Project

DESIGN AND STATISTICAL OPTIMIZATION OF PULSATILE DELIVERY SYSTEM
CONTAINING PANTOPRAZOLE SODIUM
RESHMA FATHIMA.K
GRACE COLLEGE OF PHARMACY,PALAKKAD
11-Jan-18 2

MAINMENU
• Introduction
• Aim and Objectives
• Review of Literature
• Plan of work
• Materials and Methods
• Results and Discussion
• Summary and Conclusion
• Bibliography
• Annexures
11-Jan-18 3

INTRODUCTION
• Oral control drug delivery system
• Pulsatile drug release pattern
• Circadian rhythms
• Pulsatile drug delivery system
• Chronopharmacological behavior
• GI ulcer
11-Jan-18 4

11-Jan-18 5
Gastric acid
secretion is
highest at night
Gastric and
small bowel
motility, gastric
emptying are
slower at night.

AIMANDOBJECTIVES
11-Jan-18 6
Background and Significance of the study
 Concepts of the chronopharmacokinetics
Aim and Objectives of the study
 The main aim of the research work is to develop and statistically optimize the
oral pulsatile drug release tablets containing Pantoprazole Sodium for the
treatment of peptic ulcer.

• The present study is to formulate pulsatile drug delivery system of
Pantoprazole sodium using newer excipient composition for the
immediate release of drug after a lag time of 5hrs.
• The specific aim of the study is to explore the influence of
microcrystalline cellulose and sodium starch glycolate on
physicochemical properties of sudden release pulsatile tablet containing
pantoprazole sodium after a lag time of 5hrs using 3² factorial design
inorder to achieve a site specific delivery system.
11-Jan-18 7

REVIEWOF LITERATURE
11-Jan-18 8
AUTHORS TITLE PUBLICATION CONTENTUSED
Pallab Roy et al Multiparticulate
formulation approach to
pulsatile drug delivery:
current perspectives
Journal of controlled
release (Elsevier)
2009 Vol 134 issue 2
Pulsatiledelivery, multiparticulate dosage
forms are gaining much favor over single-
unit dosage forms because of their potential
benefits like predictable gastric emptying,
no risk of dose dumping, flexible release
patterns and increased bioavailability with
less inter- and intra-subject variability.
Hong-Liang Lin et
al
Release characteristics and
in vitro–in vivo correlation
of pulsatile
pattern for a pulsatile drug
delivery system activated
by
membrane rupture via
osmotic pressure and
swelling
European Journal of
Pharmaceutics&Bio
pharmaceutics Vol
70 (2008) 289–301
This study attempted to characterize the
influence of core and coating formulations
on the release profiles to establish in
vitro/in vivo
correlations of pulsatile pattern for a
pulsatile drug delivery system activated by
membrane rupture based on three core
tablet formulations.

11-Jan-18 9
Hyma P et al Formulation &
Evaluation of
Pulsatile Drug
Delivery System of
Venlafaxine HCL
International Journal of
Pharmacy Research and
Technology 2012,
Volume 2, Issue 4, 19-22
Pulsatile drug delivery system of Venlafaxine
Hydrochloride has been successfully prepared for
oral delivery of drug. This is a type of controlled
drug delivery system which shows sustained
therapeutic action; with lag time where there is no
release of the drug during initial lag phase of drug
administration. Venlafaxine Pulsatile formulations
were prepared using sodium alginate, pectin AS104,
and sodium bicarbonate for obtaining required lag
time.
Kommineni
veditha et al
Design and
development of
pulsatile drug
delivery systems
for Salbutamol
sulphate
Pharmaceutical research
and bioscience 2(4) 2013,
372-384.
Pulsatile drug delivery systems for salbutamol
sulphate were prepared with a view to release the
salbutamol around 4am with a lag time of 6 hours
after it’s administration
(10pm).

11-Jan-18 10
Neha et al Design and Evaluation
of Chronotropic
Systems for Colon
Targeted Drug Delivery
Pharmacy Research and
Technology Volume 2,
Issue 3 2012 13-17
Modified Pulsincap and compression
coated tablets of aceclofenac, a non
steroidal anti-inflammatory drug used
for the treatment of rheumatoid arthritis
were developed to target drug release in
the colon.
G. Sanjana
reddy et al
Formulation and in
vitro evaluation of
colon specific drug
delivery of naproxen
sodium by using
pulsincap technology.
An International Journal
of Advances in
Pharmaceutical Sciences
Volume 5 Issue 1 2014
1751-1760
The purpose of the present study was to
design and evaluate an oral, site specific,
and pulsatile drug delivery system
containing Naproxen sodium as a model
drug, which can be targeted to colon in a
pH and time dependent manner.

