Jitesh M-Pharm Thesis

FORMULATION DEVELOPMENT AND
EVALUATION OF ORODISPERSIBLE
TABLETS OF PROTON PUMP INHIBITOR
By
CHAUDHARI JITESH JAGDISH

Dissertation Submitted to the
Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore,
In partial fulfillment of the requirements for the degree of
MASTER OF PHARMACY
IN
PHARMACEUTICS
Under the guidance of
Dr. GOPAL MURALIDHARAN
Department of Pharmaceutics
Nargund College of Pharmacy
Bangalore
February-2011
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BANGALORE
DECLARATION BY THE CANDIDATE
I hereby declare that the matter embodied in the

dissertation entitled “Formulation Development and
Evaluation of Orodispersible Tablets of Proton
Pump Inhibitor” is a bonafide and genuine research
work carried out by me under the guidance of
Dr. Gopal Muralidharan department of
pharmaceutics, Nargund College of Pharmacy,
Bangalore.
DATE: Mr. CHAUDHARI JITESH JAGDISH

PLACE: BANGALORE DEPARTMENT OF PHARMACEUTICS,
NARGUND COLLEGE OF PHARMACY,
BANGALORE-85.
CERTIFICATE BY THE GUIDE
This is to certify that the dissertation entitled

“Formulation Development and Evaluation of
Orodispersible Tablets of Proton Pump Inhibitor”
is a bonafide research work carried out by
Mr. Chaudhari Jitesh Jagdish submitted in
partial fulfillment for the award of the degree of
Master of Pharmacy in Pharmaceutics by the
Rajiv Gandhi University of Health Sciences,
Karnataka, Bangalore.
DATE: Dr. GOPAL MURALIDHARAN

BANGALORE-85.
CERTIFICATE BY THE CO-GUIDE
This is to certify that the dissertation entitled

“Formulation Development and Evaluation of
Orodispersible Tablets of Proton Pump Inhibitor”
is a bonafide research work carried out by
Mr. Chaudhari Jitesh Jagdish submitted in
partial fulfillment for the award of the degree of
Master of Pharmacy in Pharmaceutics by the
Rajiv Gandhi University of Health Sciences,
Karnataka, Bangalore.
DATE: Mr. HARISH JAIN

PLACE: BANGALORE DIRECTOR,
EMBIOTIC LABORATORIES (P) LTD,
BANGALORE.
ENDORSEMENT BY THE HEAD OF THE DEPARTMENT
This is to certify that the dissertation entitled “Formulation

Development and Evaluation of Orodispersible Tablets of
Proton Pump Inhibitor” is a bonafide research work carried
out by Mr.Chaudhari Jitesh Jagdish submitted in partial
fulfillment for the award of the degree of
Master of Pharmacy in Pharmaceutics by the Rajiv
Gandhi University of Health Sciences, Karnataka,
Bangalore. This work was carried out by him in the library
and laboratories of Embiotic Laboratories (P) Ltd
Bangalore under the guidance of Dr. Gopal Muralidharan
department of pharmaceutics, Nargund College of
Pharmacy, Bangalore.
DATE: Dr. C. S. R. LAKSHMI

PLACE: BANGALORE HOD PHARMACEUTICS,
BANGALORE-85.
ENDORSEMENT BY THE PRINCIPAL
This is to certify that the dissertation entitled “Formulation

Development and Evaluation of Orodispersible Tablets of
Proton Pump Inhibitor” is a bonafide research work carried
out by Mr.Chaudhari Jitesh Jagdish submitted in partial
fulfillment for the award of the degree of
Master of Pharmacy in Pharmaceutics by the Rajiv
Gandhi University of Health Sciences, Karnataka,
Bangalore. This work was carried out by him in the library
and laboratories of Embiotic Laboratories (P) Ltd
Bangalore under the guidance of Dr. Gopal Muralidharan
department of pharmaceutics, Nargund College of
Pharmacy, Bangalore.
DATE: Dr. L .V. G. NARGUND

PLACE: BANGALORE PRINCIPAL,
BANGALORE-85.
COPYRIGHT
DECLARATION BY THE CANDIDATE
I hereby declare that the Rajiv Gandhi University

of Health Sciences, Karnataka shall have the
rights to preserve, use and disseminate this
dissertation / thesis in print or electronic format for
academic / research purpose.
DATE: Mr. CHAUDHARI JITESH JAGDISH

BANGALORE-85.
© Rajiv Gandhi University of Health Sciences, Karnataka.

Dedicated to
Aai ani Papa
for their Love
&
Support
Acknowledgement
Behind every success there are lot many efforts, but efforts are fruitful due to hands making
the passage smoother. My vocabulary fails to express my esteemed regards, vast indebtedness and
sincere gratitude to my guide Dr. Gopal Muralidharan for his guidance, dedicated approach
and sustained interest at all the stages of this research and thesis work. I would also like to thanks
my co-guide Mr. Harish Jain for his personal interest in this research work and providing us a
chance to perform it in well equipped laboratories of Embiotic Laboratories (P) Ltd.
Words alone no way shall amply my deepest gratitude for Dr. C. S. R. Lakshmi
for providing quality advice which added new dimensions to my research work.
I would like to express my deepest respect to Dr. L. V. G. Nargund, Principal,
Nargund College of pharmacy, Bangalore for his enduring care and support.
I would like to express my heartfelt thanks to Prof. C. R. Mahendra Shetty, Prof.
Y. R. Shivaraj, Asst. prof. Mrs. Rama Rajesha, Asst. prof. Mrs. Preeti Karwa,
Lect. Mrs. Jayanthi A and Lect. Mr. Atul Kakade for their precious guidance.
I am immensely grateful to Asst. prof. Mrs.C. D. Saraswathi, Prof. Mrs.
Ritu Kimbahune and Lect. Mrs. Prachi kabra for analyzing me & giving me moral
support. I am also thankful to all the teaching and non teaching staff of Nargund college of
Pharmacy for being supportive to me.
I would like to extend my deepest love towards my Bachelor’s College “Mula
Education Society College of Pharmacy, Sonai” and my School/College “Tarapur
Vidya Mandir & Juniors College, Boisar” for strengthening the pillars of my
fundamental knowledge which is a source of motivation for me and will remain so forever.
Special thanks to all my Friends, Colleagues, Sniors, Juniors and to all those who
have shared some special movements with me; really you all have made my memories special.
Life can’t be imagined without my parents and all my family members; they have always
been my strengths through thick and thin and have always encouraged me to give my best.
DATE:
PLACE: BANGALORE Mr. Chaudhari Jitesh Jagdish
List of Abbreviations
λmax : Lambda max
µg : microgram
Abs : Absorbance
ACH : Acetyl choline
AMP : Adenosine mono phosphate
AUC : Area under curve
BP : British Pharmacopoeia
CCS : Croscarmellose sodium
CI : Carr‘s Index
Cocn. : Concentration
cm : Centimeter
CNS : Central nervous system
CP : Crospovidone
CPDR : Cumulative percent drug release
DDS : Drug delivery system
et al. : and others
FC : Formulation code
FDA : Food and Drug administration
FDT : Fast dispersible tablets
Fig. : Figure
FTIR : Fourier transformed infrared spectroscopy
GERD : Gastroesophageal Reflux disease

GIT : Gastrointestinal tract
gm : Gram
H+ : Hydrogen ion
HCL : Hydrochloric acid
HPLC : High performamce liquid chromatography
HR : Hausners Ratio
IP : Indian Pharmacopoeia
IR : Infra-red
K+ : Potassium ions
KBr : Potassium bromide
KHCO3 : Potassium bicarbonate
L-HPC : Hydroxy propyl cellulose low substituted
LBD : Lose bulk density
LFDT : Lansoprazole fast disintegrating tablet
M : Moles
Mannitol DC : Directly compressible Mannitol
MDDDS : Mouth dissolving drug delivering system
mins : Minutes
ml : millilitre
mm : millimetre
mg : Milligram
NaHCO3 : Sodium bicarbonate
ODDs : Oral drug delivery system

ODTs : Orodispersible tablets
OrDTs : Orally disintegration tablets
pH : Negative logarithm of hydrogen ion concentration
PhEur : European Pharmacopoeia
PPIs : Proton pump inhibitors
rpm : revolutions per minute
r2 : Correlation factor
RDGs : Rapid disintegrating granules
RT : Room temperature
RH : Relative humidity
Sec. : Second
SSF : Sodium steryl fumerate
SSG : Sodium starch glycolate
TAG : Treated agar powder
t½ : Time required to reduce the amount to its half
TBD : Tapped bulk density
USP : United States of Pharmacopoeia
UV : Ultra Violet
ABSTRACT
BACKGROUND AND OBJECTIVE:
Proton pump inhibitors are benzimidazole substitutions exhibiting potent and long-
lasting inhibition of gastric acid secretion by selective interaction with the gastric proton
pump (K+/H+ -ATPase) in the parietal cell secretory membrane.
Proton pump inhibitors have low bioavailability after oral administration, since they
undergo degradation very rapidly in the stomach followed by first- pass metabolism in the
liver. Thus attempts such as inclusion complex of proton pump inhibitors with
cyclodextrin, have been made, to improve their bioavailability. Omeprazole rectal
suppository as an alternative dosage form has also been tried; however they yielded
unsatisfactory results.
Most elderly patients, children, patients with dysphagia, have difficulty swallowing
conventional tablets or capsules. Mainly, proton pump inhibitors are available as enteric
coated pellets filled in capsules or compressed into tablets so instant relief is not achieved;
hence a need exists for a relatively fast acting orodispersible tablet form.
METHODS:
The tablets were prepared by using different approaches like superdisintegrant
addition method, combination of different superdisintegrants method, sublimation method,
a combination of both superdisintegrants and sublimationmethods, and using treated
natural gums as superdisintegrants. They were then evaluated for pre and post compression
parameters.
RESULTS:
Tablets were evaluated for general appearance, content uniformity, hardness,
friability, taste evaluation, mouth feel and in vitro dissolution studies. More than 90% of
drug was released from almost all the formulations within 10 min. Further formulations
were subjected to accelerated stability studies for 90 days. Tablets showed no appreciable
changes with respect to taste, disintegration and dissolution profiles.
INTERPRETATION AND CONCLUSION:
Results of this study indicate among the superdisintegrants tried, crospovidone
performed the best. Crospovidone (3% and 5%) showed good similarity with marketed
preparation. Bicarbonate can be used as buffer for stabilizing the drugs which are degraded
in acidic pH.
KEYWORDS:
Proton pump inhibitors; Pantoprazole sodium, Superdisintegrants; Orodispersible tablets;
Subliming agents.
Table of Contents
CHAPTER PAGE
TABLE OF CONTENTS
NO. NO.
LIST OF TABLES
LIST OF FIGUERS
1 INTRODUCTION 1
1.1 History 1
1.2 Oral route 2
1.2.1 Drawbacks of conventional tablets and capsules 4
1.3 Orodispersible tablets 4
1.3.1 Salient Features of Orodispersible tablets 5
1.3.2 An ideal ODTs should meet the following criteria 6
1.3.3 Advantages of Orodispersible tablets 6
1.4 Tablet disintegrants 7
1.4.1 Mechanism of tablet disintegration 8
1.4.1.1 Disintegration by capillary action 8
1.4.1.2 Disintegration by heat of wetting (air expansion) 9
Disintegration due to disintegrating particle-particle repulsive

1.4.1.3 9
forces
1.4.1.4 Disintegration by swelling 9
1.4.1.5 Disintegration by enzymatic reaction 10
1.4.1.6 Disintegration due to deformation 11
1.4.1.7 Disintegration due to release of gases 11
1.5 Techniques for preparing Orodispersible tablets 12
1.5.1 Freeze drying / lyophilisation 12
1.5.2 Tablet Moulding 13
1.5.3 Spray Drying 14

1.5.4 Direct Compression 14
1.5.4.1 Superdisintegrants 14
1.5.4.2 Sugar Based Excipients 14
1.5.5 Mass-Extrusion 15
1.5.6 Cotton Candy Process 15
1.5.7 Sublimation 16
1.5.8 Nanonization 17
1.5.9 Fast Dissolving Films 17
1.6 Patented technologies for Orodispersible tablets 18
1.6.1 Zydis Technology 18
1.6.2 Durasolv Technology 18
1.6.3 Orasolv Technology 19
1.6.4 Flash Dose Technology 19
1.6.5 Wow tab Technology 19
1.6.6 Flash tab Technology 20
1.7 Future perspective 21
1.8 Proton pump inhibitors and their mechanism of action 22
1.8.1 Chemistry 24
1.8.2 Stomach 25
1.8.2.1 Anatomy of the Stomach 25
1.8.2.2 Histology of the Stomach 26
1.8.2.3 Mechanical and Chemical Digestion in the Stomach 27
1.8.2.4 Physiology of gastric secretion 28
1.9 Mode of action 30
1.10 Therapeutic uses 31
1.10.1 Duodenal Ulcer 31
1.10.2 Gastric Ulcers 32
1.10.3 Helicobacter Pylori Associated Duodenal Ulcer 32

1.10.4 Symptomatic Gastroesophegal reflux disease 32
1.10.5 Reflux Esophagitis 32
1.10.6 Pharmacokinetics of Proton Pump Inhibitors 33
1.10.7 Absorption and Distribution 33
1.10.8 Metabolism 34
1.11 Need for the Development of Orodispersible tablets 36
2 OBJECTIVE 37
2.1 Objectives of the present research work 37
2.2 Why only Proton Pump Inhibitors 38
3 REVIEW OF LITERATURE 39
4 METHODOLOGY 56
4.1 Plan of work 56
4.2 Materials used 57
4.2.1 Proton Pump Inhibitors 58
4.2.2 Excipients Profile 64
4.2.2.1 Crospovidone 64
4.2.2.2 Croscarmelose sodium 65
4.2.2.3 Sodium Starch Glycolate 66
4.2.2.4 Hydroxypropyl Cellulose, Low-Substituted 67
4.2.2.5 Starch Pregelatinized 68
4.2.2.6 Sodium Bicarbonate 69
4.2.2.7 Potassium Bicarbonate 70
4.2.2.8 Tag Powder (Treated Agar Powder) 71
4.2.2.9 Guar Gum 72
4.2.2.10 Menthol 73
4.2.2.11 Thymol 74
4.2.2.12 Camphor 75
4.2.2.13 Directly compressible Mannitol 76

4.2.2.14 Aspartame 77
4.2.2.15 Talc 78
4.2.2.16 Sodium Stearyl Fumarate 79
4.3 Instruments 80
4.4 Studies under taken 81
4.4.1 Preformulation studies 81
4.4.1.1 Identification of Pantoprazole 82
4.4.1.1.1 Melting point determination 82
4.4.1.1.2 Infrared absorption spectrum 82
4.4.1.2 Preparation of standard calibration curve 82
4.4.1.2.1 Preparation of standard calibration curve of Pantoprazole 82

sodium in 0.1 N Hydrochloric acid
4.4.1.2.2 Preparation of standard calibration curve of Omeprazole 83

sodium in 0.1 N Hydrochloric acid
4.4.1.3 Compatibility studies of drug and polymers 84
4.4.1.3.1 FTIR Studies 84
4.4.2 Post formulation Studies 84
4.4.2.1 Formulation of Orodispersible tablets of Pantoprazole Sodium 84
4.4.2.1.1 Preparation of Orodispersible tablets using Superdisintigrant 85

addition method
Preparation of Orodispersible tablets using combination of 85

4.4.2.1.2
superdisintegrants and sublimation method
Preparation of Orodispersible tablets using Sublimation
4.4.2.1.3 86
method
Preparation of Orodispersible tablets using combination of

