Design of Pulsatile Tablets of Pantoprazole Sodium: Factorial Design Approach

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Saudi Journal of Medical and Pharmaceutical Sciences ISSN 2413-4929 (Print)
Scholars Middle East Publishers ISSN 2413-4910 (Online)
Dubai, United Arab Emirates
Website: http://scholarsmepub.com/
Design of Pulsatile Tablets of Pantoprazole Sodium: Factorial Design Approach
Reshma Fathima K, Sivakumar R*
Department of Pharmaceutics, Grace College of Pharmacy, Palakkad – 678 004, Kerala, India
Original Research Article
*Corresponding author
Sivakumar R
Article History
Received: 12.02.2018
Accepted: 20.02.2018
Published: 30.03.2018
DOI:
10.21276/sjmps.2018.4.3.5
Abstract: The objective of the present study was to develop and optimize an oral
pulsatile drug delivery system containing pantoprazole sodium to mimic the
circadian rhythm of the peptic ulcer by releasing the drug with a distinct
predetermined lag time. Six fast disintegration core tablets were prepared for
preliminary trials using direct compression method. The tablets were evaluated for
hardness, friability assay and dissolution study. The best formulation were selected
for optimization to study the influence of Micro crystalline cellulose (MCC) and
Sodium starch glycolate (SSG) using 32
full factorial design. The optimized
formulations were selected for coating for pulsatile delivery. The results of the
study indicate f3 formulation was suitable for scale up.
Keywords: Pantoprazole Sodium, Factorial Design.
INTRODUCTION
Pantoprazole sodium is an anti-ulcer drug belonging to the class of proton
pump inhibitor. The is effective in the treatment of duodenal or gastric ulcer,
gastro oesophageal reflux disease and in the treatment Pulsatile systems constitute
a relatively new class of device the important of which is especially connected
with the recent advances in chronopharmacology [1]. In the last decade numerous
studies in animal as well as clinical studies have provided convincing evidence,
that the pharmacokinetics and / or the drug’s effects – side effects can be modified
by the circadian time and or/ the timing of drug application with in 24 h of the day
[2-3].
The pulsatile delivery system improve the
patient compliance when the drug is release at early
morning. The designed core tablets coated by using pH
sensitive methocrylic acid copolymers (Eudragit L00
and S100) as coat and pantoprazole as core material.
The use of pH dependent and time dependent polymers
as coating materials have been reported previously [4-6]
the enteric coating prevents disintegration of core in the
gastric fluid. On reaching the Illium (pH 7.2) the tablets
losses its enteric coating and drug release occur. The lag
phase created to achieve the pulsatile delivery Thus
formulation taken at night, will be effective on morning.
Factorial design and response surface
methodology is an important statistical tool to study the
effect of several factors influencing response by varying
them simultaneously by carryout limited number of
experiments. Literature survey revealed no study
carried out to formulate a pulsatile delivery system to
demonstrate the influence of formulation variables
using factorial design approach.
The objectives of the present investigation
was to carry out a systematic statistical study on
preparation of pulsatile delivery formulation using
factorial design approach and explore the application
for the formulation development.
MATERIALS AND METHODS
Pantoprazole sodium, Sodium starch glycolate,
Aerosil, Eudragit S100 (Yarrow chem products,
Mumbai), Magnesium stearate (lobe chemie Pvt Ltd,
Mumbai).Polyethylene glycol (Sd fine chem Ltd.
Mumbai.) All the materials and reagents were of
analytical grade.
Methods
Preparation of core tablets
The direct compression technique was used for
the preparation tablets. All the raw materials were
weighed and passed through #40 mesh sieves and
mixed well as per the formula given in Table 1 to meet
the tablet weight to 245mg. The powder blend was
lubricated using Magnesium stearate and aerosil at 1%
concentration of tablet weight. The powder blend was
compressed using an 8mm convex punch machine
(Rimek Mini press-1).
Evaluation of Core Tablets
Hardness and Friability
The crushing strength of the tablets was
measured using Monsanto hardness tester. The limit for
crushing strength of the tablets was kept in the range of
3-4 kg/cm2
. The friability of the tablets was measured