DRUG PROFILE
 Drug : Pantoprazole Sodium IP
 BCS Class : Class III (high solubility, low permeability)
 Category: Anti-Ulcer Agents, Proton-pump Inhibitors
 Molecular weight : 383.37 gm/mol
 Description: White to off- white crystalline powder and is racemic has a,
acidic and weakly basic property
11-Jan-18 11

 Solubility: Pantoprazole sodium sesquihydrate is freely soluble in water,
Very slightly soluble in phosphate buffer at pH 7.4, and practically
insoluble in n- hexane.
 Stability: Pantoprazole Sodium is not stable below pH 6.
 Partition Coefficient: The partition coefficient of Pantoprazole sodium
between n-octanol and water and was found to be 1.3.
 PKa: 8.35
 pH: Between 9.0 & 11.5 (2% w/v solution in water)
11-Jan-18 12

 Bioavailability: 77%
 Peak plasma concentration: 2.52 mg/l
 tmax: 2.5 hours (under fasting conditions)
 t1/2: The mean elimination half-life is 1 hour.
 Onset time : 2-4 hrs.
 Volume of distribution: 0.15 l/kg
 Excretion: Through renal excretion
11-Jan-18 13

PLAN OF WORK
 Compatibility study
 Construction of standard curve of Pantoprazole Sodium
 Design of Pantoprazole Sodium core tablets for preliminary studies
 Optimization of core tablet using 3² factorial design
 Selection of optimized batch for coating
 Evaluation of Pulsatile coating tablets
11-Jan-18 14

MATERIALS ANDMETHODS
 Pantoprazole sodium IP ( Yarrow chem products Mumbai)
 MCC (Yarrow chem products Mumbai)
 Crosscarmellose sodium (Yarrow chem products Mumbai)
 Sodium starch glycolate (Yarrow chem products Mumbai)
 Magnesium stearate(Loba chemie pvt ltd, Mumbai)
 Colloidal silicon dioxide (Yarrow chem products Mumbai,)
11-Jan-18 15

• Eudragit S100 (Yarrow chem products Mumbai)
• Poly ethylene glycol (SDFCL fine chem Ltd)
• Titanium dioxide (Prowess Lab chemicals, Kerala)
• Tartrazine FD & C Yellow no 5 (venus chemicals and flavors, Chennai)
11-Jan-18 16

Instruments used
 Rotary punching machine (Rimek, Ahmedabad)
 Disintegration Apparatus (Electrolab, Mumbai)
 Dissolution Apparatus (Electrolab, Mumbai)
 Hardness tester (Monsanto Apparatus)
 Roche Friabilator
 FT-IR (Shimadzu, Japan)
 UV- spectrophotometer (Shimadzu, Japan)
 Software : Minitab 2002- V 12.20 (VIA tech Inc)11-Jan-18 17

Methodology
 Compatibility Study using FTIR
 Design of Pulsatile release core tablets of Pantoprazole Sodium
 Formulation of Pulsatile Pantoprazole core tablets
 Evaluation of Pulsatile Pantoprazole core tablets
 Preparation of standard curve of Pantoprazole Sodium in 0.1N HCl
 Preparation of standard curve of Pantoprazole Sodium in pH 6.8
phosphate buffer
11-Jan-18 18

Pre compression parameters
 Angle of repose
 Bulk and tapped density
 Hausner ratio
 Compressibility index
Post compression parameters
 Hardness test
 Friability test
 Weight variation test
11-Jan-18
19

 Disintegration test for core tablet containing Pantoprazole sodium
 Drug content estimation
 Dissolution test for core tablet containing pantoprazole sodium
 Statistical optimization
 Formulation of Pulsatile Pantoprazole Sodium coated tablets
 Disintegration test for coated tablet
 Dissolution study for coated tablet
11-Jan-18 20

RESULTS ANDDISCUSSIONS
Preparation of standard plot for pantoprazole sodium in 0.1N HCl
Table 1 - Calibration curve for Pantoprazole sodium
11-Jan-18 21
Concentration(µg/ml) Absorbance
0 0
5 0.167
10 0.326
15 0.491
20 0.642
25 0.802