4.4.2.1.4 86
Preparation of Orodispersible tablets using treated natural

4.4.2.1.5 87
gums to be used as Superdisintegrants
4.5 Evaluation of tablets 91
4.5.1 Pre-compression Parameters 91

4.5.1.1 Angle of Repose 91
4.5.1.2 Bulk Density 92
4.5.1.3 Carr‘s Compressibility Index 93
4.5.1.4 Hausners Ratio 93
4.5.2 Post-Compression Parameters 94
4.5.2.1 Shape and colour 94
4.5.2.2. Uniformity of thickness 94
4.5.2.3 Hardness test 94
4.5.2.4 Friability test 95
4.5.2.5 Weight variation test 95
4.5.2.6 Drug Content Uniformity 96
4.5.2.7 In vitro disintegration time 97
4.5.2.8 In vitro dissolution studies 98
4.5.2.9 Stability studies 101
4.5.2.10 Similarity factor 101
5 RESULT 103
5.1 Identification of Pantoprazole Sodium 103
5.1.1 FTIR studies 103
5.2 Standard calibration curve 107
5.2.1 Standard calibration curve of Pantoprazole Sodium 107
5.2.2 Standard calibration curve of Omeprazole 108
5.3 Evaluation 111
5.3.1 Pre compression evaluation parameters 111
5.3.2 Post compression evaluation parameters 113
5.3.3 Disintegration time 115
5.3.4 Drug content 117

5.3.5 Drug dissolution profile 118
5.3.5.1 Dissolution drug profile of Orodispersible tablet formulations 119

prepared by superdisintegrant addition method
5.3.5.2 Dissolution profile study of Orodispersible tablet formulations 120

prepared by combination of different superdisintegrants
5.3.5.3 Dissolution profile of reference marketed product 122
5.3.5.4 Comparision of dissolution profile between the selected F4 123

and F3 formulations with marketed OMEZ INSTA
5.3.6 Similarity factor 125
5.4 Stability studies 125
6 DISCUSSION 126
6.1 Identification of Pantoprazole Sodium 126
6.1.1 Melting Point Determination 126
6.1.2 Solubility 127
6.2 Standard calibration curve 127
6.2.1 Standard Calibration Curve of Pantoprazole Sodium 128
6.2.2 Standard Calibration Curve of Omeprazole Sodium 128
6.3 Compatibility studies 129
6.3.1 FTIR Studies 129
6.4 Precompression Parameters 130
6.4.1 Loose Bulk Density 130
6.4.2 Tapped Bulk Density 130
6.4.3 Angle of Repose 130
6.4.4 Carr‘s Index 131
6.4.5 Hausners Ratio 131
6.5 Formulation of Orodispersible tablets 131
6.6 Modification of the dissolution apparatus 132
6.7 Quantity of buffer 134
6.8 Evaluation of tablets 135

6.8.1 Shape of the tablets 135
6.8.2 Colour of the tablets 135
6.8.3 Thickness 135
6.8.4 Hardness test 135
6.8.5 Friability Test 135
6.8.6 Weight Variation Test 135
6.8.7 Drug Content Uniformity 136
6.9 In vitro disintegration test 136
6.10 In vitro Dissolution Studies 137
6.11 Accelerated Stability Study 138
7 CONCLUSION 139
8 SUMMARY 141
9. BIBLIOGRAPHY 143
10. ANNEXURE 150

List of Tables
Table
Tables Page No.
No.
1.4.1.5 10
List of enzymes and their use for the disintegration of tablets
1.6 Marketed products along with the technology used, their 20

inventers and the active ingradients present
4.2 Materials used with their trade and their manufacturers or 57
suppliers
4.2.2.1 64
Crospovidone
4.2.2.2 65
Croscarmelose Sodium
4.2.2.3 66
Sodium Starch Glycolate
4.2.2.4 Hydroxypropyl Cellulose, Low-Substituted 67
4.2.2.5 Starch Pregelatinized 68
4.2.2.6 Sodium Bicarbonate 69
4.2.2.7 Potassium Bicarbonate 70
4.2.2.8 Tag Powder, Agar 71
4.2.2.9 Guar Gum 72
4.2.2.10 Menthol 73
4.2.2.11 Thymol 74
4.2.2.12 Camphor 75
4.2.2.13 Directly compressible Mannitol 76
4.2.2.14 Aspartame 77
4.2.2.15 Talc 78
4.3 Instruments used for the research work 80
Formulations of Orodispersible tablets using superdisintegrant

4.4.2.1.1 addition method 88
4.4.2.1.2 Formulations of Orodispersible tablets using combination of 89
superdisintegrants
4.4.2.1.3 Formulations of Orodispersible tablets using sublimation 89
method
4.4.2.1.4 Formulations of Orodispersible tablets using a combination of 90
superdisintegrants and subliming agent
4.4.2.1.5 Formulations of Orodispersible tablets using natural gums as 90
superdisintegrants
4.5.1.1 Relationship between Angle of Repose () and flow properties. 91
4.5.1.3 Grading the powders for their flow properties according to 93

Carr‘s Index
4.5.1.4 Grading the powders for their flow properties according to 94

Hausner Ratio
4.5.2.4 Acceptable limit of Friability 95
4.5.2.5 Percentage deviation in weight variation 96
4.5.2.8 Summary of general dissolution conditions 99
5.1.1.1 Different IR peaks for Pantoprazole sodium 104
5.1.1.2 Different IR peaks for formulation code F4 105
5.1.1.3 Different IR peaks of formulation code F3 106
5.2.1 Calibration Curve of Pantoprazole sodium in 0.1N 107

Hydrochloric acid
5.2.2a Concentration of Omeprazole in Omeprazole sodium 109
5.2.2b Calibration Curve of Omeprazole in 0.1N Hydrochloric acid 109
Evaluation of powder blend prepared by superdisintegrant

5.3.1.1 111
addition method
Evaluation of powder blend prepared by combination of

5.3.1.2 112
different superdisintegrants
5.3.1.3 Evaluation of powder blend prepared by sublimation method 112
Evaluation of powder blend prepared by combination of

5.3.1.4 112
5.3.1.5 Evaluation of precompression powder blend prepared by 112

treated natural gums used as Superdisintegrants
Evaluation of Orodispersible tablets prepared by using

5.3.2.1 113
superdisintegrant addition method
Evaluation of Orodispersible tablet formulations prepared by

5.3.2.2 114
using combination of different superdisintegrants
5.3.2.3 Evaluation of Orodispersible tablet formulations prepared by 114

using Sublimation method
Evaluation of Orodispersible tablet formulations prepared by

5.3.2.4 using combination of superdisintegrants and sublimation 114
method
5.3.2.5 Evaluation of Orodispersible tablet formulations prepared by 115

using treated natural gums used as superdisintegrants.
5.3.3 In vitro Disintegration Time 116
5.3.4 Drug Content 117
5.3.5.1 Cumulative percent drug release from Orodispersible tablets 119

prepared by superdisintegrant addition method
Cumulative percent drug release from Orodispersible tablet

5.3.5.2 formulations prepared by combination of different 120
superdisintegrants
5.3.5.3 Dissolution profile of OMEZ INSTA 122
Comparative table showing cumulative percent drug release of

5.3.5.4 the selected formulations F4 and F3 with marketed formulation 123
OMEZ INSTA
5.3.6 Similarity factor of formulation F4 and F3 125
5.4 Stability studies 125/

List of Figures
Figure
Figure Page No.
No.
1.2 Different types of oral drug delivery systems 3
1.4 8
Common steps in tablet disintegration
1.4.1.2 10
Disintegration of tablet by wicking and swelling
1.4.1.6 11
Disintegration by deformation and repulsion
1.4.1.7 12
Release of gas during tablet disintegration
1.5.6 Steps involved in manufacturing of Orodispersible tablets by 16

sublimation
1.8.1.1 Structure of Omeprazole 24
1.8.1.2 Structure of Lansoprazole 24
1.8.1.3 Structure of Pantoprazole 24
1.8.1.3 Structure of Rabeprazole 24
A-Inhibition of Gastric H+/K+-ATPase
1.8.2.4 30
B- Conversion of Omeprazole to a sulfenamide in the acidic
secretory canaliculi of the Parietal cell
1.9 Mode of action of Proton pump Inhibitors 31
4.2.1 Chemical Structure of Pantoprazole Sodium 58
4.5.2.7 Method used for the disintegration of the Orodispersible tablets 98
4.5.2.8 Modification done in the dissolution apparatus 100
5.1.1.1 FTIR scan of Pantoprazole sodium 104
5.1.1.2 FTIR scan of Formulation code F4 105

5.1.1.3 FTIR scan of Formulation code F3 106
5.2.1a Calibration curve of Pantoprazole sodium in 0.1N Hydrochloric 107

acid
5.2.1b Ultra violet scan of Pantoprazole sodium in 0.1 N Hydrochloric 108

acid
5.2.2 Calibration curve of Omeprazole in 0.1N Hydrochloric acid 110
5.3.5.1 Cumulative percent drug release from Orodispersible tablet 120

formulations prepared by superdisintegrant addition method
5.3.5.2 Cumulative percent drug release from Orodispersible tablet 121

prepared by combination of different superdisintegrants
5.3.5.3 Cumulative percent drug release of OMEZ INSTA which was 123
taken as standard
5.3.5.4 Cumulative percent drug release of the best formulation F3, F4 124
and standard formulation
6.1.2 Solubility of drug in different medium 127
6.5 Study performed in 500 ml of 1.2 pH of Omez Insta, F4 and F3 133

Formulation Development & Evaluation of Orodispersible Tablets of Proton Pump Inhibitor
1. INTRODUCTION
1.1 HISTORY
Pharmacy is the art and science of drug preparation and dispensing.
Pharmaceutics is a branch of pharmacy which deals mainly with the formulation and
development of a dosage forms. It has contributed tremendously either directly or
indirectly to the growth of medical science. It is rightly said by Isaac Newton that ‘If you
have to see further it’s only by climbing on the shoulder of a giant’; in the recent past
unbelievable advances in the field of medical sciences have occurred, most of which
some might have not been thought of a decade back. This was made possible by some
simple but tremendously innovative achievements in the field of pharmacy.
Medicine is an art that has been practiced since time immemorial whose exact
start cannot be predicted as its history is routed right from the development of human
civilization and is continued till now. The use of herbs and natural medicaments to
relieve pain or to aid the sick in coping with their afflictions has been a part of all
societies. In the Western world, medicine has developed since the time of the Greeks and
Romans. The Hippocratic Oath reminds us of this nearly 2500-year history. Much prior
to the modern day allopathic medicine, others systems like the oldest documented system
of medicine- Ayurveda as well as Unani, and Siddha existed. However, the progress of
medicine has been very different from that of many other arts within society. It has come
of age after an incredibly long maturation period. As a function capable of offering a
successful treatment for a human ailment, medicine is very much a development of the
last 100–150 years. Indeed, the major advances have come in the last 50–75 years.1
Dept of Pharmaceutics, Nargund College of Pharmacy, Bangalore Page1

It is a triumph of modern pharmaceutics that most of the people do not give a
thought to the difference between a white powder and a tablet, and think that ―a drug is a
drug is a drug‖. This huge presumption is doubtless, because we do not anymore make
pharmaceutical formulation ourselves, and precious few of us have ever understood that
complicated process. However, as suggested by A. Fox ―A drug is not a drug is not a
drug‖ because when administered to a human being, in the general case, it contains
numerous things which we might have not even thought off.1
1.2 ORAL ROUTE
The oral route of drug administration is the most important and convenient
method of administering drug. It is probable that at least 90% of all the drugs used to
produce systemic effect are administered by the oral route. When a new drug is
discovered the pharmaceutical company makes every effort to ensure that the drug can be
so formulated that it is capable of being administered orally. If it cannot be administered
by oral route, and should a more complex parentral route be the only alternative, then the
drug is primarily relegated for administration in a hospital setting or physician‘s office. If
self administration of drugs cannot be achieved, the sales of the drug may constitute only
a small fraction what the market would be otherwise.2
Tablets and capsules have emerged as the most popular solid oral dosage forms
used today. This includes conventional and controlled-release tablets as well as hard and
soft gelatin capsules.2 Tablet formulation and design may be described as the process
whereby the formulator ensures that the correct amount of the active drug in the right
form is delivered at or over the proper time at the proper rate and in the desired location,
while having its chemical integrity protected to that point.3

Fig. No. 1.2 Different types of oral drug delivery systems (ODDs)
By comparison, liquid oral dosage forms, such as syrups, suspensions, solutions,
and elixirs are usually designed to contain one dose of medication in 5 to 30 ml. Such
dosage measurements are typically contributing an error ranging from 20 to 50% when
the drug is self-administered by the patient. However, tablets and capsules have the
advantage of being unit dosage forms in which one usual dose of the drug has been
accurately placed in it. 2
However most elderly patients, children, and patients with dysphagia have
difficulty in swallowing conventional tablets and hard gelatin capsules, and therefore do
not take medication as prescribed by physicians. It is estimated that 35% of the general
population, 30 to 40% of elderly nursing home patients, and 25 to 50% of patients
hospitalized for acute neuromuscular disorders and head injuries have dysphagia. The
main causes of dysphagia include esophageal disorder such as achalsia, Gastro
Esophageal Reflux Disease GERD, cardiovascular conditions such as aneurysm,

autoimmune diseases such as Sjondrome Sygren‘s, Auto Immune Deficiency syndrome,
(AIDS). Thyroid surgery, radiation therapy to head and neck or oral cavity, and other
neurological diseases such as cerebral palsy etc.2
1.2.1 Drawbacks of conventional tablets and capsules
Ghosh et al.4 have described a survey conducted in patients having difficulty in
swallowing tablets and identified the reasons for this difficulty. More than 26 percent of
patients reported problems in swallowing tablets. Prominent complaints were size of the
tablet, surface of the tablet, forms of tablets, taste of the tablets. Twice as many women as
men experienced swallowing problems. Paediatric and geriatric patients in particular
experienced the greatest difficulty in swallowing tablets as well as people who are ill and
supine in bed and those patients who are busy travelling without having asses to water
than younger patients in swallowing tablets.
1.3 ORODISPERSIBLE TABLETS
ODTs are becoming increasingly sophisticated as pharmaceutical scientists
acquire a better understanding of the physicochemical and biochemical parameters
pertinent to their performance. Recent advances in novel drug delivery (NDDS) aim to
enhance safety and efficacy of drug molecule by formulation and to achieve better patient
compliance. One such approach is orally disintegrating tablets (OrDTs) which has gained
considerable attention as a preferred alternative to conventional tablets and capsules over
the past three decades.