Reshma Fathima K & Sivakumar R., Saudi J. Med. Pharm. Sci., Vol-4, Iss-3 (Mar, 2018): 333-339
using a Roche friabilator (Electrolab, India). Twenty
tablets were weighed and rotated for 4 min at 25 rpm.
The tablets were then reweighed and the percentage
friability was calculated.
Disintegration study for Core Tablets
Disintegration procedures for the Pantoprazole
sodium Pulsatile core tablets using 900 ml of 6.8 pH
phosphate buffer at 37°C. Six tablets were dropped into
individual tubes of the basket-rack assembly. Disks
were not mounted on the tubes and the time at which all
six tablets had disintegrated was recorded.
Dissolution study for Core Tablets
The dissolution studies for the pantoprazole
sodium core tablets were carried out using dissolution
test apparatus USP II paddle type. The dissolution
medium consisted of 900 ml of phosphate buffer of pH
6.8 for 60 min. The temperature of the medium was
maintained at 37±0.5°C. The speed of rotation of the
paddle was kept at 50 rpm. Aliquots of 5ml were
withdrawn after every 15 minutes. These samples were
diluted to make up the volume of 50ml with pH 6.8
buffer. The samples so withdrawn were replaced with
the fresh dissolution medium equilibrated at the same
temperature. The drug released at the different time
intervals from the dosage form is measured by UV
visible spectrophotometer, by measuring the absorbance
for the sample solutions at 289nm [7 -9]
Effect of Variables
To study the effects of variables on core tablets
performance and characteristics, different batches were
prepared using 32
factorial design. Amount of
microcrystalline cellulose and SSG were selected as
two independent variables. Hardness, friability,
disintegration and dissolution were selected as
dependent variables. Values of all variables and batch
codes are as shown in Table 2.
Optimization of Core Tablets
The factorial design is a technique that allows
identification of factors involved in a process and
assesses their relative importance. In addition, any
interaction between factors chosen can be identified.
Construction of a factorial design involves the selection
of parameters and choice of responses. Optimization
has been done by using 32
full factorial designs, where
the amount of MCC (X1) and the amount of SSG (X2)
were taken as independent variables.
Formulation of pulsatile tablets
The coating solution was developed by
dissolving Eudragit S 100 (20%) in acetone and
isopropyl alcohol mix solvents and then Polyethylene
glycol (2%), Titanium dioxide (5%) was added and
stirring. The resulting solution was adjusted with
acetone and isopropyl alcohol mixed solvents. The core
tablets were coated using dipping and drying method
and increase in weight percent after coating was
determined as the coating level.
Evaluation of pulsatile tablets
The thickness of the Eudragit S coating was
measured using screw gauge and was expressed in mm.
The core tablets were selected randomly and weighed
individually for weight variation. The test requirement
is meeting if none of the individual weights are less
than 90 % or more than the 110% of the average.
Disintegration test for coated tablet
The disintegration time of the coated tablets
was determined using the USP model disintegration
apparatus. Six tablets were placed in the basket rack
assembly, and were run for 2 hours in 0.1 N HCl media
with the discs. The tablets were removed from the
solution, gently dried by bloating. The test was then
continued by placing the tablets in phosphate buffer pH
6.8, for 3 h, maintaining the temperature at 37±2°C
Dissolution study for coated tablet
The dissolution studies of the pulsatile tablets
containing pantoprazole sodium was carried out using
900 ml of 0.1N HCl for 2h followed by pH 6.8
phosphate buffer solutions. The set condition was
37±0.5°C, 50 rpm, and paddle type USP XX111
apparatus. Aliquots withdrawn for every one hour
intervals and were replenished immediately with the
same volume of fresh buffer medium. Aliquots,
following suitable diluents were assessed
spectrophotometrically at 289nm.
Statistical analysis of data
Response of different batches obtained using
factorial design is shown in Table 2. The Obtained data
were subjected to multiple regression analysis using
design software (USA) data were fitted in second order
polynomial equation.
Y= b0 +b 1X1 + b2 X2 + b11 X1X2 + b22X2X2 + b12 X1X2
Where y is the dependent variables, b0 is the
arithmetic mean response of the nine runs, and b1 is the
estimated coefficient for the factors X1. The main
effects (X1 and X2) represent the average result of
changing one factor at a time from its low to high value.
On the basis of the preliminary trial a 32
full factorial
design was employed to study the effects of
independent variables on dependent variables. Response
surface plots were generated using mini tab software.
Results of the multiple regression analysis are all
parameters study is summarized in table 3.
Coating for optimized formulation
On the basis of factorial design approach core
tablet batch (f3) was selected for further development
of pulsatile tablets. The coating solution was prepared
using Eudragit S. Dissolving Eudragit S (20%) in
acetone and isopropyl alcohol mix solvents and then