Preparation of standard plot for pantoprazole sodium in pH 6.8
phosphate buffer
Table 2 - Calibration curve for pantoprazole sodium
11-Jan-18 22
Concentration (µg/ml) Absorbance
0 0
5 0.179
10 0.368
15 0.562
20 0.744
25 0.945

Compatibility studies by FTIR
 FTIR spectrum of Pantoprazole sodium was used to study the possible
interaction between pantoprazole sodium and its composition.
 The results of the study indicates FTIR spectrum of Drug and Excipients
did not differed with major peaks of pantoprazole sodium.i.e, all the
major peaks of the drug appeared on the blend indicate that there is no
possible interaction between drug and excipients.
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11-Jan-18 24
FTIR spectrum of Pantoprazole sodium FTIR spectrum of Pantoprazole sodium, MCC, CCS,
Eudragit S 100
FTIR spectrum of Pantoprazole sodium, MCC, SSG,
Eudragit S 100

Table 3 – Interpretation of FTIR spectrum
S.No Interpretation Pantoprazole Sodium Mixture-1 Mixture-2
1 N-H 3507.41 3500.28 3489.22
2 O-H 2982.14 3352.00 3352.00
3 C-H 2933.48 2943.47 2943.81
4 C-O 1674.91 1589.42 1726.99
5 C-F 1589.23 1490.85 1589.39
6 S=O 1492.04 1456.72 1490.07
11-Jan-18 25

Table 4 - Composition of Pantoprazole sodium Tablets for preliminary trial batch
11-Jan-18 26
Sl.no Ingredients
D1(mg) D2(mg) D3(mg) D4(mg) D5(mg) D6(mg)
1 Pantoprazole
Sodium I.P
40 40 40 40 40 40
2 MCC 200 200 200 200 200 200
3 CCS 1 1.5 2 - - -
4 SSG - - - 1 1.5 2
5 Magnesium
stearate
2 2 2 2 2 2
6 Aerosil 2 2 2 2 2 2
7 Total weight 245 245 245 245 245 245

Table 5 - Precompression parameters of trial batch of pantoprazole sodium
formulation
Sl.no Parameters D1 D2 D3 D4 D5 D6
1 Bulk density(g/cc) 0.61 0.57 0.62 0.75 0.57 0.65
2 Tapped density(g/cc) 0.70 0.65 0.70 0.89 0.63 0.72
3 Carrs index(%) 12.8 12.3 11.4 15.7 9.52 9.72
4 Hausners ratio
1.14
1.14 1.12 1.18 1.10 1.10
5 Angle of repose 31°12' 31°02' 29°18' 32°34' 33°28' 35°14'
11-Jan-18 27

Weight Variation test
Table 6- Pantoprazole sodium core tablets were prepared by direct compression method.
The tablets obtained were complied with pharmacopoeial specifications
11-Jan-18 28
Average weight of tablet (mg) % Deviation
125 or less ±10
125-250 ±7.5
250 mg or more ±5

Sl.no D1(g) D2(g) D3(g) D4(g) D5(g) D6(g)
1 0.244 0.261 0.244 0.251 0.243 0.270
2 0.248 0.260 0.249 0.254 0.250 0.264
3 0.246 0.240 0.246 0.260 0.249 0.260
4 0.250 0.244 0.251 0.261 0.253 0.259
5 0.251 0.249 0.268 0.254 0.254 0.248
6 0.248 0.238 0.263 0.249 0.259 0.246
7 0.245 0.240 0.264 0.262 0.244 0.251
8 0.252 0.245 0.247 0.242 0.240 0.250
9 0.239 0.246 0.240 0.249 0.242 0.249
10
11
0.240
passed
0.248
passed
0.252
passed
0.245
passed
0.249
passed
0.246
passed
Table 7 - Weight Variation data for pantoprazole sodium core tablets

Friability test
Table 8 - Friability study of Tablets for all preliminary trial batch
11-Jan-18 30
Batch code Friability(%)
D1 0.76
D2 0.82
D3 0.56
D4 0.58
D5 0.49
D6 0.78

Table 9 - Drug content estimation of preliminary trial batch of
pantoprazole sodium core tablet
Batch code Drug content (%)
D1 75.82
D2 79.42
D3 83.02
D4 91.57
D5 95.17
D6 92.25
11-Jan-18 31

Table 10- Disintegration test
11-Jan-18 32
Batch code Disintegration time(sec)
D1 120
D2 122
D3 124
D4 120
D5 117
D6 118