Products of ODT technologies entered the market in the 1980s and have grown
steadily in demand, and their product pipelines are rapidly expanding. New ODT
technologies address many pharmaceutical and patients needs, ranging from enhanced
life-cycle management to convenient dosing for paediatric, geriatric, and psychiatric
patients with dysphagia. The mouth dissolving tablets (MDT) or ODTs by overcoming
the drawback associated with conventional tablets. These tablets disintegrate/dissolve/
disperse in saliva within few seconds.5 USFDA has defined OrDTs tablet as ―A solid
dosage form containing medicinal substances, which disintegrate rapidly, usually within a
matter of seconds, when placed upon the tongue‖.
Recently European Pharmacopoeia also adopted the term ―ODT‖ as a tablet that is
intended to be placed in the mouth where it disperses rapidly before swallowing. These
dosage forms dissolve or disintegrate in the patient‘s mouth within 15 seconds to 3
minutes without the need of water or chewing.6
Fast dissolve, quick dissolve, rapid melt, quick disintegrating, mouth dissolving,
orally disintegrating, orodispersible, melt-in-mouth, tablets etc are some of the terms
which are used to refer to this unique form of drug delivery, which has many advantages
over the conventional oral solid dosage forms.7
1.3.1 Salient Features of Orodispersible Tablets
The performance of ODTs depends on the technology used during their
manufacture. The necessary property of such tablets is the ability to disintegrate rapidly
and disperse or dissolve in saliva, thereby obviating the need for water. Various
technologies have been developed that enable ODT to perform this unique function.

1.3.2 An ideal Orodispersible tablet should meet the following criteria
1) Ease of administration to the patient who cannot swallow, and patient who refuse
to swallow such as paediatric, geriatric and psychiatric patients.
2) Ability to be swallowed without water which is highly convenient for patients
who are travelling or when immediate access to water is difficult.
3) Rapid dissolution and absorption of the drug, which will produce quick onset of
action.
4) Result in an increase in bioavailability compared to conventional drugs.
5) Have sufficient strength to withstand the rigors of the manufacturing process and
post manufacturing handling.
6) Exhibit low sensitivity to environmental conditions such as humidity and
temperature.
7) Be easily adaptable for manufacture using existing processing and packaging
machinery.
8) Good mouths feel to change the perception of medication as bitter pill particularly
in paediatric patients.
1.3.3 Advantages of Orodispersible tablets
1) Improved safety since the risk of choking or suffocation during oral
administration seen with conventional formulations is overcome.
2) New business opportunity like product differentiation, product promotion, patent
extensions and life cycle management.

3) Utility in cases such as motion sickness, sudden episodes of allergic attack or
coughing, where an ultra rapid onset of action required.
4) Stability for longer duration of time, since the drug remains in solid dosage form
till it is consumed.
5) Cost effective manufacturing. 8,9,6,7.
However it should be noted that high drug loading is possible in case of ODTs.
1.4 TABLET DISINTEGRANTS
For a drug to be readily absorbable by the body, it has first to be in solution. For
most tablets, the first important step toward solution is breakdown of the tablet into
smaller particles or granules, a process known as disintegration as specified in the
USP/NF. Before a tablet dissolves, it has to disintegrate first, unless the tablet is
designed for quick surface erosion. The materials used as disintegrants include starches,
agar, amylose, cellulose and its derivatives, gum and its derivatives, gelatin, resins, and
silicone compounds.
Research has established that one should not automatically expect a correlation
between disintegration and dissolution. However, since the dissolution of a drug from the
fragmented tablet appears to control partially or completely the appearance of the drug in
the blood, disintegration is still used as a guide to the formulator in the preparation of an
optimum tablet formula and as an in-process control test to ensure batch-to-batch
uniformity.2
In the tablet disintegration process, several factors may affect the disintegration.
They include the rate of water absorption, porosity of the tablet, processing parameters,

and effect of active ingredients, surfactants, binders, and lubricants. Fast disintegration
always requires fast absorption of water into the centre of the tablet. Thus, having open
pore structures inside the tablets is very important for making fast dissolving tablets.6
Fig. No. 1.4 Common steps in tablet disintegration
1.4.1 Mechanism of tablet disintegration
The tablet breaks to primary particles by one or more of the mechanisms described
below:-
1.4.1.1 Disintegration by capillary action10
Disintegration by capillary action is always the first step. When tablets are placed
in suitable aqueous medium, the medium penetrates into the tablet and replaces the air
adsorbed on the particles, which weakens the intermolecular bond and breaks the tablet
into fine particles. Water uptake by tablet depends upon hydrophilicity of the drug
excipient and on tableting conditions. For disintegration by capillary action maintenance

of porous structure and low interfacial tension towards aqueous fluid is necessary to help
disintegration by creating a hydrophilic network around the drug particles.
1.4.1.2 Disintegration by heat of wetting (air expansion)10
When disintegrants with exothermic properties gets wetted, localized stress is
generated due to capillary air expansion, which helps in disintegration of tablet. This
explanation, however, is limited to only a few types of disintegrants and cannot describe
the action of most modern disintegrating agents.
1.4.1.3 Disintegration due to disintegrating particle-particle repulsive forces10
Another mechanism of disintegration attempts to explain the swelling of tablet
made with ‗non-swellable‘ disintegrants. Guyot-Hermann has proposed a particle
repulsion theory based on the observation that nonswelling particle also cause
disintegration of tablets. The electric repulsive forces between particles are the
mechanism of disintegration and water is required for it. Researchers found that repulsion
is secondary to wicking.
1.4.1.4 Disintegration by swelling10
Perhaps the most widely accepted general mechanism of action for tablet
disintegration is swelling Tablets with high porosity show poor disintegration due to lack
of adequate swelling force. On the other hand, sufficient swelling force is exerted in the
tablet with low porosity. It is worthwhile to note that if the packing fraction is very high,
fluid is unable to penetrate in the tablet and disintegration is again slows down.

Fig. No. 1.4.1.4 Disintegration of tablet by wicking and swelling
1.4.1.5 Disintegration due enzymatic reaction
Enzymes presents in the body could act as disintegrants. By destroying the
binding action of binders some of the enzymes which act on the binders are listed in the
Table1 shown below.
Table no. 1.4.1.5 List of enzymes and their use for the disintegration of tablets
Enzymes Binder
Amylase Starch
Protease Gelatin
Cellulose Cellulose and its derivatives
Invertase Sucrose

1.4.1.6 Disintegration due to deformation
Hess et al. had proved that during tablet compression, disintegrated particles get
deformed and these deformed particles get into their normal structure when they come in
contact with aqueous media or water. Occasionally, the swelling capacity of starch was
improved when granules were extensively deformed during compression. This increase in
size of the deformed particles produces a faster breakup of the tablet. This may be a
mechanism of starch and has only recently begun to be studied.
Fig. No. 1.4.1.6 Disintegration by deformation and repulsion
1.4.1.7 Disintegration due to release of gases 10
Carbon dioxide released within tablets on wetting due to interaction between
bicarbonate or carbonate with citric acid or tartaric acid. The tablet disintegrates due to
generation of pressure within the tablet. This effervescent mixture is used when it is
desired to formulate very rapidly dissolving tablets or fast disintegrating tablet. As these
disintegrants are highly sensitive to small changes in humidity level and temperature,

strict control of environment is required during manufacturing of the tablets. The
effervescent blend is either added immediately prior to compression or can be added in to
two separate fraction of formulation.
Fig. No. 1.4.1.7 Release of gas during tablet disintegration
1.5. TECHNIQUES FOR PREPARING ORODISPERSIBLE TABLETS

Some of the techniques reported for the formulation of mouth ODTs are described below:
1.5.1. Freeze drying / lyophilisation11
Freeze drying/ lyophilisation are the process in which water is sublimed from the
product after it is frozen. This technique creates an amorphous porous structure that can
dissolve rapidly. Briefly, the procedure involves dispersion of the active drug and
aqueous solution of a carrier/polymer which is poured on the walls of preformed blister
packs. The trays holding the blister packs are then passed through liquid nitrogen freezing
tunnel to freeze the drug solution or dispersion. The frozen blister packs are next placed
in refrigerated cabinets to continue the freeze-drying. After freeze-drying the aluminium

foil backing is applied on a blister-sealing machine. Finally the blisters are packaged and
shipped. The freeze-drying technique has demonstrated improved absorption and increase
in bioavailability. The major disadvantages of lyophillization technique are that it is
expensive and time consuming; fragility makes conventional packaging unsuitable for
these products and poor stability under stressed conditions.
1.5.2 Tablet Moulding
Moulding process is of two kinds; solvent method and heat method. Solvent
method involves moistening the powder blend with a hydro alcoholic solvent followed by
compression at low pressures in moulded plates to form a wetted mass (compression
moulding). The solvent is then removed by air-drying. The tablets manufactured in this
manner are less compact than compressed tablets and posses a porous structure that
hastens dissolution. The heat moulding process involves preparation of a suspension that
contains a drug, agar and sugar (e.g. mannitol or lactose) and pouring the suspension in
the blister packaging wells, solidifying the agar at the room temperature to form a jelly
and drying at 30°C under vacuum. The mechanical strength of moulded tablets is a matter
of great concern. Binding agents, which increase the mechanical strength of the tablets,
need to be incorporated. Taste masking is an added problem to this technology.
The taste masked drug particles are prepared by spray congealing a molten
mixture of hydrogenated cottonseed oil, sodium carbonate, lecithin, polyethylene glycol
and an active ingredient into a lactose based tablet triturate form. Compared to the
lyophillization technique, tablets produced by the moulding technique are easier to scale
up for industrial manufacture.

1.5.3 Spray Drying 12
In this technique, gelatin can be used as a supporting agent and as a matrix,
mannitol as a bulking agent and sodium starch glycolate (SSG) or crosscarmellose
sodium (CCS) or Crospovidone (CP) are used as superdisintegrants. Tablets
manufactured from the spray-dried powder have been reported to disintegrate in less than
20 seconds in aqueous medium. The formulation contained bulking agent like mannitol
and lactose, a superdisintegrant like SSG & CCS and acidic ingredient (citric acid) and/or
alkaline ingredients (e.g. sodium bicarbonate). This spray-dried powder, which
compressed into tablets showed rapid disintegration and enhanced dissolution.
1.5.4 Direct Compression
Direct compression represents the simplest and most cost effective tablet
manufacturing technique. This technique can now be applied to preparation of ODT
because of the availability of improved excipients especially superdisintegrants and sugar
based excipients.
1.5.4.1 Superdisintegrants: Many orally disintegrating tablet technologies are based on
direct compression, the addition of superdisintegrants principally affects the rate
of disintegration and hence the dissolution. The presence of other formulation
ingredients such as water-soluble excipients and effervescent agents further
fastens the process of disintegration.
1.5.4.2 Sugar Based Excipients: This is another approach to manufacture ODT by direct
compression. The use of sugar based excipients especially bulking agents like

dextrose, fructose, isomalt, lactilol, maltilol, maltose, mannitol, sorbitol, starch
hydrolysate, polydextrose and xylitol, which display high aqueous solubility and
sweetness, and hence impart taste masking property and a pleasing mouth feel.
Mizumito et al. have classified sugar-based excipients into two types on the basis
of moulding and dissolution rate.
Type1 Saccharides (lactose & mannitol): low mouldability but high dissolution rate.
Type2 Saccharides (maltose & maltilol): high mouldability and low dissolution rate.
1.5.5 Mass-Extrusion 13, 14
This technology involves softening the active blend using the solvent mixture of
water- soluble polyethylene glycol and methanol and subsequent expulsion of softened
mass through the extruder or syringe to get a cylinder of the product into even segments
using heated blade to form tablet. The dried cylinder can also be used to coat granules for
bitter drugs and thereby achieve taste masking.
1.5.6 Cotton Candy Process
The flashdose is a mouth dissolving DDS (MDDDS) manufactured using
Shearform technology in association with Ceform TI technology to eliminate the bitter
taste of the medicament. The Shearform technology is employed in the preparation of a
matrix known as ‗floss‘, made from a combination of excipients, either alone or with
drugs. The floss is a fibrous material similar to cotton-candy fibers, commonly made of
saccharides such as sucrose, dextrose, lactose and fructose at temperatures ranging
between 180–266°F. However, other polysaccharides such as polymaltodextrins and
polydextrose can be transformed into fibers at 30–40% lower temperature than sucrose.

This modification permits the safe incorporation of thermo labile drugs into the
formulation. The tablets manufactured by this process are highly porous in nature and
offer very pleasant mouth feel due to fast solubilization of sugars in presence of saliva.
1.5.7 Sublimation
To generate a porous matrix, volatile ingredients are incorporated in the
formulation that is later subjected to a process of sublimation. Highly volatile ingredients
like ammonium bicarbonate, ammonium carbonate, benzoic acid, camphor, naphthalene,
urea, urethane and phthalic anhydride may be compressed along with other excipients
into a tablet. This volatile material is then removed by sublimation leaving behind a
highly porous matrix. Tablets manufactured by this technique have been reported to
usually disintegrate in 10-20 sec. Even solvents like cyclohexane; benzene can be used as
pore forming agents.
Fig. no. 1.5.6 Steps involved in manufacturing of ODTs by sublimation

1.5.8 Nanonization
A recently developed Nanomelt technology involves reduction in the particle
size of drug to nanosize by milling the drug using wet-milling technique. The
nanocrystals of the drug are stabilized against agglomeration by surface adsorption on
selected stabilizers, which are then incorporated into MDTs. This technique is especially
advantageous for poorly water soluble drugs. Other advantages of this technology include
fast disintegration/dissolution of nanoparticles leading to increased absorption and hence
higher bioavailability and reduction in dose, cost effective manufacturing process,
conventional packaging due to exceptional durability and wide range of doses (up to 200
mg of drug per unit).
1.5.9 Fast Dissolving Films
It is a new frontier in MDDDS that provides a very convenient means of taking
medications and supplements. In this technique, a non-aqueous solution is prepared
containing water soluble film forming polymer (pullulan, carboxy methylcellulose,
hydroxypropyl methylcellulose, hydroxyl ethylcellulose, hydroxyl propylcellulose,
polyvinyl pyrrolidone, polyvinyl alcohol or sodium alginate, etc.), drug and other taste
masking ingredients, which is allowed to form a film after evaporation of solvent. In case
of a bitter drug, resin adsorbate or coated microparticles of the drug can be incorporated
into the film. This film, when placed in mouth, melts or dissolves rapidly, releasing the
drug in solution or suspension form. The features of this system include paper thin films
of size less than 2X2 inches, dissolution in 5 sec, instant drug delivery and flavoured after
taste.6

