apparatus with phosphate buffer of

pH 6.8. The volume of medium was 900 ml and temperature was 37±0.5°C. The time in seconds

taken for complete disintegration of the tablet with no palatable mass remaining in the apparatus

was measured.

In vitro dissolution study of core tablet15

In-vitro dissolution study of core tablet was performed using USP Type II dissolution apparatus

(Paddle type) at speed of 50 rpm. 900 ml of phosphate buffer pH 6.8 was utilized as dissolution

medium. The temperature of the medium was maintained at 37 ± 0.5°C. Aliquot of dissolution

Initial weight − Final weight

% Friability = X 100

Initial weight



medium 5 ml were withdrawn at specific time intervals (5, 10, 15, 20, 30, 45, 60 & 90 min) and

filtered each with whatman filter paper. Equal amount of fresh dissolution medium was replaced

immediately after each withdrawal. The amount of drug present in each sample was determined

by UV-Visible spectrophotometer at 340 nm.

In vitro dissolution study of press coated tablet15, 16

The in-vitro drug release studies of press-coated tablets of prepared formulations were carried

out using USP dissolution test apparatus type-II (Paddle type) using 900 ml of 0.1N HCL for 2

hrs and then replaced with phosphate buffer pH 6.8 at speed of 50 rpm at 37 ± 0.5 ºC and the

aliquot of dissolution medium 5 ml were withdrawn at specific time intervals and filtered each

with whatman filter paper. Equal amount of fresh dissolution medium was replaced immediately

after each withdrawal. The absorbance of the resulting solution was measured at the 338nm

(0.1N HCL pH 1.2) and 340nm (phosphate buffer 6.8 pH) using UV spectrophotometer.

5. Statistical analysis and validation of design

Statistical analysis and validation of model were performed using design expert 9.0 software

(Stat-Ease Inc., USA). The responses were analyzed using ANOVA, the individual response

parameters were evaluated using F test and polynomial equation was generated for each response

using multiple linear regression analysis. Counter plot and 3D surface plot were constructed

using design expert software. By utilizing design expert software, one final formulation

corresponding to the predicted optimum polymer ratio and coating level were prepared to

determine the validity of the model generated. Afterward, the observed experimental data of the

response properties were quantitatively compared with those of the predicted values.

6. Stability study of optimized formulation

Accelerated stability study of optimized press coated pulsatile tablets was performed as per the

ICH guideline Q1C. Optimized PCPT of Zaltoprofen was wrapped in aluminum foil and stored

in stability chamber at 40 ± 2 °C/ 75 ± 5 % RH for a period of 1 month. After a period of one

month tablets were withdrawn from chamber and evaluated for uniformity of weight, friability,

hardness, drug content and in vitro drug release study.

RESULT AND DISCUSSION

1. Preformulation study

1.1) Organoleptic evaluation: The color, odor, and taste of the drug were characterized and

recorded using descriptive terminology; the results were shown in the below table 5.



Table 5: Organoleptic evaluation

Properties Results

Description Crystalline

Taste Bitter

Odor Odorless

Color White to light yellow

1.2) Drug excipients compatibility Study: The FTIR spectra of pure drug and mixture of press

coated tablet blend were shown in below figure 1 and 2. From the result it can be concluded that

functional group peaks remain same even after physical mixture was prepared using excipients

and APIs. From the observation peaks it can be established that both APIs and excipients are

compatible with each other without any significant interaction

Figure 1: FTIR spectra of pure drug



Figure 2: FTIR spectra of press coated pulsatile tablet powder blend

1.3) Solubility study of zaltoprofen: The result of solubility study of zaltoprofen was shown in

below table 6. In pH 7.4 solubility (1.690 ± 0.0629) of Zaltoprofen was higher as compare to pH

6.8 (1.325 ± 0.0320) and pH 1.2 (0.0047 ± 0.0001), Moreover solubility of Zaltoprofen in pH 6.8

was higher as compare to pH 1.2 So, it was concluded that as the pH increases the solubility of

Zaltoprofen also increases with it and Zaltoprofen has a pH dependent solubility profile.

Table 6: Solubility study of zaltoprofen

Batch

code

pH Solubility*(mg/ml)

S1 1.2 0.0047 ± 0.0001

S2 6.8 1.325 ± 0.0320

S3 7.4 1.690 ± 0.0629

2. Evaluation of tablet: The result of pre and post compression evaluation parameters of core

tablet of zaltoprofen was shown in below table 7 and 8.