Table 11 - Dissolution study of pantoprazole sodium core tablets in pH 6.8
phosphate buffer
Batch code Percentage drug release(%)
(60min)
D1 75.82
D2 79.42
D3 83.02
D4 91.57
D5 95.17
D6 92.25
11-Jan-18 33

Table 12 - Experimental Design for optimization
Independent variables for preparation of optimized batch
11-Jan-18 34
code variable -1 0 +1
X1 Amount of MCC(mg) 180 200 220
X2 Amount of SSG(mg) 1 1.5 2
Factor details Factor level

Table 13 - Dependent / Response variables
Code Dependent variable
Y1 Hardness(g/cc)
Y2 Friability(%)
Y3 Disintegration time(sec)
Y4 Invitro drug release(%)
11-Jan-18 35

Table 14 - Evaluated parameters of pantoprazole sodium core tablet for factorial design
11-Jan-18
36
Independent
variables
Dependent variables
code X1 X2
Y1
(kg/cm2)
Y2
(%)
Y3
(sec)
Y4
(%)
f1 -1 -1 3.8±0.2 0.78±0.2 121±0.80 83.70
f2 -1 0 3.8±0.2 0.79±0.1 123.3±0.7 85.50
f3 -1 +1 4.1±0.5 0.65±0.1 117±1 95.85
f4 0 -1 4.3±0.2 0.62±0.1 125.3±0.7 85.50
f5 0 0 4.1±0.4 0.64±0.1 122.6±0.4 86.85
f6 0 +1 4.3±0.2 0.65±0.2 125.6±0.4 89.10
f7 +1 -1 4.8±0.2 0.57±0.1 127±1 81.22
f8 +1 0 4.8±0.2 0.56±0.1 125±1 83.02
f9 +1 +1 5.1±0.2 0.53±0.1 125±1 85.50
Note: values are average of 3 such determinations

11-Jan-18 37
Term Coefficient P
Constant 4.12222 0.000
X1 0.50000 0.001
X2 0.10000 0.095
X1*X1 0.16667 0.104
X2*X2 0.16667
0.104
X1*X2 -0.00000 1.000
Table 15 - Regression Coefficients for Hardness (kg/cm2)

11-Jan-18 38
Term Coefficient P
Constant 0.65667 0.000
X1 -0.09333 0.016
X2 -0.02333 0.305
X1*X1 0.01000 0.780
X2*X2 -0.03000 0.427
X1*X2 -0.02250 0.403
Table 16 - Regression Coefficients for Friability (%)

11-Jan-18 39
Table 17 - Regression Coefficients for Disintegration time (sec)
Term Coefficient P
Constant 124.000 0.000
X1 2.667 0.416
X2 -1.000 0.625
X1*X1 -1.000 1.000
X2*X2 -0.000 0.727
X1*X2 0.500 -

11-Jan-18 40
Term Coefficient P
Constant 86.000 0.000
X1 -2.550 0.061
X2 3.333 0.031
X1*X1 -1.350 0.435
X2*X2 1.700 0.340
X1*X2 -1.950 0.164
Table 18 - Regression Coefficients for Invitro release study

STATISTICAL OPTIMIZED FORMULA
 A statistical model in co-operating interactive and polynomial terms was
used to evaluate the responses.
 Y=b0+b1X1+b2X2+b12X1X2+b11X1X2+b22X2X2
 Y= Dependent variable
 b- Arithmetic mean response of 9 runs
 bi - (b1,b2,b12,b11,b22) is estimated coefficient factor X1
11-Jan-18 41

Polynomial Equations for factorial fit
• Hardness (Y1) = 4.12222+ 0.50000 X1+ 0.1000 X2 + 0.16667 X1X2 + 0.16667 X2X2 -0.00000 X1X2
• Friability (Y2) = 0.65667-0.9333 X1 - 0.02333 X2 + 0.01000 X1X1 - 0.03000 X2X2 - 0.02250 X1X2
• Disintegration time (Y3) = 124.000 + 2.667 X1 – 1.000 X2 – 1.000 X1X1 -0.000 X2X2 + 0.500 X1X2
• Invitro release (Y4) = 86.000 – 2.550 X1 + 3.333 X2 – 1.350 X1X1 + 1.700 X2X2 – 1.950 X1X2
11-Jan-18 42

 The values of the correlation coefficient indicate a good fit shows the
plot of amount of MCC(X1) and amount of SSG (X2) versus Hardness,
Friability, Disintegration time and Invitro release of tablets respectively.
The data demonstrates that code f3 containing 180 mg of X1 and 2 mg of
X2 were optimized one based on in-vitro dissolution study (Y4).
11-Jan-18 43