1.6 PATENTED TECHNOLOGIES FOR ORODISPERSIBLE

TABLETS
1.6.1 Zydis Technology 15
Zydis formulation is a unique freeze dried tablet in which drug is physically
entrapped or dissolved within the matrix of fast dissolving carrier material. When zydis
units are put into the mouth, the freeze-dried structure disintegrates instantaneously and
does not require water to aid swallowing. The zydis matrix is composed of many material
designed to achieve a number of objectives. To impart strength and resilience during
handling, polymers such as gelatin, dextran or alginates are incorporated. These form a
glossy amorphous structure, which imparts strength. To obtain crystallinity, elegance and
hardness, saccharides such as mannitol or sorbitol are incorporated. Water is used in the
manufacturing process to ensure production of porous units to achieve rapid
disintegration while various gums are used to prevent sedimentation of dispersed drug
particles in the manufacturing process. Collapse protectants such as glycine prevent the
shrinkage of zydis units during freeze-drying process or long-term storage. Zydis
products are packed in blister packs to protect the formulation from moisture in the
environment.
1.6.2 Durasolv Technology 16, 17
Durasolv is the patented technology of Cima labs. The tablets made by this
technology consist of drug, filler and a lubricant. Tablets are prepared by using
conventional tabletting equipment and have good rigidity. These can be packaged into

conventional packaging system like blisters. Durasolv is an appropriate technology for
product requiring low amounts of active ingredients.
1.6.3 Orasolv Technology 18
CIMA labs have also developed Orasolv Technology. In this system active
medicament is taste masked. It also contains effervescent disintegrating agent. Tablets are
made by direct compression technique at low compression force in order to minimize oral
dissolution time. Conventional blenders and tablet machine are used to produce the
tablets. The tablets produced are soft and friable.
1.6.4 Flash Dose Technology 19
Flash dose technology has been patented by Fuisz Nurofen meltlet, a new form of
ibuprofen as melt in mouth tablets (MIM) prepared using flash dose technology is the
first commercial product launched by Biovail Corporation. Flash dose tablets consist of
self-binding shear form matrix termed as ―floss‖. Shear form matrices are prepared by
flash heat processing.
1.6.5 Wow tab Technology 20
Wow tab technology is patented by Yamanouchi Pharmaceutical Co. WOW
means ―Without Water‖. In this process, combination of low mouldability saccharides
and high mouldability saccharides is used to obtain a rapidly melting strong tablet. The
active ingredient is mixed with a low mouldability saccharide (eg lactose, glucose, and

mannitol) and granulated with a high mouldability saccharide (eg Maltose,
oligosaccharides) and compressed into tablets.11
1.6.6 Flash tab Technology 19,20
Prographarm laboratories have patented the Flash tab technology. Tablet prepared
by this system consists of an active ingredient in the form of micro crystals. Drug micro
granules may be prepared by using the conventional techniques like coacervation, micro
encapsulation and extrusion spheronisation. All the processing, utilized conventional
tabletting technology.
Table 1.6 Marketed products along with the technology used, their inventors and
the active ingredients present
Patent Basis of Technology developed Active Ingredient
Technology Technology by Company (Brand Name)
Zydia Lyophilization R.P.Scherer. inc Loratidine
Quicksolv Lyophilization Janssen Pharmaceutics Risperidone
Lyoc Lyophilization Farmalyoc Phloroglucinol Hydrate
Flashtab Direct compression Ethypharm Ibuprofen
Orasolv Direct compression Cima Labs, Inc. Paracetamol
Durasolv Direct compression Cima Labs, Inc Zolmitriptan
Wowtab Direct compression Yamanouchi Pharma Famotidine
Ziplets DC Microcaps Eurand International Ibuprofen
Advatab Diffuscap CR Tech. Eurand International Cetrizine
Tramadol
Flashdose Cotton Candy Fuisz Technology
hydrochloride
Micromask taste
Oraquick KV Pharm Hyoscyamine Sulfate
masking

1.7. FUTURE PERSPECTIVE
With continued innovations in pharmaceutical excipients, one can expect the
emergence of more novel technologies for MDTs in the days to come. These innovations
may involve modifying formulation composition and processing to achieve new
performance end-points or the merger of new technological advances with traditional
pharmaceutical processing techniques for the production of novel mouth dissolving
dosage forms. It is reasonable to expect that future trends in innovations of drug delivery
systems will continue to bring together different technological disciplines to create novel
technologies.5

1.8 PROTON PUMP INHIBITORS AND THEIR MECHANISM OF

ACTION
The term acid-peptic disorder encompasses a variety of relatively specific medical
conditions in which injuries by gastric acid (and activated pepsin) is thought to play an
important role. These disorders include gastroesophageal reflux disease (GERD), benign
―peptic‖ ulcers of the stomach and duodenum, ulcers secondary to the use of
conventional non-steroidal anti-inflammatory drugs (NSAIDs), and ulcers due to rare
Zollinger-Ellison syndrome. It appears that exposure of the involved tissue of acid is
essential to the development of clinical symptoms in most instances of these diseases.
Control of acidity is therefore a cornerstone of therapy in these disorders, even though
this approach may not address the fundamental pathophysiological process.
Mankind has lived with peptic ulcers since ancient times. Perhaps the first
description of this malady is the one inscribed on the pillars of the temple of Aesculapius
of Epidaurus from around the fourth century B.C.: ―A man with an ulcer in his stomach.
He incubated and saw a vision: the god seemed to order his followers to seize and hold
him, that he might incise his stomach. So he fled, but they caught and tied him to the
doorknocker. Then Asklepios opened his stomach, cut out the ulcer, sewed him again,
and loosed his bonds.‖ Many prominent people have suffered from indigestion and
ulcers, including the Roman emperor Marcus Aurtlius, whose death has been attributed
by some to a perforated ulcer and whose physician was none other than Galen himself.
Acid neutralization was recognised as effective treatment more than 12 centuries ago by
Paulus Aeginata, who prescribed a mixture of Samian and Lemnian earths and milk, not
unlike the milk- antacid regimens of the need twentieth century.

Since then, considerable advances in understanding the pathogenesis and
treatment of acid-peptic conditions have occurred, culminating in the discovery of
Helicobacter pylori (H. Pylori) and PPIs. We now know that eradication of H. Pylori
effectively promotes healing of peptic ulcers and prevents their recurrence in most cases.
PPIs have become the drugs of choice in prompting healing from erosive esophagitis and
peptic ulcer because of their ability to nearly completely suppress acid production.21
In 1977 George Sachs & John Forte discovered the ―Proton pump‖ in the human
body. After a lot of efforts in 1982 the first published clinical study was on omeprazole.
PPIs were approved for prescription in 1989.21PPIs are widely used for treating acid-
induced inflammation, ulcers of the stomach and duodenum, GERD, erosive esophagitis,
heartburn, upper gastrointestinal bleeding in critically ill patients, and Zollinger-Ellison
Syndrome. They are also used in combination with antibiotics for eradicating H. pylori
infection of the stomach.22
PPIs are the most potent suppressors of gastric acid secretion are inhibitors of the
gastric H+,K+-ATPase proton pump. In typical doses, these drugs diminish the daily
production of acid (basal and stimulated) by 80% to 95%. Five PPIs are available for
clinical use: Omeprazole and its S-isomer, Esomeprazole, Lansoprazole, Rabeprazole and
Pantoprazole. These drugs have different substitutions on their pyridine and/or
benzimidazole groups but are remarkably similar in their pharmacological properties.

1.8.1 Chemistry
H3C OCH3 OCH2CF3
CH3 CH3
N N
N N
S S
N O N O
H3CO H H
Fig No. 1.8.1.1 Structure of Omeprazole Fig. No. 1.8.1.2 Structure of Lansoprazole
OCH3 O (CH2)3OCH3
OCH3 CH3
N N
F2HCO N
N
S S
N O N O
H H
Fig. No.1.8.1.3 Structure of Pantoprazole Fig No. 1.8.1.3 Structure of Rabeprazole
Omeprazole is a racemic mixture of R- and S-isomers; the S-isomer,
esomeprazole (S-omeprazole), is eliminated less rapidly than R-omeprazole, which
theoretically provides a therapeutic advantage because of the increased half-life. Despite
claims to the contrary, all PPIs have equivalent efficacy at comparable doses.22
Pantoprazole 5-(difluromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl) methyl]
sulfinyl] -1 H- benzimidazole, Omeprazole 5-methoxy-2-(((4-methoxy-3,5-dimethyl-2-
pyridinyl) methyl) sulfinyl)-1H-benzimidazole). A molecule with benzimidazole

substitution exhibits potent and long-lasting inhibition of gastric acid secretion by
selectively interacting with the gastric proton pump (K /H -ATPase) in the parietal cell
secretory membrane.23
1.8.2 Stomach
The stomach is typically a J-shaped enlargement of the GIT directly inferior to the
diaphragm in the epigastric, umbilical, and left hypochondriac regions of the abdomen.
The stomach connects the esophagus to the duodenum, the first part of the small
intestine.24
1.8.2.1 Anatomy of the Stomach
The stomach has four main regions: the cardia, fundus, body, and pylorus. The
Cardia (CAR-dē-a) surrounds the superior opening of the stomach. The rounded portion
superior to the left of the cardia is the fundus (FUN-dus) inferior to the fundus is the
larger central portion of the stomach, called the body. The region of the stomach that
connects to the duodenum is the pylorus (pī-LOR-us; pyl-= gate; -orus=guard); it has
two parts, the pyloric antrum (AN-trum =cave), which is connects to the body of the
stomach, and the pyloric canal, which leads into duodenum. When the stomach is empty,
the mucosa lies in large folds, called rugae (ROO-gē = wrinkles), that can be seen with
unaided eye. The pylorus communicates with the duodenum of the small intestine via a
sphincter called pyloric sphinter. The concave medial border of the stomach is called the
lesser curvature, and the convex lateral border is called the greater curvature.24

1.8.2.2 Histology of the Stomach
The stomach wall is composed of the same four basic layers as the rest of the
GIT, with certain modifications. The surface of the mucosa is a layer of simple columnar
epithelial cells called surface mucous cells. The mucosa contains a laminal propria
(areolar connective tissue) and muscularis mucosae (smooth muscle). Epithelial cells
extend down into the lamina propria. Where they form columns of secretory cells called
gastric glands that line many narrow channels called gastric pits. Secretions from seeral
gastric glands flow into each gastric pit and then into the lumen of the stomach.24
Fig. No. 1.8.2 Anatomy and physiology of stomach
The gastric glands contain three types of exocrine gland cells that secrete their
products into the stomach lume; mucous neck cells, cheif cells, and parietal cells, both

surface mucous cells and mucous neck cells secrete mucus. Parietal cells produce
intrinsic factor, which is needed for absorption of vitamin B12, and hydrochloric acid. The
chief cells secrete pepsinogen and gastric lipase. The secretions of the mucous, parietal,
and chief cells form gastric juice, which totals 2000-3000 ml/day. In addition, gastric
glands include a type of enteroendocrine cells, the G cell, which is located mainly in the
pyloric antrum and secretes the hormone gastrin into the bloodstream.24
1.8.2.3 Mechanical and Chemical Digestion in the Stomach
Parietal cells secrete hydrogen ions (H+) and chloride ions (Cl-) separately into the
stomach lumen, the net effect are secretion of hydrochloric acid (HCl). Proton pumps
powered by H+/K+ ATPases actively transport H+ into the lumen while bringing
potassium ions (K+) into the cell. At the same time Cl- and K+ diffuse out through Cl- and
K+ channels in the apical membrane. The enzyme carbonic anhydrase, which is
especially plentiful in parietal cells, catalyzes the formation of carbonic acid (H2CO3)
from water (H2O) and carbon dioxide (CO2). As carbonic acid dissociates, it provides a
ready source of H+ for the proton pumps but also generates bicarbonate ions (HCO3-). As
HCO3- builds up in the cytosol, it exits the parietal cell in exchange for Cl - via Cl-/HCO3-
antiporters in the basolateral membrane. HCO3- diffuses into nearby blood capillaries.
This ―alkaline tide‖ of bicarbonate ions entering the bloodstream after a meal may be
large enough to slightly elevate blood pH and make urine more alkaline.
The strongly acidic fluid of the stomach kills many microbes in food, and HCl
partially denatures (unfolds) proteins in food and stimulates the secretion of hormones
that promote the flow of bile and pancreatic juice. Enzymatic digestion of proteins also
begins in the stomach. The only proteolytic (protein-digesting) enzyme in the stomach is

pepsin, which is secreted by chief cells. Because pepsin breaks certain peptide bonds
between the amino acids making up proteins, a protein chain of many amino acid are
broken down into smaller peptide fragments. Pepsin is most effective in the very acidic
environment of the stomach (pH 2); it becomes inactive at higher pH.23
1.8.2.4 Physiology of gastric secretion
Gastric acid secretion is a complex, continuous process in which multiple central
and peripheral factors contribute to a common endpoint: the secretion of H+ by parietal
cells. Neuronal (acetylcholine, ACh), paracrine (histamine), and endocrine (gastrin)
factors all regulate acid secretion. Their specific receptors (M3, H2, and CCK2 receptors,
respectively) are on the basolateral membrane of parietal cells in the body and fundus of
the stomach. The H2 receptor is a GPCR that activates the Gs-adenylylcyclase-cyclic
AMP-PKA pathway. ACh and gastrin signal through GPCRs that couple to the Gq-PLC-
IP3-Ca2+ pathway in parietal cells. In parietal cells, the cyclic AMP and the Ca2+-
dependent pathways activate H+,K+-ATPase (the proton pump), which exchanges
hydrogen and potassium ions across the parietal cell membrane. This pump generates the
largest known ion gradient in vertebrates, with an intracellular pH of about 7.3 and an
intracanalicular pH of about 0.8.
The most important structures for CNS stimulation of gastric acid secretion are
the dorsal motor nucleus of the vagal nerve, the hypothalamus, and the solitary tract
nucleus. Efferent fibers originating in the dorsal motor nuclei descend to the stomach via
the vagus nerve and synapse with ganglion cells of the enteric nervous system. ACh
released from postganglionic vagal fibers directly stimulates gastric acid secretion
through muscarinic M3 receptors on the basolateral membrane of parietal cells. The CNS

predominantly modulates the activity of the enteric nervous system via ACh, stimulating
gastric acid secretion in response to the sight, smell, taste, or anticipation of food (the
"cephalic" phase of acid secretion). ACh also indirectly affects parietal cells by
increasing the release of histamine from the enterochromaffin-like (ECL) cells in the
fundus of the stomach and of gastrin from G cells in the gastric antrum.
ECL cells, the source of gastric histamine secretion, usually are in close proximity
to parietal cells. Histamine acts as a paracrine mediator, diffusing from its site of release
to nearby parietal cells, where it activates H2 receptors. The critical role of histamine in
gastric acid secretion is dramatically demonstrated by the efficacy of H2-receptor
antagonists in decreasing gastric acid secretion.21
Gastrin, which is produced by antral G cells, is the most potent inducer of acid
secretion. Multiple pathways stimulate gastrin release, including CNS activation, local
distention, and chemical components of the gastric contents. Gastrin stimulates acid
secretion indirectly by inducing the release of histamine by ECL cells; a direct effect on
parietal cells also plays a lesser role.21
Somatostatin (SST), which is produced by antral D cells, inhibits gastric acid
secretion. Acidification of the gastric luminal pH to <3 stimulates SST release, which in
turn suppresses gastrin release in a negative feedback loop. SST-producing cells are
decreased in patients with H. pylori infection, and the consequent reduction of SST's
inhibitory effect may contribute to excess gastrin production.21

1.9 MODE OF ACTION
PPIs are prodrugs that require activation in an acid environment. After absorption
into the systemic circulation, the prodrug diffuses into the parietal cells of the stomach
and accumulates in the acidic secretory canaliculi. Here, it is activated by proton-
catalyzed formation of a tetracyclic sulfenamide trapping the drug so that it cannot
diffuse back across the canalicular membrane.21
Fig no. 1.9a A Inhibition of Gastric H+/K+-ATPase proton pump
B- Conversion of Omeprazole to a sulfenamide in the acidic secretory canaliculi of

the Parietal cell.
The activated form then binds covalently with sulfhydryl groups of cysteines in
the H+/K+-ATPase, irreversibly inactivating the pump molecule. Acid secretion resumes
only after new pump molecules are synthesized and inserted into the luminal membrane,
providing a prolonged (up to 24- to 48-hour) suppression of acid secretion, despite the

much shorter plasma half-lives (0.5 to 2 hours) of the parent compounds. Because they
block the final step in acid production, the PPIs are effective in acid suppression
regardless of other stimulating factors.21
Fig. no. 1.9b Mode of action of Proton Pump Inhibitors.
1.10 THERAPEUTIC USES
1.10.1 Duodenal Ulcer 25
The recommended adult dose Of PPIs for the oral treatment of duodenal ulcer is
40 mg as PPIs are given once daily in the morning. Healing usually occurs within 2
weeks. For patients not healed after this initial course of therapy, an additional course of
2 weeks is recommended.