2.1) Evaluation of core tablet



Table 7: Pre and post compression evaluation parameters of core tablet

Pre

compression

evaluation

parameters

Angle of

Repose

Bulk

Density

Tapped

Density

Compressibility

Index

Hausner’s

Ratio

Result 30.31 ± 0.56 0.40 ±0.0050

0.48 ±0.0073

16.66 ± 0.21 1.20 ± 0.0058

Post

compression

evaluation

parameters

Uniformity

of

Weight

Thickness Hardness Friability

test

Disintegration

time

Result 158.1 ± 1.04

2.73 ± 0.058

3.57 ± 0.058

0.56

56.33 ± 3.49

Table 8: In vitro dissolution study of core tablet

Time (min) 0 5 10 15 20

% CDR 0 85.78 ± 2.07 91.9 ± 1.55 94.87 ± 1.41 98.04 ± 1.32

Figure 3: In vitro drug release study of core tablet

2.2) Evaluation of press coated tablet: The result of pre compression evaluation parameters of

powder blend were shown in below table 9. From the result of pre compression evaluation

parameters it can be concluded that powder blend has a good flow property.



2.2.1) Pre compression evaluation of press coated tablet

Table 9: Pre compression evaluation of press coated tablet

Batch code Angle of

Repose*

(ѳ)

Bulk

Density*

(g/cm3)

Tapped

Density*

(g/cm3)

Compressibility

Index*(%)

Hausner’s

Ratio*

F1 21.98±0.56 0.34±0.011 0.41±0.016 16.99±0.56 1.20±0.01

F2 22.61±0.29 0.28±0.0067 0.34±0.0096 17.95±2.01 1.21±0.03

F3 22.52±0.33 0.28±0.0057 0.33±0.013 15.31±2.21 1.18±0.03

F4 21.29±0.66 0.35±0.011 0.42±0.016 17.32±0.56 1.21±0.01

F5 21.72±0.81 0.30±0.0073 0.36±0.010 17.15±0.41 1.21±0.01

F6 21.90±0.87 0.29±0.0061 0.35±0.015 16.96±1.84 1.20±0.02

F7 19.95±0.57 0.37±0.012 0.45±0.019 18.37±0.64 1.22±0.01

F8 19.72±0.34 0.29±0.010 0.35±0.017 20.18±1.39 1.19±0.05

F9 20.48±0.36 0.29±0.0061 0.35±0.015 18.08±0.39 1.20±0.02

2.2.2) Post compression evaluation of press coated tablet

Table 10: Post compression evaluation of press coated tablet

Batch

code

Uniformity

of

Weight

(mg)

Thickness*

(mm)

Hardness*

(kg/cm2)

Friability

test

(%)

Drug

content*

(%)

F1 458.65±1.18 4.65±0.05 5.90±0.10 0.26 99.27±0.32

F2 508.75±1.65 5.08±0.08 5.93±0.06 0.23 98.84±0.14

F3 558.35±1.26 5.47±0.06 6.07±0.12 0.21 99.39±0.50

F4 458.45±1.05 4.67±0.03 6.13±0.15 0.17 100.06±0.14

F5 508.6±1.09 5.03±0.06 6.13±0.06 0.15 99.78±0.68

F6 558.5±1.05 5.43±0.06 6.20±0.17 0.10 98.42±0.19

F7 458.5±1.23 4.63±0.06 5.83±0.06 0.30 98.67±0.32

F8 508.7±1.21 5.57±0.08 6.17±0.15 0.15 99.97±0.14

F9 558.9±1.33 5.43±0.06 6.07±0.23 0.21 98.97±0.30

The results of post compression evaluation parameters of press coated tablets were shown in

above table 10. From the result it can be concluded that



Weight variation:

Deviation in weight of factorial batches tablets are within the limit described in table 4 indicated

that there was no significant weight variation in the prepared press coated tablets. Hence, all the

tablets formulations passed the weight variation test.

Thickness:

Thickness of tablet was found to be in the range from 4.63 ± 0.06 to 5.57 ± 0.08

Hardness:

Hardness of all formulation prepared by direct compression was found to be 5.83 ± 0.06 to 6.20

± 0.17 kg/cm2.

Friability:

The percentage friability was less than 1% in all the formulations, indicating that the friability is

within the prescribed limits. The results of friability indicates that the tablet posses good

mechanical strength.

Drug content:

Drug content in press coated tablets was found to be in the range of 98.42 ±0.19 to 100.06±0.14

that is within the acceptable limit.