Polyethylene glycol (2%), Titanium dioxide (5%) was
added and stirring. The resulting solution was adjusted
with acetone and isopropyl alcohol mixed solvents.
The core tablets were coated using dipping and drying
method and increase in weight percent after coating
was determined as the coating level. Prepared pulsatile
tablets were characterized for following parameter.
In vitro release study for optimized pulsatile tablets
The dissolution studies of the optimized
pulsatile tablets containing pantoprazole sodium was
carried out using 900 ml of 0.1N HCl for 2h followed
by pH 6.8 phosphate buffer solutions. The set condition
was 37±0.5°C, 50 rpm, and paddle type USP XX111
apparatus. Aliquots withdrawn for every one hour
intervals and were replenished immediately with the
same volume of fresh buffer medium. Aliquots,
following suitable diluents were assessed
spectrophotometrically at 289nm.
RESULTS AND DISCUSSION
Amount of MCC and SSG were found to be critical in
preparation hence selected variables in the 32
factorial
designs.
Table-1: Composition of core tablets of Pantoprazole Sodium for Preliminary trial
Ingredients (mg) D1 D2 D3 D4 D5 D6
Pantoprazole 40 40 40 40 40 40
MCC 200 200 200 200 200 200
Cross Carmellose - - - 1 1.5 2
SSG 1 1.5 2 - - -
Magnesium stearate 2 2 2 2 2 2
Aerosil 2 1.5 1 2 1.5 1
Total weight 245 245 245 245 245 245
Table-2: Lay out of 32
full factorial designs
Independent variables Dependent variables
Code X1 X2 Y1 (Kg Cm2
) Y2 (%) Y3(S) Y4(%)
f1 -1 - 1 3.8 0.78 115 83.7
f2 -1 0 4.0 0.79 116 85.5
f3 -1 +1 4.2 0.65 117 95.8
f4 0 -1 4.4 0.62 118 85.5
f6 0 +1 4.6 0.64 120 86.8
f7 +1 -1 4.8 0.57 121 89.1
f8 +1 0 5.0 0.56 123 81.2
f9 +1 +1 5..5 0.53 127 85.5
Note: all the values are average of three such determinations
Table-3: Summary of regression analysis and results of measured responses
Parameters Coefficients
β0 β1 β2 β11 β22 β12 r2
p
Y1 4.122 0.50 0.10 0.166 0.166 0.001
Y2 0.656 -0.93 -0.02 -0.010 -0.030 0.016
Y3 124.0 2.66 -1.00 -1.000 -0.000 0.416
Y4 86.00 -2.55 3.33 -1.35 1.70 0.031

1
4.0
0
4.4
4.8
-1
5.2
0 -1
1
H a r dne ss ( k g/ cm 2 )
X 2
X 1
S urfa ce P lot of H a rdne s s (k g/ cm 2 ) v s X 2 , X 1
Fig-1: Surface Plot for Hardness
X 1
X2
1.00.50.0-0.5-1.0
1.0
0.5
0.0
-0.5
-1.0
>
–
–
–
–
< 4.00
4.00 4.25
4.25 4.50
4.50 4.75
4.75 5.00
5.00
(k g /c m 2)
H ard n ess
C ontour P lot of H a r dne s s (k g/ c m 2 ) v s X 2 , X 1
Fig-2: Contour Plot for Hardness
1
0
0.6
0.7
-1
0.8
0 -1
1
F r ia bility ( % )
X 2
X 1
S ur fa c e P lo t o f F r ia bility (% ) v s X 2 , X 1
Fig-3: Surface Plot for Friability

X 1
X2
1.00.50.0-0.5-1.0
1.0
0.5
0.0
-0.5
-1.0
>
–
–
–
–
< 0.55
0.55 0.60
0.60 0.65
0.65 0.70
0.70 0.75
0.75
F riab ility (% )
C ontour P lo t o f F r ia bility (% ) v s X 2 , X 1
Fig-4: Contour plot for Friability
1
120
0
122
124
-1
126
0 -1
1
Disinte gr a tio n tim e ( se c)
X 2
X 1
S ur fa c e P lo t o f D is inte gr a tio n tim e (s e c ) v s X 2 , X 1
Fig-5: Surface plot for disintegration time
X 1
X2
1.00.50.0-0.5-1.0
1.0
0.5
0.0
-0.5
-1.0
>
–
–
–
–
< 120.0
120.0 121.5
121.5 123.0
123.0 124.5
124.5 126.0
126.0
tim e (sec )
D isin teg ratio n
C ontour P lot of D is inte gra tion tim e (s e c) v s X 2 , X 1
Fig-6: Contour plot for disintegration Time