1.10.2 Gastric Ulcer
The recommended adult oral dose of PPIs for the oral treatment of gastric ulcer is
40 mg given once daily in the morning. Healing usually occurs within 4 weeks. For
patients not healed after this initial course of therapy, an additional course of 4 weeks is
recommended.
1.10.3 Helicobacter Pylori Associated Duodenal Ulcer 25
PPIs/Clarithromycin/Metronidazole Triple Combination Therapy: The recommended
dose for H. pylori eradication is treatment for seven days with PPIs 40 mg together with
clarithromycin 500 mg and metronidazole 500 mg, all twice daily.
PPIs/Clarithromycin/Amoxicillin Triple Combination Therapy: The recommended dose
for H. pylori eradication is treatment for seven days with PPIs 40 mg together with
clarithromycin 500 mg and amoxicillin 1000 mg, all twice daily.
1.10.4 Symptomatic Gastroesophegal reflux disease 25
The recommended adult oral dose for the treatment of symptoms of GERD,
including heartburn and regurgitation, is 40 mg once daily for up to 4 weeks. If
significant symptom relief is not obtained in 4 weeks, further investigation is required.
1.10.5 Reflux Esophagitis 25
The recommended adult oral dose of PPIs is 40 mg, given once daily in the
morning. In most patients, healing usually occurs within 4 weeks. For patients not healed
after this initial course of therapy, an additional 4 weeks of treatment is recommended.

For the prevention of relapse in patients with reflux esophagitis, the recommended
adult oral dose is 20 mg PPIs are given once daily in the morning and the dose is
increased to 40 mg once daily in the morning in the case of recurrence.
1.10.6 Pharmacokinetics of Proton pump inhibitor 21
Since an acidic pH in the parietal cell acid canaliculi is required for drug
activation, and since food stimulates acid production, these drugs ideally should be given
about 30 mins before meals. Concurrent administration of food may reduce somewhat the
rate of absorption of PPIs, but this effect is not thought to be clinically significant.
Concomitant use of other drugs that inhibit acid secretion, such as H2-receptor
antagonists, might be predicted to lessen the effectiveness of the PPIs, but the clinical
relevance of this potential interaction is unknown.
1.10.7 Absorption and Distribution
PPIs are absorbed rapidly in both rat and dog. Peak plasma levels are attained
within 15 to 20 mins in the rat and after about 1 hour in the dog. Oral bioavailability is
33% in the rat and 49 % in the dog. Following absorption, autoradiography and
quantitative tissue distribution experiments have shown that PPIs get rapidly distributed
to extra vascular sites. Following administration of PPIs, distribution of radioactivity in
the blood and most organs is found to be uniform initially. After 16 hours, radiolabelled
PPIs are predominantly detected in the stomach wall. After 48 hours, the entire
administered radioactivity is found to have been excreted. Penetration of the blood-brain
barrier by radiolabelled PPIs is very low. Protein binding in the rat and dog is 95% and
86%, respectively.26

1.10.8 Metabolism
PPIs get readily bound to serum proteins (98%) and almost completely
metabolized in the liver. Renal elimination represents the major route of excretion (about
82%) for the metabolites of PPIs. If we consider pantoprazole for e.g. the main
metabolite of pantoprazole sodium in both the serum and urine is desmethylpantoprazole
as a sulphate conjugate. The half-life of the main metabolite (about 1.5 hours) is not
much longer than that of pantoprazole sodium (approximately 1 hour).Once in the small
bowel, PPIs are rapidly absorbed, highly protein bound, and extensively metabolized by
hepatic CYPs, particularly CYP2C19 and CYP3A4. Several variants of CYP2C19 have
been identified. Asians are more likely than Caucasians or African-Americans to have the
CYP2C19 genotype that correlates with slow metabolism of Pantoprazole (23% vs. 3%,
respectively), which has been suggested to contribute to heightened efficacy and/or
toxicity in this ethnic group. Although the CYP2C19 genotype is correlated with the
magnitude of gastric acid suppression by Pantoprazole in patients with gastroesophageal
reflux disease, there is no evidence that the CYP2C19 genotype predicts clinical efficacy
of these. 26
Because not all pumps or all parietal cells are active simultaneously, maximal
suppression of acid secretion requires several doses of the PPIs. For example, it may take
2 to 5 days of therapy with once-daily dosing to achieve the 70% inhibition of proton
pumps that is seen at steady state. More frequent initial dosing (e.g., twice daily) will
reduce the time to achieve full inhibition but is not proven to improve patient outcome.
Since the proton pump inhibition is irreversible, acid secretion will be suppressed for 24

to 48 hours, or more, until new proton pumps are synthesized and incorporated into the
luminal membrane of parietal cells.21
Pantoprazole sodium alone is absorbed rapidly following administration of a 40
mg enteric coated tablet. Its oral bioavailability compared to the i.v. dosage form is 77%
and does not change upon multiple dosing. Following an oral dose of 40 mg, C max is
approximately 2.5mg/mL with a tmax of 2 to 3 h. The AUC is approximately 5 mgh/L.
Pantoprazole sodium shows linear pharmacokinetics after both i.v. and oral
administration. Therefore, elimination half-life, clearance and volume of distribution are
independent of the dose. Concomitant intake of food has no influence on the
bioavailability of pantoprazole sodium. Chronic renal failure does not lead to drug
accumulation with once-a-day dosing of the PPIs. Hepatic disease substantially reduces
the clearance of esomeprazole and lansoprazole. Thus, in patients with severe hepatic
disease, dose reduction is recommended for esomeprazole and should be considered for
lansoprazole.25

1.11 NEED FOR THE DEVELOPMENT OF ORODISPERSIBLE

TABLETS
To prevent degradation of PPIs by acid in the gastric lumen, oral dosage forms are
mostly supplied in different formulations: (1) enteric-coated drugs contained inside
gelatin capsules (omeprazole, esomeprazole, and lansoprazole); (2) enteric-coated
granules supplied as a powder for suspension (lansoprazole); (3) enteric-coated tablets
(pantoprazole, rabeprazole, and omeprazole. The delayed-release and enteric-coated
tablets dissolve only at alkaline pH substantially improve the oral bioavailability of these
acid-labile drugs.
Until recently, the requirement for enteric coating posed a challenge to the
administration of PPIs in patients for whom the oral route of administration is not
available. These patients and those requiring immediate acid suppression now can be
treated powdered drug combined with sodium bicarbonate (pantoprazole) which has less
patient compliance then tablet formulation or parenterally with pantoprazole or
lansoprazole, both of which are approved for intravenous administration in the United
States. An intravenous formulation of esomeprazole is available in Europe but not in the
United States. Thus an orodispersible tablet is a need to be developed which increases the
patient compliance by many folds.

2. OBJECTIVE
The purpose of this research is to prepare ODTs consisting of superdisintegrnts
and PPIs by direct compression method and to evaluate their quick disintegration and
immediate release properties. The effect of various formulations and process variables on
the particle morphology, micromeritics properties, in- vitro release behaviour, etc.
Pantoprazole will be used as a representative drug for the PPI in this research project.
Methods used for Pantoprazole will be equally applicable to other PPIs.
2.1 OBJECTIVES OF THE PRESENT RESEARCH WORK
1. Fabrication of Pantoprazole loaded ODTs as immediate releasing DDS employing
superdisintegrating agents and bicarbonates.
2. Increase in stability which is achieved by incorporation of the bicarbonates for
increasing the stability of the drug.
3. To make available most of the drug at the site of action thus higher suppression of
acid secretion.
4. To increase patient convenience and compliance.
5. To compare the various formulations using different excipients and choosing the
best formulation as per ICH guidelines.
6. Characterized of the incompatibilities by FTIR.
7. Estimated the drug concentration in the prepared formulations.
8. Calculate the disintegration time of various formulations.
9. Evaluated the ODTs by in vitro dissolution and the mechanism of
release/dissolved.
10. Stability studies were conducted for the optimized formulations.

2.2 WHY ONLY PPIS
 PPIs are the most potent suppressors of gastric acid secretion thus inhibiting the
gastric H+/K+-ATPase (PP). In typical doses, these drugs diminish the daily
production of acid (basal and stimulated) by 80% to 95%.
 They are the drugs of choice for the treatment of various gastro intestinal
disorders.
 Administration of conventional tablets of PPIs has been reported to exhibit longer
lag time as they are enteric coated and fluctuations in the plasma drug levels,
resulting either in reduction in drug conc. in the blood.
 Administration of conventional tablets of PPIs does not let the accumulation of
the drug at the site of action thus instant relief is not achieved; fast dissolution and
absorption of the drug which will result quick onset of action and accumulation of
PPI at the site of action.
 Dose of PPIs is less so it is a potent candidate for ODTs.
 Most elderly patients, children, and patients with dysphagia have difficulty in
swallowing conventional tablets and hard gelatin capsules, and therefore do not
take medication as prescribed by physicians. It is estimated that 35% of the
general population, 30 to 40% of elderly nursing home patients, and 25 to 50% of
patients hospitalized for acute neuromuscular disorders and head injuries have
dysphagia will be benefited by this invention.

3. REVIEW OF LITERATURE
Jungnickle PW. reviews the pharmacology, clinical efficacy, and tolerability of
pantoprazole in comparison with those of other available PPIs. Like other PPIs,
pantoprazole exerts its pharmacodynamic actions by binding to the proton pump
(H+/K+-adenosine triphosphatase) in the parietal cells but, compared with other PPIs, its
binding may be more specific for the proton pump. Pantoprazole is well absorbed when
administered as an enteric-coated, delayed-release tablets, it was hepatically metabolized
via cytochrome P2C19 to hydroxyl pantoprazole, an inactive metabolite that
subsequently undergoes sulfate conjugation. The elimination half-life ranges from 0.9 to
1.9 hours was found to be independent of dose. Pantoprazole has similar efficacy to other
PPIs in the healing of gastric and duodenal ulcers, as well as erosive esophagitis, and as
part of triple-drug regimens for the eradication of Helicobacter pylori from the gastric
mucosa. It is well tolerated, with the most common adverse effects being headache,
diarrhea, flatulence, and abdominal pain. In clinical studies, it has been shown to have no
interactions with various other agents, including carbamazepine, cisapride, cyclosporine,
digoxin, phenytoin, theophylline, and warfarin.27
Bell W, Staar U. et al studied the action of the H+/K+ -ATPase inhibitors such as
pantoprazole and omeprazole by comparing then in different in vitro test systems. In a
gastric membrane vesicle under conditions it shows acidification of the vesicle interior,
pantoprazole and omeprazole inhibited H+/K+-ATPase activity. Their study showed that
both drugs inhibited, with similar potency, papain activity at pH 3.0 inactivated the
enzyme in a similar time-dependent manner; at pH 5.0 omeprazole was more potent

than pantoprazole and enzyme inhibition was faster than with pantoprazole. The results
indicate that pantoprazole is a potent inhibitor of H+/K+-ATPase under highly acidic
conditions and that it is more stable than omeprazole at a slightly acidic pH such
as pH 5.0.28
Li XQ. et al. compared the potency and specificity of the currently used PPIs,
omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole, as inhibitors of
four cytochrome P450 enzymes (CYP2C9, 2C19, 2D6, and 3A4), they performed in vitro
studies using human liver microsomal preparations and recombinant CYP2C19. They did
the sample analysis using selected reaction monitoring liquid chromatography/tandem
mass spectometry. With several systems for CYP2C19 activity (two marker reactions, S-
mephenytoin 4-hydroxylation and R-omeprazole 5-hydroxylation, tested in either human
liver microsomes or recombinant CYP2C19), the five PPIs showed competitive inhibition
of CYP2C19 activity for lansoprazole, omeprazole, esomeprazole, pantoprazole, and
rabeprazole. Their data suggest that, although the inhibitory profiles of the five studied
PPIs were similar, lansoprazole and pantoprazole are the most potent in vitro inhibitors of
CYP2C19 and CYP2C9, respectively. Esomeprazole showed less inhibitory potency
compared with omeprazole and it‘s R-enantiomer. The inhibitory potency of rabeprazole
was relatively lower than the other PPIs, but its thioether analog showed potent inhibition
on the P450 enzymes investigated, which may be clinically significant.29
Tutuian R. et al. evaluated the effect of once-daily doses of pantoprazole, 10, 20
and 40 mg, on gastric acidity in healthy volunteers. They selected thirty-six subjects
which received pantoprazole in a three-way crossover design study. Ambulatory 24-h

intragastric pH and distal oesophageal pH were monitored at baseline and on the last day
of each treatment period. The measured endpoints were the median intragastric and
oesophageal pH, the percentage of time the intragastric pH < 4 and oesophageal pH < 4
and the area under the curve for gastric acidity over 24 h. Safety was evaluated by
incidence and severity of adverse events. In conclusion, pantoprazole demonstrates a
dose-related effect in the range 10–40 mg once daily. The once-daily dose of 40 mg
provides the highest and most consistent control of gastric pH, especially at night.30
Raghunath AS. et al. reviewed the available preclinical and clinical studies
comparing esomeprazole with lansoprazole in the healing and maintenance of erosive
esophagitis, and to compare the budgeting impact of the 2 strategies. Comparative
tolerability was also reviewed. The search terms used were gastroesophageal reflux
disease, reflux esophagitis, and proton pump inhibitor; all comparisons of esomeprazole
and lansoprazole at any dose were considered. The comparative studies that were
identified fell into 4 categories: (1) Intragastric acid suppression studies; (2) Randomized
controlled trials in the healing of erosive esophagitis; (3) Randomized controlled trials in
the maintenance of erosive esophagitis; and (4) Health economic analyses. Based on
these studies, when healing doses (esomeprazole 40 mg once daily, lansoprazole 30 mg
once daily) and low doses (20 and 15 mg once daily, respectively) were compared, it was
seen that the data for esomeprazole and lansoprazole indicate clinical and cost-
effectiveness advantages for esomeprazole in the healing and maintenance of erosive
esophagitis compared with lansoprazole.31