2.2.3) In vitro dissolution study of press coated tablet

Table 11: Cumulative percentage drug release of factorial batches F1 to F9

% Cumulative drug release

Time

(min) F1 F2 F3 F4 F5 F6 F7 F8 F9

0 0 0 0 0 0 0 0 0 0

30 0 0 0 0 0 0 0 0 0

60 0 0 0 0 0 0 0 0 0

90 0 0 0 0 0 0 0 0 0

120 0 0 0 0 0 0 0 0 0

150 0 0 0 0 0 0 0 0 0

180 0 0 0 0 0 0 0 0 0

210 0 0 0 0 0 0 0 0 0

240 2.56 0 0 0 0 0 0 0 0



±0.79

270

42.53

±0.66 0 0

15.89

±1.57 0 0 0 0 0

300

69.21

±1.12

22.94

±1.18 0

53.47

±2.87

2.75

±1.71 0

26.1

±1.70 0 0

330

80.14

±1.68

62.02

±2.19 0

75.98

±1.32

42.7

±1.32 0

63.45

±1.64

6.84

±1.34 0

360

87.42

±0.86

79.56

±1.41

29.27

±1.57

85.47

±2.61

66.75

±1.13

10.6

±0.92

79.85

±1.32

45.31

±1.27 0

390

93.39

±0.91

86.45

±1.48

64.35

±1.13

89.96

±2.24

80.22

±1.36

49.08

±1.00

86.78

±1.02

69.71

±0.95

17.64

±1.09

420

97.72

±1.15

90.47

±1.15

78.94

±1.44

94.88

±1.34

87.62

±0.85

70.67

±1.17

91.12

±1.14

80.43

±1.47

59.47

±1.88

450

95.45

±1.16

87.21

±1.37

98.39

±1.09

93.66

±1.28

83.18

±1.04

96.23

±1.00

89.31

±1.23

78.54

±1.31

480

98.16

±0.65

91.79

±1.32

97.59

±0.98

89.52

±0.72

98.69

±1.16

94.36

±1.33

85.75

±1.56

510

96.18

±1.1

94.60

±1.05

98.32

±1.21

90.04

±1.05

540

98.24

±0.82

98.43

±1.02

95.10

±1.04

570

98.32

±1.18

2.2.3.1) Lag time of factorial batches press coated tablets:

Table 12: Lag time of factorial batches

Batch code F1 F2 F3 F4 F5 F6 F7 F8 F9

Lag Time* (t10%)

(min)

246

290

343

265

306

360

287

333

385



Figure 4: In vitro drug release profile of factorial batches F1 to F9

The result of in vitro drug release study was shown in above table 11. Formulation F1, F4 and F7

contain different percentage weight ratio of EC: EL (75:25, 80:20, 85:15) and has shown lag

time of 246, 265 and 287 respectively, whereas formulation F1, F2, F3 contain different coating

level (300,350,400) and has shown lag time of 246, 290 and 343 respectively. Formulation F2,

F5 and F8 contain different percentage weight ratio of EC: EL (75:25, 80:20, 85:15) and has

shown lag time of 290, 306 and 333 respectively, whereas formulation F4, F5, F6 contain

different coating level (300,350,400) and has shown lag time of 265, 306 and 360 respectively.

Formulation F3, F6 and F9 contain different percentage weight ratio of EC: EL (75:25, 80:20,

85:15) and has shown lag time of 343, 360 and 385 respectively, whereas formulation F7, F8, F9

contain different coating level (300,350,400) and has shown lag time of 287, 333 and 385

respectively. From the result it was concluded that as the ratio of ethyl cellulose to eudragit L

100 and coating level increased lag time was also increased with it. Moreover from the result it

can be conclude that coating level has more significant effect on lag time compare to percentage

weight ratio of EC: EL.

2.2.4) In vitro ruptured behavior of press coated pulsatile tablet:



Figure 5: Rupture behavior of press coated pulsatile tablet in dissolution media

A: Press coated tablet in 1.2 pH

B: Press coated tablet started to rupture in 6.8 pH after lag time

C: Completely ruptured press coated tablet

3) Statistical analysis of factorial design: The results summarized in table 13 clearly indicate

that both the dependent variables lag time (t10%) (min) and Cumulative percentage drug release

at 7 hour (%) are strongly affected by the selected independent variable. The selected

independent variables show a wide variation among the 9 batches (F1 to F9)

Table 13: 32 design layout with respective observed responses

Batch

Code

X1

(% weight ratio

of EC:EL)