1
80 0
85
90
-1
95
0 -1
1
n-v itr o r e le a se study ( % )
X 2
X 1
S urfa ce P lot of In-v itro re le a se study (% ) v s X 2 , X 1
Fig-7: Surface Plot for in vitro Release Study
X 1
X2
1 .00.50.0-0.5-1.0
1.0
0.5
0.0
-0.5
-1.0
>
–
–
–
–
–
–
< 82
82 84
84 86
86 88
88 90
90 92
92 94
94
(% )
stu d y
release
In -v itr o
C o nto ur P lo t o f In-v itr o r e le a s e s tudy (% ) v s X 2 , X 1
Fig-8: Contour Plot for in vitro Release Study
Statistical analysis of data
Response of different batches obtained using
factorial design is shown in Table 3. Obtained data were
subjected to multiple regression analysis using design
software (USA) data were fitted in second order
polynomial equation.
Y= b0 +b 1X1 + b2 X2 + b11 X1X2 + b22 X2X2 + b12
X1X2
Where y is the dependent variables, b0 is the
arithmetic mean response of the nine runs, and b1 is the
estimated coefficient for the factors X1. The main
effects (X1 and X2) represent the average result of
changing one factor at a time from its low to high value.
On the basis of the preliminary trial a 32
full factorial
design was employed to study the effects of
independent variables on dependent variables. Response
surface plots were generated using mini tab software.
Results of the multiple regression analysis are all
parameters study is summarized in Table 3 and Fig 1-8.
Effect on hardness
To study the effect of MCC and SSG on
hardness of the tablets Eq.(1) was generated after fitting
the observed coefficient in Eq . (2).
Y= b0 +b 1X1 + b2 X2 + b11 X1X2 + b22 X2X2 + b12
X1X2
Y1 = 4.122+ 0.50 X1 +0.10 X2 +0.166 X1X1 +
0.166X2X2 - 0.00X1X2
The values for hardness of the tablets Y1
ranges between 3.8-5.1Kg/cm2
and were significantly
influenced (P = <0.05) by one study factor (X1).
Hardness was found to an inverse function of
X1 and X2. Hardness of the tablets slightly increased
with increasing amount of MCC and SSG. Both MCC
and SSG showed inhibitory effect of on hardness. MCC
alone were more predominant than SSG on hardness of
the tablet. It has indicated by the observed respective
coefficient. (Table 3)
Effect on friability
To understand the effect of concentration of
MCC and SSG on friability of tablets was fitted in Eqs
(1) to generate Eq. (3) respectively.
Y2 = 0.656 – 0.93X1 – 0.023X2 + 0.010X1X1 – 0.030
X2X2 – 0.02X1 X2

The value for friability of tablets Y2 ranges
between 0.53- 0.78% indicated all the formulation were
successfully passed the friability test. Optimum
concentration of MCC significantly influences the
friability values. i.e increased value of friability. But
SSG and combination of SSG and MCC favorable for
the reduction of friability.
Effect of disintegration and dissolution
The drug dissolution and disintegration are
important variables for bioavailability of drug. These
parameters are dependent on the process of preparation,
physiochemical properties of drug and formulation
variables. The drug disintegration varied from 117 to
127 sec. The value for disintegration time of tablets
ranges between 117-127 sec. The response was
insignificant by the one study factor. Combination of
SSG and MCC significantly influence the disintegration
time.
Y3 = 124.00 + 2.667 X1 – 1.00 X2– 1.00X1X1– 0.00
X2X2 + 0.500 X1X2
Dissolution studies for core tablets
In vitro release studies were carried out using
USP XX111 dissolution assembly. The release profile
obtained for all the formulations were shown in Fig 2. It
was observed that the drug release from the
formulations increase amount of MCC and SSG. 80 –
90 % of incorporated drug within 30 min after lag time
of 5 h. The negative results of MCC and SSG indicate
both the excipients insignificant value so that the values
are not considered for the study.
Y4 = 86.0 – 2.55 X1 + 3.33 X2 – 1.35 X1X1 + 1.70 X2X2
– 1.95 X1X2
Evaluation of pulsatile tablets
On the basis of hardness, friability,
disintegration and dissolution f5 was selected as better
formulation for designing pulsatile tablets. The release
of the drug from the tablets is strongly affected by the
PH of the medium. During the dissolution study the
cumulative percentage of pantoprazole from the tablets
was plotted as a function of time.
CONCLUSION
As indicated in introduction, the main aim of
the work described here was to design new pulsatile
delivery tablets of pantoprazole using factorial design
approach for better treatment out come for peptic ulcer.
The present study demonstrates that the pantoprazole
pulsatile tablets could be successfully designed for
chronopharmcological effects to reduce the symptoms
of peptic ulcer at early morning. Preparation of Pulsatile
tablets using factorial design was found to be well
suited and sound approach to obtain the successful
formulations. Inclusion of MCC and sodium starch
glycolate greatly influence the quality of formulation.
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