Numans ME. et al. estimated the diagnostic test characteristics of successful PPI
treatment with objective measures of GERD by performing a meta-analysis based on the
published literature. They reviled that for a successful short-term treatment with a PPI in
patients suspected of having GERD does not confidently establish the diagnosis when
GERD is defined by currently accepted reference standards.32
Ren S. et al. evaluated the chemical stability of a PPIs, rabeprazole sodium, in
simulated intestinal fluid (pH 6.8) containing various generally recognized as safe listed
excipients, including Brij 58, Poloxamer 188, Cremophor RH40, Gelucire 44/14 and PEG
6000. After incubation at 37 and 60°C, the amounts of rabeprazole and its degradation
product, thioether rabeprazole, were quantitated by HPLC analysis. The main degradation
product was separated and characterized by LC/MS. The degradation of rabeprazole
followed first-order kinetics. In the absence of any excipients, the rate constants (k)
obtained at 37 and 60°C were 0.75 and 2.78 h−1, respectively. In contrast, the addition of
excipients improved its stability. Among several excipients tested in this study, Brij 58
displayed the greatest stabilizing effect. The stabilizing mechanisms of these hydrophilic
polymeric excipients with optimal HLB values could be partially explained in terms of
their solubilizing efficiency and micellar formation for thioether-rabeprazole. In
conclusion, rabeprazole formulations that contain suitable excipients would improve its
stability in the intestinal tract, thereby maximizing bioavailability.33
Armstrong D. et al. compared acid suppression (time with pH > 3.0, 4.0, 5.0 and
6.0) produced by standard doses of oral esomeprazole and IV pantoprazole in healthy
subjects. They concluded, in healthy subjects, esomeprazole, 40 mg oral dose dispersed

in water, produces greater acid suppression than pantoprazole 40 mg IV oral dose after 1
and 5 days of medication.34
Wahbi AAM. et al. showed that the compensation method and other
chemometric methods (derivative, orthogonal function and difference spectrophotometry)
have been applied to the direct determination of omeprazole, lansoprazole and
pantoprazole in their pharmaceutical preparations. Colourimetric methods are time
consuming and need special reagents. The Amax method has been proved to be inaccurate
due to matrix interference. They reported that the other methods are not stability
indicating, while the present methods using difference spectrophotometry eliminate acid
induced degradation products proved to be stability indicating. The spectrophotometric
methods are more versatile and easy to apply than the polarographic and voltammetric
methods. The chromatographic methods need special equipment that may not be
available in certain Q. C. laboratories. The disadvantage of the proposed methods was
that they cannot be applied to biological fluids containing these compounds and their
conjugated forms. They validated these methods; the limits of detection where carried
out. These proposed methods have been applied to the determination of the three drugs in
their grastro-resistant formulations. The difference spectrophotometric method is
unaffected by the presence of acid induced degradation products; hence can be used as a
stability indicating assay.35
Moustafa AAM. et al. introduced spectrophotometric procedures for
determination of two irreversible PPIs, lansoprazole and pantoprazole sodium
sesquihydrate Two methods were based on charge transfer complexation reaction of these

drugs, where they act as n-donors, with either p acceptor 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone and with s acceptor as iodine. A third method was also investigated
depending on ternary complex formation with eosin and copper. The coloured products
were quantified spectrophotometrically using absorption bands. The suggested methods
have the advantages of being simple, accurate, sensitive and suitable for routine analysis
in control laboratories. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and iodine methods
utilize a single step reaction and single solvent. The iodine acceptor method was more
sensitive in the case of lansoprazole than pantoprazole. The ternary complex method did
not require prior extraction procedure and have the advantages of sensitivity, simplicity
and reproducibility. All these methods can be used as general methods for the
spectrophotometric determination of lansoprazole and pantoprazole sodium sesquihydrate
in bulk and in pharmaceutical formulations. They are convenient for Q.C. and routine
determination of these drugs.36
Ramakrishna NVS. et al. developed a very sensitive and selective HPLC method
with UV detection and validated for quantitation of pantoprazole in human plasma.
Following a single-step liquid–liquid extraction with methyl tertbutyl ether/diethyl ether
(70/30, v/v), the analyte and internal standard (zonisamide) were separated using an
isocratic mobile phase of 10milli moles of phosphate buffer (pH 6.0)/acetonitrile (61/39,
v/v) on reverse phase Waters symmetry C18 column. A linear range of 20–5000 µg/mL
was established. This HPLC method was validated with between-batch and within-batch
respectively. This validated method is sensitive and repeatable enough to be used in
pharmacokinetic studies.37

Rajic KK. et al. developed first-order UV-derivative spectrophotometry,
applying zero-crossing method was developed for the determination of omeprazole,
omeprazole sulphone, pantoprazole sodium salt, and N-methylpantoprazole in
methanol/ammonia 4.0% v/v, where the sufficient spectra resolutions of drug and
corresponding impurity were obtained, using the amplitudes. Method showed good
linearity, accuracy and precision (repeatability and reproducibility). They experimentally
determined values of LOD (µg/ml-1). Zero-crossing method in the first-order derivative
spectrophotometry showed the impurity/drug intermolecular interactions, due to the
possible intermolecular hydrogen bonds, confirmed by divergences of experimentally
obtained amplitudes for impurities OMS and NPA in comparison to expected values
according to regression equations of calibration graphs.38
Farinha A. et al. demonstrated that the increasing number of omeprazole
containing products available in the market raises questions of therapeutic equivalence
and/or generic substitution. The bioequivalence evaluation between two or more
formulations provides information about in vivo performance. The products are
considered to have a similar therapeutic efficacy when used under the same therapeutic
conditions. They reported the design, results and some important aspects involved in a
bioequivalence study between two solid oral formulations from different manufacturers.
Some important findings were the high intra-subject variability observed for Cmax and the
variability observed between subject profiles, probably caused by the multi unit type of
formulations studied.39

Choi HG, Jung JH. et al. developed omeprazole buccal adhesive tablets, and
also studied the release and bioavailability of omeprazole delivered by buccal adhesive
tablets composed of sodium alginate, hydroxypropylmethylcellulose, magnesium oxide
and CCS. They concluded that CCS enhanced the release of omeprazole from the tablets.
The analysis of the release mechanism showed that CCS changed the release profile of
omeprazole from first to zero-order release kinetics by forming porous channels in the
tablet matrix. However, it decreased the bioadhesive forces and stability of omeprazole
tablets in human saliva. The tablet where composed of omeprazole: sodium alginate:
hydroxypropylmethylcellulose: magnesium oxide: CCS in the ratio of 20:24:6:50:10 mg
which may be attached to the human cheek without collapse and also enhanced the
stability of omeprazole in human saliva for at least 4 hrs, giving a fast release of
omeprazole. The plasma conc. of omeprazole in hamsters increased to maximum at 45
min after buccal administration and remained at the high level for 6 hrs. The buccal
bioavailability of omeprazole in hamsters was 13.763.2%. These results demonstrate that
the omeprazole buccal adhesive tablet would be useful to deliver omeprazole which
degrades very rapidly in acidic aqueous medium and undergoes hepatic first-pass
metabolism after oral administration.40
Another report by Choi HG, Jung JH. et al. developed an omeprazole buccal
adhesive tablet, they studied the release and bioavailability of omeprazole delivered by
buccal adhesive tablets composed of sodium alginate, hydroxypropylmethylcellulose,
magnesium oxide and CCS. Their studied concluded that CCS enhanced the release of
omeprazole from the tablets. The analysis of the release mechanism showed that CCS
changed the release profile of omeprazole from first to zero-order release kinetics by

forming porous channels in the tablet matrix. However, it decreased the bioadhesive
forces and stability of omeprazole tablets in human saliva. The tablet where composed of
omeprazole–sodium alginate– hydroxypropylmethylcellulose –magnesium oxide–CCS
(20:24:6:50:10 mg). It may be attached to the human cheek without collapse and it
enhanced the stability of omeprazole in human saliva for at least 4 h, giving a fast release
of omeprazole. Their results demonstrate that the omeprazole buccal adhesive tablet
would be useful to deliver omeprazole which degrades very rapidly in acidic aqueous
medium and undergoes hepatic first pass metabolism after oral administration.41
Gohel MC. et al. developed a more relevant in vitro dissolution method to
evaluate a carbamazepine floating DDS. In this method glass beaker was modified by
adding a side arm at the bottom of the beaker so that the beaker can hold 70 ml of 0.1 N
HCl dissolution mediums and allow collection of samples. The tablet did not stick to the
agitating device in the proposed dissolution method. The drug release followed zero order
kinetics in the proposed method. The proposed test may show good in vitro in vivo
correlation (IVIVC) since an attempt is made to mimic the in vivo conditions.42
Garcia CV. et al. developed and validated a dissolution test for rabeprazole
sodium coated tablets using a reverse-phase liquid chromategraphic method. After test
sink conditions, dissolution medium and stability of the drug, the best conditions were:
paddle at 75 rotations per minute (rpm) stirring speed, HCl 0.1M and borate buffer pH
9.0 as dissolution medium for acidic and basic steps, respectively, volume of 900ml for
both. The quantitation method was also adapted and validated. Less than 10% of the label
amount was released in the acid step, while more than 95% was achieved over 30min in

the basic one. The dissolution profile for tablets was considered satisfactory. The
dissolution test developed was adequate for its purpose and could be applied for quality
control of rabeprazole tablets, since there is no official monograph. The dissolution test
developed and validated for rabeprazole sodium coated tablets was considered
satisfactory. It was carefully studied in order to guarantee the drug stability during all
analysis time. The conditions that allowed the dissolution profile determination were
borate buffer pH 9.0 medium, paddle (USP apparatus II) and 75 rpm stirring speed. The
method demonstrated to be adequate for quality control of rabeprazole sodium dosage
form, since there is no official monograph.43
Bladh N. et al. developed a packet (sachet) formulation of esomeprazole for
suspension for use in patients who have difficulty swallowing. They performed in vitro
characteristics of the new esomeprazole formulation, including stability in suspension
and suitability for administration orally or via enteral tubes. It also describes the
pharmacokinetic profile of the esomeprazole 40-mg packet compared with that of
existing solid dosage forms (capsules and tablets) in a clinical bioequivalence study. In
these analyses, the packet (sachet) formulation of esomeprazole was chemically stable in
suspension and when administered orally and via enteral tubes. The formulation had a
short reconstitution time, remaining fully dispersed in water for at least 30 mins, and was
dispersed in applesauce, apple juice, or orange juice without compromising its stability or
dispersion characteristics. The packet formulation met the regulatory definition for
bioequivalence to the tablet and capsule formulations.44

Baldi F. et al. developed a lansoprazole fast disintegrating tablet a new, patient-
friendly and more convenient formulation of lansoprazole which can be taken with or
without water is the first PPI to be made available as an orally disintegrating tablet. It
represents an innovative DDS, comprising enteric-coated microgranules of lansoprazole
compressed with an inactive, rapidly dispersing matrix to form a tablet. When the tablet
is placed on the tongue and sucked gently it disintegrates rapidly in the mouth, releasing
the enteric-coated microgranules which are swallowed with the patient‘s saliva without
water. Alternatively, the tablet can be swallowed with a drink of water. Studies have
shown that the bioavailability of lansoprazole fast disintegrating tablet is comparable to
lansoprazole capsules, at both 15 and 30 mg doses; the indications and recommended
dosages for lansoprazole fast disintegrating tablet are therefore identical to lansoprazole
capsules. The new formulation may be of particular benefit to those with active life-styles
who do not always have water available, patients who have difficulty in swallowing, and
elderly patients. The new formulation will offer greater flexibility in the prescribing of
lansoprazole, may improve patient compliance with treatment, and may be of particular
benefit to patients who have difficulty in swallowing and elderly patients. Future studies,
comparing the two lansoprazole formulations in different clinical settings, will provide
more information on the real advantages offered by LFDT.45
Silver DI. et al. invented an enteric coated sub-tablets in an orally disintegrating
tablet which comprises of. An inner core, such as, sugar particles or granules, which can
be spherical or any other useful shape, coated with a drug, preferably, an acid sensitive
drug, such as lansoprazole, where the drug layer preferably comprises a film forming
agent, such as hydroxypropyl methylcellulose and an excipient, such as talc, preferably,

extra fine talc, in addition to the drug. The ―first coating layer,‖ Subcoat I, which is
totally free of both any alkaline stabilizing agent and the drug, where the inert first
coating layer preferably comprises a film forming agent, such as hypromellose, and an
excipient, such as talc, preferably, extra fine talc. Subcoat II which is also called as
―alkaline stabilizing layer,‖ that comprises an alkaline stabilizing agent, such as
magnesium carbonate, and can further comprise a film forming agent, such as
hypromellose. The outermost layer which is also called as ―outer coating,‖ that comprises
an enteric coating where the enteric coating is preferably polymeric, such as methacrylic
copolymer, e.g., those solid under the trade name eudragit.46
Kundu S. and Sahoo PK. in their article noted that OrDTs are formulated to
improve patient compliance and convenience. It offers as a good alternative drug delivery
for geriatric and paediatric patient. OrDTs are prepared by various technologies and so
formulation scientists have more alternatives to choose the best technology according to
the specific drug profile. OrDT administration is easy for patients who have problems of
deglutition or for those persons who would like their treatment without simultaneous
ingestion of liquid. In addition of the above advantages it gives pharmacokinetic
parameters which are equivalent to those obtainable with existing tablets or gel
capsules.47
Kumaresan C. et al. demonstrated different ways for the formulation of the oral
dispersible tablets and how the product performance depends on the drug suitability and
excipients selection in the delivery system. He described the ideal characteristics of the

drug and excipients required to be employed in the formulation of oral dispersible tablets
and taste masking methods and manufacturing methods48
Hirani JJ. et al. illustrated various different applications of OrDTs and their use
in today‘s pharmaceutical market. They also highlighted the various novel patented
procedures for the manufacturing of OrDTs along with their inventors and their
advantages and disadvantages. They also highlighted the challenges likely to be faced by
the formulator in the formulation of OrDT, along with criteria for the selection of the
drug.49
Fu Fu. et al. showed how the popularity of FDTs has increased tremendously
over the last decade. There are about 40 drugs that have been formulated and marketed as
FDTs using various technologies. The key to FDT formulations is fast disintegration,
dissolution, or melting in the mouth and this can be achieved by producing the porous
structure of the tablet matrix or adding superdisintegrant and/or effervescent excipients.
FDTs prepared by direct compression usually have good mechanical properties, and the
strength can be enhanced further by subsequent treatment, such as moisture treatment.
The clinical studies show FDTs can improve patient compliance, provide a rapid onset of
action, and increase bioavailability. Considering the many benefits of FDTs, it is only a
matter of time until a majority of oral formulations are prepared in FDT forms.50
Fini A. et al. prepared eight formulations containing ibuprofen in the form of
orally disintegrating tablets. Rapid-disintegrant tablets transform into easy-to-swallow
suspension on contact with the saliva, after ingested in mouth. These are particularly
useful for pediatric or geriatric patients, can be taken without liquids and facilitate

treatment of emergent pain, irrespective of the place and situation where it may arise. The
developed formulations have suitable characteristics that distinguish them from common
solid dosage forms, such as rapid disaggregation, combining advantages of both liquid
and conventional tablet formulations, ease of swallowing and possible taste-masking
components for an acceptable taste in the mouth. The presence of a superdisaggregant
makes it possible to produce sufficiently hard tablets that still disaggregate within
seconds and most of the developed tablets can be considered as ‗‗fast dispersible‖. They
can also be programmed not only for oral dispersibility, but also for delayed release, with
dissolution of the drug taking place far from the buccal district. Finally these tablets can
be prepared by means of a conventional tabletting technique and are designed to exert a
control of the side effects of the drug at gastric level. Formulations containing Kollidon
CL as superdisintegrant can represent examples of fast dispersible/slow releasing tablets
that offer an alternative to traditional tablets for orally dispersible ibuprofen tablets.51
Schiermeier S. et al formulated fast dispersible tablets that disintegrate either
rapidly in water, to form a stabilized suspension, or disperse instantaneously in the mouth
to be swallowed without the aid of water. A direct compression method was used to
prepare these two types of tablets containing coated ibuprofen as a high dosed model
drug. The properties of the water dispersible tablet, such as porosity, hardness,
disintegration time and increase in viscosity after dispersion, were investigated. The
selected tablet formulation, containing 26% galactomannan and 5% CP, disintegrates
before the galactomannan starts to swell. These tablets disperse in water within 40 s and
show a crushing strength of 95 N. To develop an ODTs, a rotatable central composite
design was applied to predict the effects of the quantitative factors mannitol and CP as