 From the above study f3 formulation was considered as a best formulation based
on evaluation parameters.
 In this batch f3 show satisfactory hardness, maximum drug release and
disintegrated within 2 minute.
 A pulsatile drug release, where the drug is released rapidly after a well defined
lag time.
 Here the core tablet f3 show maximum drug release. So f3 formulation is
susceptible for coating.
11-Jan-18 44

Table 19 - Formula for coating solution
Code Ingredients Percentage(%)
f3 Eudragit S 100 20
PEG 2
Titanium dioxide 5
Acetone Q.S
Isopropyl alcohol Q.S
Tartrazine Q.S
11-Jan-18 45

Dissolution study of pantoprazole sodium pulsatile release tablet(f3
coated tablet)
11-Jan-18 46

Table 19 - Dissolution study of pantoprazole sodium pulsatile release
tablet(f3 coated tablet)
Sl.no Time(hrs) Percentage drug release(%)
1 1 4.2
2 2 4.95
3 3 5.62
4 4 6.97
5 5 8.32
6 6 95.17
11-Jan-18 47

DISCUSSION
• The Pulsatile delivery system of Pantoprazole sodium were developed.
• Statistical data
• Y=b0+b1X1+b2X2+b11X1X1+b22X2X2+b12X1X2
• Effect on Hardness
• Effect on Friability
• Effect of Disintegration and Dissolution
11-Jan-18 48

SUMMARY
 Main aim of the study
 Core tablets were prepared
 Core tablets were evaluated
 Best formulation (D5)
 32 factorial design
 Tablets were coated
 Coated tablets were evaluated
11-Jan-18 49
pH 1.5-3.5
Transit time :2hrs
pH 5-6
Transit time: 5
minutes
pH 7-8 slightly
alkaline
Transit time : 2hrs
pH 7-8
Transit time : 3-6hrs
Tablet

CONCLUSION
 The work described design of new pulsatile delivery tablets of
pantoprazole using factorial design approach for better treatment
outcome for peptic ulcer.
 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.
11-Jan-18 50

 These results render the designed pantoprazole pulsatile tablets as possible
candidate for peptic ulcer patient with enhanced patient compliance.
 Pantoprazole sodium is anti-ulcer drug to achieve chronotherapeutic delivery of
drug for improved patient compliance the newer device was successfully
developed and optimized.
 The optimized dosage form (f3) can be taken at bedtime and released the content
in the early morning hours when ulcer symptoms are more severe.
 Also the formulation suitable for large scale production.
11-Jan-18 51

BIBLIOGRAPHY
 Geest S, Koker J, Demeester J, De Smedt S, Hennink WE. “Pulsed Invitro release
and in vivo behavior of exploding microcapsules”, J. Control. Release [2009];
135:268-73.
 Dashevsky A, Mohammad A, “Development of pulsatile multiparticulate drug
delivery system coated with aqueous dispersion Aquacoat ECD” Int.J.Pharm.
[2006]; 318:124-31.
 Gothoskar AV, Joshi AM ,Joshi NH., “Pulsatile drug delivery systems: A
review”, Drug Delivery Technology, [2004]; 4(5): 1-11.
11-Jan-18 52

 Sadaphal K.P., Thakare V.M., Gandhi. B.R., “Formulation and Evaluation of
pulsatile drug delivery system for chronobiological disorder: Asthma”
International Journal of Drug Delivery 3, [2011]; 348-356
 Sumit Chakraborty , Sibaji Sarkar, Sujit Kumar Debnat, “Formulation
Development and Evaluation of Pantoprazole Enteric Coated Tablets”,
International Journal of ChemTech Research, [2009], 1(3), 663-666
 Haribansh Narayan Singh, Shivangi Saxena, Sunil Singh, “Pulsatile drug delivery
System : Drugs used in pulsatile formulations”, Research. J. Pharma. Dosage
forms and Tech, [2013]; 5(3), 115-121.
11-Jan-18 53

PUBLICATIONS
 Reshma Fathima K*, Sivakumar R, Rina Parveen, “Current status on
pulsatile drug delivery systems –An overview”, Acta biomedical
Scientia, [2016]; 3(3):162-168.
 Reshma Fathima K*, Sivakumar R; “Design and evaluation of Pulsatile
drug delivery system containing Pantoprazole Sodium”, AJBPR, [2016]
3(3)
11-Jan-18 54

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