(%)

X2

(Coating level)

(Mg)

Y1

(Lag time)

(t10%) (Min)

Y2

(Cumulative

percentage

drug release

at 7 hour)

(%)

F1 75:25 300 246 97.72

F2 75:25 350 290 90.47

F3 75:25 400 343 78.94

F4 80:20 300 265 94.88

F5 80:20 350 306 87.62

F6 80:20 400 360 70.67

F7 85:15 300 287 91.12

F8 85:15 350 333 80.43

F9 85:15 400 385 59.47



3.1) Summary output of multiple regression analysis for effect of X1 and X2 on response Y1

and Y2 : The result of the analysis of variance (ANOVA) for responses Y1 and Y2 (P > 0.05)

were shown in table 14. The F value in the ANOVA table was the ratio of model mean square

(MS) to the appropriate error (i.e. residual) mean square. The larger the F value and the more

likely that the variance contributed by the model was significantly larger than random error. In

the table model F-value and high R square values suggested that these models were significant.

The results of multiple linear regression analysis (table 15) reveal that both the coefficient b1 and

b2 bear a positive sign for lag time (Y1). Therefore, increasing the ethyl cellulose content and

coating level was expected to prolong lag time. For response cumulative drug release at 7 hr

(Y2), both the coefficient b1 and b2 bear a negative sign; indicate antagonistic effect of both

independent variables (X1 & X 2). Therefore, an increase in ethyl cellulose content and coating

level leads to decrease in cumulative drug release in 7 hr. The polynomial equation for each

response variable was as follow:

Y1 = 307.22+21.00 X1+48.33X2 + 3.67 X12+4.67X2

2

Y2 = 87.08-6.02 X1-12.44 X2-3.22 X1X2-4.04 X22

Table 14: Result of Analysis of variance

For Lag Time

Regression DF SS MS F R2

4 16733.11 4138.28 2596.52 0.9996

Residual

4 6.44 1.61

For cumulative drug release at 7 hour

Regression DF SS MS F R2

4 1219.90 304.97 158.40 0.9937

Residual

4 7.70 1.93



Table 15: Summary of result of regression analysis

For Lag Time

Co-efficient b0 b1 b2 b12 b11 b22

Co-efficient

value

+ 307.22 + 21.00 + 48.33 + 0.25 + 3.65 + 4.67

P- Value 0.0001 0.0001 0.0001 0.7509 0.0365 0.0194

For cumulative drug release at 7 hour

Co-efficient b0 b1 b2 b12 b11 b22

Co-efficient

value

+ 87.08 - 6.02 - 12.44 - 3.22 - 1.36 - 4.04

P- Value 0.0006 0.0010 0.0001 0.0113 0.1921 0.0157

4) Optimization of compression coated tablet: The application of desirability function gives

possibility to predict the optimum levels of the independent variables. Optimized checkpoint

formulation was designed accordance to the ramp plot and overlay plot as shown in table 16

(solution).

Table 16: Optimization of compression coated tablet

Constraints

Name Goal Lower Limit Upper Limit

Weight ratio of EC:

EL (%)

In range 0 20

Coating Level (mg) In range 300 400

Lag time (min) Targeted to 300

Cumulative drug

release at 7 hr (%)

In range 80 90

Solution

Weight ratio of EC:

EL (%)

Coating Level

(mg)

Lag time (min) Cumulative

drug release

at 7 hr (%)

Desirability

76.48: 23.52 356 300 89.15 1.0



4.1) Generation of Contour Plot and Response Surface Plot for Response Y1

Figure 6: Counter plot showing the effect on lag time using different combination of

percentage weight ratio of ethyl cellulose: eudragit L 100 and coating level

Figure 7: Response surface plot showing the effect of percentage weight ratio of ethyl

cellulose: eudragit L 100 and coating level on lag time



4.2) Generation of Contour Plot and Response Surface Plot for Response Y2

Figure 8: Counter plot showing the effect on cumulative percentage drug release at 7 hour

using different combination of percentage weight ratio of ethyl cellulose: eudragit L 100

(X1) and coating level (X2)

Figure 9: Response surface plot showing the effect of percentage weight ratio of ethyl

cellulose: eudragit L 100 (X1) and coating level (X2) on cumulative



4.3) Generation of Contour plot and Ramp plot for optimized formula

Figure 10: Ramp plot of optimized checkpoint formulation

Figure 11: 3D surface plot of optimized checkpoint formulation

4.5) In vitro drug release of optimized formula: Optimized checkpoint formulation was

prepared and the result of in vitro drug release study was shown in below table 17. Result of the

in vitro drug release study of optimized checkpoint formulation suggests pulsatile release from

the press coated tablet with a lag time of 302 min.