well as compression force on the characteristics of the tablet. Special emphasis was paid
to the development of a wetting test, replacing the normal disintegration method. An
optimum tablet formulation, containing 34% mannitol and 13% CP, provides a short
wetting time of 17 sec and a sufficient crushing strength of 40 N. It was concluded that
fast dispersible tablets with acceptable hardness and desirable taste could be prepared
within the optimum region.52
Venkatesh GM. et al. invented a coated multi-particulate pharmaceutical dosage
form such as an OrDT presentation for delivering atomoxetine or a pharmaceutically
acceptable salt thereof, a selective norepinephrine reuptake inhibitor indicated for the
treatment of ADHA, into the body to maintain a therapeutically effective amount of
atomoxetine in the plasma. The dosage form may comprise one or more populations of
coated atomoxetine-contaoning particles (beads, pellets, granules etc.) providing a pre-
designed rapid release profile after a predesigned lag-time of about 0 to 6 hours following
oral administration.53
Puttewar TY. et al. illustrated how organoleptic characteristics of pharmaceutical
products, i.e., mainly appearance, odour and taste are essential factors in assessing the
consumer acceptability. Thus taste masking of oral pharmaceuticals has become a
potential tool to improve patient compliance and commercial success of the product. Ion
exchange resins are solid and suitably insoluble high molecular weight polyelectrolytes
that can exchange their mobile ions of equal charge with the surrounding medium. The
resulting ion-exchange is reversible and stoichiometric with the displacement of one ionic
species by another. They developed Doxilamine ODTs with considerable increase in drug

release as compared to marketed formulations; seven formulations were developed and
studied. To prevent bitter taste and unacceptable odour of the drug, the drug was taste
masked with weak cation exchange resins like Indion 234, Indion 204 and Indion 414.
They characterised the drug according to different compendial methods, on the basis of
identification by UV spectroscopy, pH, organoleptic properties and other tests. Among
the three resins, they selected one resin for further studies i.e., Indion 234, because of
high drug loading capacity. Drug–resin complex was prepared using batch method and
effect of various processing parameters viz. drug–resin ratio, pH, temperature and drug
conc. was studied to optimize the loading conditions54
Okuda Y. et al. took the challenge to design a new orally disintegrating tablet
(ODT) that has high tablet hardness and a fast oral disintegration rate using a new
preparation method. To obtain rapid disintegration granules (RDGs), a saccharide, such
as trehalose, mannitol, or lactose, was spray-coated with a suspension of corn starch
using a fluidized-bed granulator (suspension method). As an additional disintegrant, CP,
light anhydrous silicic acid, or hydroxypropyl starch was also included in the suspension.
The RDGs obtained possessed extremely large surface areas, narrow particle size
distribution, and numerous micro-pores. When tabletting these RDGs, it was found that
the RDGs increased tablet hardness. The newly developed ODT was found to have
superior properties as an ODT, comparatively high hardness of tablet, and fast oral
disintegration rate. As the method to prepare this ODT (suspension method) is simple and
does not requires the special equipment, this technology is expected to provide better
ODTs for many kinds of drugs that can improve the quality of life of patients.55

Shoukri RA. et al. developed a lyophilized ODT that enhanced the in vitro
dissolution and in vivo absorption of nimesulide, which is a drug with poor solubility and
poor bioavailability. The ODTs were prepared by freeze-drying an aqueous dispersion of
nimusulide containing a matrix former, a sugar alcohol, and a collapse protectant. In
addition, different disintegration accelerators were tested. The influence of formulation
parameters on the disintegration time and in vitro dissolution of nimesulide from ODTs
along with other tablet characteristics was investigated. Results obtained from
disintegration and dissolution studies showed that lyophilized ODTs disintegrated within
few seconds and showed significantly faster dissolution rate of nimesulide compared to
the plain powder drug and nimesulide in commercially available immediate release tablet.
They demonstrated that an orally rapidly disintegrating tablet of nimesulide is a
promising formulation resulting in nimesulide being rapidly dissolved and effectively
absorbed into the blood stream with significantly higher bioavailability when compared
to standard immediate releasing oral dosage form. The study suggests that ODT
formulation developed in this work may be an alternative to conventional formulations of
nimesulide.56
Kuno Y. et al. proposed a new tablet preparation method that employs the phase
transition of sugar alcohols. In this method, tablets where produced by compressing a
powder containing two sugar alcohols with high and low melting points, and subsequent
heating at a temperature between the high and low melting points. A combination of two
sugar alcohols and the heating process is needed to prepare RDT with sufficient hardness.
Tablet hardness is related to the increase of inter-particle bonds or the bonding surface
area in tablets induced by the phase transition of the lower melting point sugar alcohol.57

4. METHODOLOGY
4.1 PLAN OF WORK
1. Design of ODTs formulations: By direct compression
2. Evaluation for the precompression parameters:
 Bulk density
 Tapped density
 Angle of repose
 Carr‘s Inndex
 Hausner‘s ratio
3. Evaluation of ODTs formulations:
 Colour
 Shape
 Hardness
 Friability
 Tablet thickness
 Weight variation
 Drug content uniformity
 In vitro dispersion time
 In vitro dissolution rate
4. Drug-excipient interaction studies: Done by FTIR.
5. Short-term accelerated stability studies for the selected formulations.

4.2 MATERIALS USED
Table No. 4.2 Materials used with their grade and their manufacturers or suppliers.
Sr. No. Materials Grade Manufacturer/Supplier
1. Pantoprazole sodium A.G Vasudha pharma chem ltd.
2. Omeprazole sodium A.G Vasudha pharma chem ltd.
3. CP A.G K. P. Pharmaceuticals.
4. CCS A.G K. P. Pharmaceuticals.
5. SSG A.G Vara Pharma chem. ltd
6. L-HPC A.G Vara Pharma chem. ltd
7. Pregelatinized starch A.G Rosswell industries
8. Sodium Bicarbonate A.G Qualigen fine chem
9. Potassium Bicarbonate A.G Qualigen fine chem
10. Agar gum Tag powder A.G SD fine chem.
11. Gaur gum A.G SD fine chem.
12. Camphor A.G Hindustan crystals
13. Menthol A.G Hindustan crystals
14. Thymol A.G Hindustan crystals
15. Mannitol DC A.G Hebei Huaxi Pharmaceutical. China
16. Aspartame A.G Sinosweet co ltd.
17. Sodium Stearyl Fumarate A.G Rosswell industries
18. Talc A.G Fine chem. Ltd. Mumbai
19. HCl L.G Ranbaxy fine chem. Ltd
20. Ethanol L.G Ranbaxy fine chem. Ltd
Here A.G indicates Analytical grade and L.G indicates Laboratory grade

4.2.1 Proton Pump Inhibitors
For this research work Pantoprazole Sodium was used as a representative for the class
of PPIs.
Category: Antiulcer
Chemical designation: Pantporazole sodium is chemically designated as 5-
(difluromethoxy)-2-[[(3,4-dimethoxy-pyridin-2-yl) methyl] sulphinyl]benzimidazol-1-
ide, sesquihydrate.
OCH3
OCH3
F2HCO
N
N O
H
Fig. No. 4.2.1 Chemical Structure of Pantoprazole Sodium
Empirical Formula: C16H14F 2N3 NaO4S,1 H 2O
Molecular weight: 432.4.
Melting Point: Because of gradual degradation of pantoprazole sodium during heating,
the melting point cannot be determined.

Description: Pantoprazole sodium is a white to off- white power which contains not less
than 98.0 percent and not more than 102.0 percent of C16H14F 2N3 NaO4S,1 H2O
calculated on the anhydrous basis.
Solubility: Pantoprazole sodium is freely soluble in ethanol, soluble in water, and
slightly soluble in hexane.
PKa: 3.92 pyridine; 8.19 benzimidazole
pH: 1% aqueous solution has a pH of 10.05 and 10% aqueous solution has a pH of 10.85.
Storage: Store protected from light and moisture, between 2°C to 8°C.
Usual strength: 20 to 40mg.58
Clinical pharmacology:
Pantoprazole is a prodrug that requires activation in an acid environment. After
absorption into the systemic circulation, the prodrug diffuses into the parietal cells of the
stomach and accumulates in the acidic secretory canaliculi. Here, it is activated by
proton-catalyzed formation of a tetracyclic sulfenamide, trapping the drug so that it
cannot diffuse back across the canalicular membrane. The activated form then binds
covalently with sulfhydryl groups of cysteines in the H+/K+-ATPase, irreversibly
inactivating the pump molecule. Acid secretion resumes only after new pump molecules
are synthesized and inserted into the luminal membrane, providing a prolonged (up to 24-
to 48-hour) suppression of acid secretion, despite the much shorter plasma half-lives (0.5
to 2 hours) of the parent compounds. Because they block the final step in acid production,
the PPIs are effective in acid suppression regardless of other stimulating factors.

Therapeutic Uses:
It is used principally to promote healing of gastric and duodenal ulcers and to treat
GERD, including erosive esophagitis, which is either complicated or unresponsive to
treatment with H2-receptor antagonists. It is also mainstay in the treatment of
pathological hypersecretory conditions, including the Zollinger-Ellison syndrome.
Pantoprazole Sodium is FDA approved for treatment and prevention of recurrence of
nonsteroidal antiinflammatory drug (NSAID)-associated gastric ulcers in patients who
continue NSAID use. In addition, it is FDA approved for reducing the risk of duodenal
ulcer recurrence associated with H. pylori infections.
Adverse effects:
Pantoprazole sodium generally causes remarkably few adverse effects. The most
common side effects are nausea, abdominal pain, constipation, flatulence, and diarrhea.
Subacute myopathy, arthralgias, headaches, and skin rashes also have been reported. As
noted above, all PPIs are metabolized by hepatic CYPs and therefore may interfere with
the elimination of other drugs cleared by this route.
Contraindications:
Pantoprazole sodium is contraindicated in patients with a history of
hypersensitivity to pantoprazole sodium or to any constituents of the medication.

Warnings:
When gastric ulcer is suspected, the possibility of malignancy should be excluded
before therapy with pantoprazole sodium is instituted since treatment with pantoprazole
sodium may alleviate symptoms and delay diagnosis.
Use in Pregnancy: There are no adequate or well-controlled studies in pregnant women.
It should not be administered to pregnant women unless the expected benefits outweigh
the potential risks to the foetus.
Use in Nursing Mothers: It is not known whether pantoprazole sodium is secreted in
human milk. It should not be given to nursing mothers unless its use is believed to
outweigh the potential risks to the infant.
Use in Children: The safety and effectiveness of pantoprazole sodium in children has not
yet been established.
Precautions:
Carcinogenicity: Effects of long-term treatment relate to hypergastrinemia, possible
enterochromaffin-like (ECL) cell hyperplasia and carcinoid formation in the stomach,
adenomas and carcinomas in the liver and neoplastic changes in the thyroid.
Pediatric and Geriatric studies: Short-term and long-term treatment with pantoprazole
sodium in a limited number of patients up to 6 years have not resulted in any significant
pathological changes in gastric oxyntic exocrine cells. A slight increase in AUC (12%)
and Cmax (7%) for pantoprazole sodium occurs in elderly volunteers when compared to
younger volunteers. The daily dose used in elderly patients, as a rule, should not exceed
the recommended dosage regimens.

Hepatic insufficiency: The half-life increased to 7 - 9 h, the AUC increased by a factor
of 5 to 7, and the Cmax increased by a factor of 1.5 in patients with liver cirrhosis
compared with healthy subjects following administration of 40 mg pantoprazole.
Similarly, following administration of a 20 mg dose, the AUC increased by a factor of 5.5
and the Cmax increased by a factor of 1.3 in patients with severe liver cirrhosis compared
with healthy subjects.59
Renal insufficiency: No dose reduction is required when pantoprazole sodium is
administered to patients with impaired kidney function as the difference in AUCs
between patients who are dialyzed and those who are not is 4%.
Drug drug interactions: Pantoprazole sodium is metabolized in the liver via the CYP
450 system. Pharmacokinetic drug interaction studies in man did not demonstrate the
inhibition of the oxidative metabolism of the drug. Pantoprazole sodium does not interact
with carbamazepine, caffeine, diclofenac, ethanol, glibenclamide, metoprolol, antipyrine,
diazepam, phenytoin, nifedipine, theophylline, warfarin, digoxin, or oral contraceptives.
Concomitant use of antacids or consumption of food does not affect the pharmacokinetics
of pantoprazole sodium. Changes in absorption should be taken into account when drugs
whose absorption is pH dependent, e.g., ketoconazole, are taken concomitantly.
Clinical studies have shown that there is no pharmacokinetic interaction between
pantoprazole and the following antibiotic combinations: metronidazole plus
clarithromycin, metronidazole plus amoxicillin, amoxicillin plus clarithromycin.

In a preclinical study, pantoprazole in combination therapy with various
antibiotics (including tetracycline, clarithromycin, and amoxicillin) was shown to have a
potentiating effect on the elimination rate of H. pylori infection.
Others: Generally, daily treatment with any acid blocking medicines over a long time
(e.g. longer than 3 years) may lead to malabsorption of cyanocobalamin caused by hypo-
or achlorhydria. Rare cases of cyanocobalamin deficiency under acid-blocking therapy
have been reported in the literature and should be considered if respective clinical
symptoms are observed.58
Symptoms and treatment of overdosage
Some reports of overdosage with pantoprazole have been received. No consistent
symptom profile was observed after ingestion of high doses of pantoprazole. Doses of up
to 240 mg i.v. were administered and were well tolerated.
Treatment should be supportive and symptomatic. Pantoprazole is not removed by

60, 61
hemodialysis.

4.2.2 Excipient Profiles

4.2.2.1 Crospovidone
Table No. 4.2.2.1 Crospovidone
Synonyms: Crosslinked povidone; E1202; Kollidon CL; Kollidon CL-

M;Polyplasdone XL; Polyplasdone XL-10;
polyvinylpolypyrroli-done; PVPP; 1-vinyl-2-pyrrolidinone
homopolymer
Nonpropietary BP-CP, PhEur- Crospovidonum, USPNF- CP

Names:
Chemical Name and 1-Ethenyl-2-pyrrolidinone homopolymer [9003-39-8]

CAS Registry No.:
Description: White to creamy-white, finely divided, free flowing, practically

tasteless, odourless or nearly odourless, hygroscopic powder.
Structural Formula:
Empirical Formula (C6H9NO)n >10,00,000.

&Molecular Weight:
Solubility and storage Since CP is hygroscopic, it should be stored in an airtight

conditions: container in a cool, dry place.
Functional categories: Tablet disintegrant.
Applications: Used as disintegrant and dissolution agent at a conc of 2-5%.
Incompatibilities: CP when exposed to a high water level, may form molecular

adduct with some materials.