Table 17: Cumulative percentage drug release of optimized checkpoint formulation

Time (min) % CDR

0 0

30 0

60 0

90 0

120 0

150 0

180 0

210 0

240 0

270 0

300 7.75 ± 0.89

330 47.37 ±1.44

360 71.01 ± 1.30

390 80.75 ± 0.70

420 87.80 ± 0.53

450 93.27 ± 0.50

480 97.68 ± 0.92

Figure 12: In vitro drug release profile of optimized checkpoint formulation



5) Stability study of optimized formulation: The result of accelerated stability study was

shown in below table and it suggest that there were no significant changes in percentage

cumulative drug release and lag time of the optimized formulation after a period of one month

stored in stability chamber at 40 ± 2 °C/ 75 ± 5 % RH. Hence the press coated tablets were

found to be stable after one month accelerated stability study.

5.1) Post compression evaluation parameters of optimized formulation before and after

stability study

Table 18: Post compression evaluation parameters of optimized formulation before and

after stability study

Parameter Before After 1 month

Accelerated condition

40˚C ± 75% RH

Uniformity of weight (%) 514.10 ± 2.00 513.85 ± 1.78

Hardness (kg/cm2)

6.33 ± 0.20 6.40 ± 0.1

Friability (%)

0.19 0.23

Drug content (%) 99.65 ± 0.46 98.60 ± 0.41

5.2) Comparison of in vitro drug release of optimized formulation (A1) before and after

stability study

Table 19: Comparison of cumulative percentage drug release of optimized formulation

(A1) before and after stability study

Time

(min)

%CDR

Before stability

study

%CDR After 1

month

Accelerated

condition

40˚C ± 75% RH

0 0 0

30 0 0

60 0 0

90 0 0



120 0 0

150 0 0

180 0 0

210 0 0

240 0 0

270 0 0

300 7.75 ± 0.89 14.34 ± 1.09

330 47.37 ±1.44 52.83 ± 1.01

360 71.01 ± 1.30 75.22 ± 0.88

390 80.75 ± 0.70 84.51 ± 0.75

420 87.80 ± 0.53 89.98 ± 1.36

450 93.27 ± 0.50 94.36 ± 0.53

480 97.68 ± 0.92 97.28 ± 0.31

Figure 13: Comparison of in vitro drug release profile of optimized formulation (A1) before

and after stability study



CONCLUSION

The present investigation was aimed to develop press coated pulsatile tablet (PCPT) of

Zaltoprofen for the treatment of rheumatoid arthritis. The result of FTIR analysis confirmed

presence of Zaltoprofen and showed compatibility between drug and polymer without any

significant interaction. Solubility study of Zaltoprofen was carried out by equilibrium solubility

method. The result of solubility study suggested that Zaltoprofen is a drug with pH dependent

solubility profile. Zaltoprofen pulsatile release tablets were prepared by compression coating

technique. Initially core tablets were prepared by direct compression, tablets were found

satisfactory in terms of hardness, thickness, uniformity of weight, drug content, disintegration

time and in vitro drug release study. Press coated pulsatile tablet was optimized using 32 full

factorial design. Percentage weight ratio of ethyl cellulose: eudragit L 100 (X1) and coating level

(X2) were selected as an independent variable. Lag time (Y1 = t10%) and cumulative percentage

drug release at 7 hour (Y2) were selected as a dependent variable. All the factorial batches press

coated tablets were prepared by direct compression method and tablets were evaluated for

uniformity of weight, hardness, thickness, drug content, friability and in vitro drug release study.

From the result of in vitro drug release study it can be concluded that as the concentration of

ethyl cellulose to eudragit L 100 (%) and coating level (mg) increased lag time increased and

cumulative percentage drug release at 7 hour decreased. Optimized check point formulation was

design according to the result of overlay plot and desirability function and characterized under

same condition as outlined for factorial batches. The results of stability study of optimized batch

were confirmed good compatibility and stability with selected excipients. In conclusion, the

novel PCPT developed for Zaltoprofen could be a promising chronomodulated therapeutic

system for the relief of morning pain and stiffness in patients with rheumatoid arthritis.

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For Correspondence Chetan G. Kukadiya Email: [email protected]

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