4.2.2.2 Croscarmelose sodium
Table No. 4.2.2.2 Croscarmelose Sodium
Synonyms: Ac-Di-Sol; crosslinked carboxymethylcellulose sodium;

Explocel; modified cellulose gum; Nymcel ZSX; Pharmacel
XL; Primellose; Solutab; Vivasol
Nonpropietary Names: BP-Croscramellose sodium, PhEur- Carmellosum natricum

conexum, USPNF- Croscarmellose sodium.
Chemical Name and Cellulose, carboxymethyl ether, sodium salt, cross linked
CAS Registry No.: [74811-65-7].
Description: CCS occurs as an odourless, white or greyish white powder.
Structural Formula:
Empirical Formula and The USPNF 23 describes carboxymethylcellulose calcium as

Molecular Weight: the calcium salt of a polycarboxymethyl ether of cellulose.
Solubility: Insoluble in water. Practically insoluble in acetone, ethanol.
Functional categories: Tablet and capsule disintegrant.
Use: Disintegrant in capsules 10–25 & in tablets 0.5–5.0
Applications: It is used in oral pharmaceutical formulations as a disintegrant

for capsules, tablets, and granules.
Stability and Storage It is a stable though hygroscopic material. It should be stored in
Conditions: a well closed container in a cool, dry place.
Incompatibilities: The efficacy of disintegrants may be slightly reduced when

formulations are prepared by wet-granulation process.

4.2.2.3 Sodium Starch Glycolate
Table No. 4.2.2.3 Sodium Starch Glycolate

Synonyms: Carboxymethyl starch, sodium salt; Explosol; Explotab;
Glycolys; Primojel; starch carboxymethyl ether, sodium
salt; Tablo; Vivastar P.
Nonpropietary Names: BP: Sodium starch glycollate, PhEur:Carboxymethylamylum
natricum, USPNF: SSG.
Chemical Name and Sodium carboxymethyl starch [9063-38-1]
CAS Registry No.:
Description: SSG is a white to off-white, odourless, tasteless, free-flowing

powder.
Structural Formula:
Melting point: Does not melt, but chars at approximately 200°C.
Functional categories: Tablet and capsule disintegrant.
Applications: It is commonly used in tablets prepared by either direct

compression or wet-granulation processes. The usual conc.
employed in a formulation is between 2% and 8%, with the
optimum conc. about 4%, although in many cases 2% is
sufficient.
Stability and storage SSG is stable and should be stored in a well-closed container.
properties:
Incompatibilities: SSG is incompatible with ascorbic acid.
4.2.2.4 Hydroxypropyl Cellulose, Low-Substituted

Table No. 4.2.2.4 Hydroxypropyl Cellulose, Low-Substituted

Synonyms Hyprolose, low-substituted; L-HPC
Nonpropietary Names JP: Low-substituted hydroxypropylcellulose, USPNF: Low

substituted hydroxypropyl cellulose
Chemical Name and Cellulose, 2-hydroxypropyl ether (low substituted) [78214-
CAS Registry No.: 412].
Description L-HPC occurs as a white to yellowish white powder or

granules. It is odourless and it is tasteless.
Structural Formula:
Fig: Where is R is H or [CH2CH(CH3)O]mH

Empirical Formula: (—OCH2CHOHCH3).
Grade: LH-11, LH-21, LH-31, LH-22, LH-32, LH-20, LH-30
Solubility and storage L-HPC is a stable, though hygroscopic, material. The powder
conditions: should be stored in a well- closed container.
Melting point: Its decomposition is at 275°C.
Functional categories: Tablet and capsule disintegrant; tablet binder.
Applications: It is primarily used in tableting as a disintegrant, and as a

binder in wet granulation.
Stability and Storage L-HPC is a stable, though hygroscopic, material. The powder
Conditions: should be stored in a well- closed container.
Incompatibilities: It may react with as alkaline substance.

4.2.2.5 Starch Pregelatinized
Table No. 4.2.2.5 Starch Pregelatinized

Synonyms: Compressible starch; Instastarch; Lycatab C; Lycatab
PGS; Merigel; National 78-1551; Pharma-Gel; Prejel;
Sepistab ST 200; Spress B820; Starch 1500 G; Tablitz;
Unipure LD; Unipure WG220.
Nonpropietary Names: Pregelatinised starch, PhEur: Amylum pregelificatum,
USPNF: Pregelatinized starch.
Chemical Name and Pregelatinized starch [9005-25-8].
CAS Registry No.:
Description: Pregelatinized starch occurs as a moderately coarse to

fine, white to off-white coloured powder. It is odourless
and has a slight characteristic taste.
Structural Formula:
Fig: Where is R is H or [CH2CH(CH3)O]mH

Empirical Formula: (C6H10O5) n where n = 300–1000
Solubility and storage It is practically insoluble in organic solvents. Slightly

conditions: soluble to soluble in cold water.
Moisture content: pregelatinized maize starch is hygroscopic.
Functional categories: Tablet and capsule diluent, disintegrant and tablet binder.
Applications: Pregelatinized starch is a modified starch used in oral

capsule and tablet formulations as a binder, diluent, and
disintegrant. In comparison to starch.

4.2.2.6 Sodium Bicarbonate
Table No. 4.2.2.6 Sodium Bicarbonate

Synonyms: Baking soda; E500; Effer-Soda; monosodium carbonate;
sodium acid carbonate; sodium hydrogen carbonate.
Nonpropietary Names: Sodium bicarbonate, JP: Sodium bicarbonate, PhEur: Natrii
hydrogenocarbonas, USP: Sodium bicarbonate.
Chemical Name and Carbonic acid monosodium salt [144-55-8]
CAS Registry No.:
Description: Sodium bicarbonate occurs as an odourless, white,

crystalline powder with a saline, slightly alkaline taste. The
crystal structure is monoclinic prisms
Empirical Formula: NaHCO3
Molecular Weight: 84.01
Solubility: It is practically insoluble in Ethanol (95%) and Ether,

soluble in Water.
Moisture content: The moisture content is less than 1% w/w. Above 85%
relative humidity it rapidly absorbs excessive amounts of
water and may start to decompose with loss of CO2.
Functional categories: Alkalizing agent; therapeutic agent.
Uses: Buffer in tablets 10–40 (%); Effervescent tablets 25–50 (%);

Isotonic injection/infusion 1.39 (%).
Melting point: 270°C (with decomposition).
Applications: It is generally used in pharmaceutical formulations as a
source of carbon dioxide in effervescent tablets and
granules. It is also widely used to produce or maintain an
alkaline pH in a preparation. Additionally, sodium
bicarbonate is used in solutions as a buffering agent.

4.2.2.7 Potassium Bicarbonate
Table No. 4.2.2.7 Details about Potassium Bicarbonate

Synonyms: Carbonic acid monopotassium salt; E501; monopotassium
carbonate; potassium acid carbonate; potassium hydrogen
carbonate.
Nonpropietary Names: BP: Potassium bicarbonate, PhEur: Kalii hydrogenocarbonas,
USP: Potassium bicarbonate.
Chemical Name and Potassium bicarbonate [298-14-6]
CAS Registry No.:
Description: Potassium bicarbonate occurs as colourless, transparent

crystals or as a white granular or crystalline powder. It is
odourless, with a saline or weakly alkaline taste.
Empirical Formula: KHCO3
Solubility: Soluble 1 in 4.5 of water at 0°C, 1 in 2.8 of water at 20°C, 1

in 2 of water at 50°C; practically insoluble in ethanol (95%).
Functional categories: Alkalizing agent; therapeutic agent.
Applications: Used as an excipient, generally used in formulations as a

source of carbon dioxide in effervescent preparations, at conc.
of 25- 50% w/w. It is of particular use in formulations where
sodium bicarbonate is unsuitable, for example, when the
presence of Na+ ions in a formulation needs to be limited or is
undesirable.
Storage: Potassium bicarbonate should be stored in a well-closed
container in a cool, dry location.
Incompatibilities: Potassium bicarbonate reacts with acids and acidic salts with
the evolution of carbon dioxide.

4.2.2.8 Tag Powder (Treated Agar Powder)
Table No. 4.2.2.8 Tag Powder, Agar

Synonyms: Agar-agar; Bengal isinglass; Ceylon isinglass; Chinese
isinglass; E406; gelosa; gelose; Japan agar; Japan isinglass;
layor carang.
Nonpropietary Names: JP: Agar, PhEur: Agar, USPNF: Agar.
Chemical Name and Agar [9002-18-0]

CAS Registry No.:
Description: It occurs as transparent, odourless, tasteless strips or as a

coarse or fine powder. It may be weak yellowish-orange,
yellowish-gray to pale-yellow coloured, or colourless. Agar is
tough when damp, brittle when dry.
Structural Formula: Agar is a dried, hydrophilic, colloidal polysaccharide complex

extracted from the agarocytes of algae of the Rhodophyceae. The
structure is believed to be a complex range of polysaccharide chains
having alternating linkages.
Solubility: It is soluble in boiling water to form a viscous solution

practically insoluble in ethanol (95%), and cold water. A 1%
w/v aqueous solution forms a stiff jelly on cooling.
Functional categories: Emulsifying agent; stabilizing agent; suppository base;
suspending agent; sustained-release agent; tablet binder;
thickening agent; viscosity-increasing agent.
Applications: Agar is widely used as a stabilizing agent. It is used in a
handful of oral tablet and topical formulations. It has also been
investigated for possessing sustained-release activity in gels,
beads, microspheres, and as a disintegrant in tablets.
Storage: It is mostly stable at pH 4–10 and should be stored in a cool,
dry, place.

4.2.2.9 Guar Gum
Table No. 4.2.2.9 Guar Gum

Synonyms: E412; Galactosol; guar flour; jaguar gum; Meyprogat; Mey-
prodor; Meyprofin.
Nonpropietary Names: BP: Guar galactomannan, PhEur: Guar galactomannanum,
USPNF: Guar gum.
Chemical Name and Galactomannan polysaccharide [9000-300]
CAS Registry No.:
Description: Gaur gum occurs as transparent, odourless, tasteless strips or

as a coarse or fine powder. It may be weak yellowish-orange,
yellowish-gray to pale-yellow coloured, or colourless.
Emperical Formula: (C6H12O6)n =220 000
Structural Formula: It consists of linear chains of (1→4)-b-D-mannopyranosyl

units with a-D-galactopyranosyl units attached by (1→6)
linkages. The ratio of D-galactose to D-mannose is between 1
: 1.4 and 1 : 2.
Solubility: It is practically insoluble in organic solvents. In cold or hot
water, guar gum disperses and swells almost immediately to
form a highly viscous, thixotropic sol. The optimum rate of
hydration occurs at ph 7.5–9.0. Finely milled powders swell
more rapidly and are more difficult to disperse. Two to four
hours in water at room temperature are required to develop
maximum viscosity.
Functional categories: Suspending agent; tablet binder; tablet disintegrant; viscosity-
increasing agent.
Use: It is used as emulsion stabilizer up to 1%, tablet binder Up to
10%, thickener for lotions and creams Up to 2.5%
Applications: Guar gum is a galactomannan, commonly used in cosmetics,
food products, and pharmaceutical formulations. It has also
been investigated in the preparation of sustained-release
matrix tablets in the place of cellulose derivatives such as
methylcellulose
Storage: Guar gum powder should be stored in a well-closed container
in a cool, dry place.

4.2.2.10 Menthol
Table No. 4.2.2.10 Menthol

Synonyms: Hexahydrothymol; 2-isopropyl-5-methylcyclohexanol; 4-
isopropyl-1-methylcyclohexan-3-ol; 3-p-menthanol; p-
menthan 3-ol; dl-menthol; peppermint camphor;
Nonpropietary Names: BP: Racementhol, JP: dl-Menthol, PhEur: Mentholum
racemicum, USP: Menthol.
Chemical Name and (1RS,2RS,5RS)-()-5-Methyl-2-(1 methylethyl)cyclohexanol
CAS Registry No.: [15356-70-4] Note that the following CAS No.s have also
been used: [1490-04-6] and [89-78-1].
Description: Racemic menthol is a mixture of equal parts of the
(1R,2S,5R)- and (1S,2R,5S)-isomers of menthol.
Emperical Formula: C10H20O
Structural Formula:
.
Solubility: Very soluble in ethanol (95%), chloroform, ether, fatty oils
and liquid paraffin; soluble in acetone and benzene; very
slightly soluble in glycerin; practically insoluble in water.
Functional categories: Flavouring agent; therapeutic agent.
Melting point: 34°C.
Applications: It is widely used as a flavouring agent or odour enhancer. It

exerts a cooling or refreshing sensation that is exploited in
many topical preparations.
Storage: Menthol should be stored in a well-closed container at a
temperature not exceeding 25°C, since it sublimes readily.

4.2.2.11 Thymol
Table No. 4.2.2.11 Thymol
Synonyms: Acido trimico; 3-p-cymenol; p-cymen-3-ol; Flavinol; 3-

hydroxy-p-cymene; 3hydroxy-1-methyl-4-isopropylbenzene.
Nonpropietary Names: Thymol, Thymolum
Chemical Name and Thymol [89-83-8]

CAS Registry No.:
Description: It occurs as colourless or often large translucent crystal, or as

a white crystalline powder and have a pungent caustic taste.
Structural Formula:
.
Solubility: Soluble in chloroform, ethanol (95%), ether, glacial acetic
acid, olive oil, water. Freely soluble in essential oils, fixed
oils, and fats. Sparingly soluble in glycerine.
Functional categories: Flavouring agent; therapeutic agent.
Use: Menthol is used as Inhalation 0.02–0.05 %, as an Oral

suspension 0.003%, Oral syrup 0.005–0.015%, Tablets 0.2–
0.4%, Topical formulations 0.05–10.0%, Toothpaste 0.4%,
Mouthwash 0.1–2.0%, Oral spray 0.3%.
Storage: Thymol should be stored in well-closed, light-resistant
containers, in a cool, dry, place. Thymol is affected by light.

4.2.2.12 Camphor
Table No. 4.2.2.12 Camphor

Synonyms: 2-bornanone,2-camphanone bornan-2-one, Formosa.
Nonpropietary Names: Camphor
Chemical Name and 1,7,7-trimethylbicyclo [2.2.1]heptan-2-one [464-48-2]

CAS Registry No.:
Description: White or colourless crystals.
Structural Formula:
.
Functional categories: Flavourings agent; therapeutic agent.
Applications: Modern uses include camphor as a plasticizer for

nitrocellulose, as a moth repellent, as an antimicrobial
substance.
Storage: Camphor should be stored in well-closed, light-resistant
containers, in a cool, dry, place.

4.2.2.13 Directly Compressible Mannitol
Table No. 4.2.2.13 Directly Compressible Mannitol

Synonyms: Cordycepic acid; C PharmMannidex; E421; manna sugar;
D-mannite; mannite; Mannogem; Pearlitol.
Nonpropietary BP: Mannitol, JP: D-Mannitol, PhEur: Mannitolum,
Names: USP:Mannitol
Chemical Name and D-Mannitol [69-65-8]

CAS Registry No.:
Description: It occurs as a white, odourless, crystalline powder/ granules. It

has a sweet taste, approximately as sweet as glucose and half
as sweet as sucrose, and imparts a cooling sensation in the
mouth.
Emperical Formula: C6H14O6.
Structural Formula:
.
Functional Diluent; diluent for lyphilized preparations; sweetening agent;
categories: tablet and capsule diluent; tonicity agent.
Use: Menthol is used as Inhalation 0.02–0.05 %, as an Oral

suspension 0.003%, Oral syrup 0.005–0.015%, Tablets 0.2%.
Applications: It is primarily used as a diluent (10–90%) in tablet
formulations.
Storage: Mannitol is stable in the dry state and in aqueous solutions.
The bulk material should be stored in a well-closed container

4.2.2.14 Aspartame
Table No. 4.2.2.14 Aspartame

Synonyms: 3-Amino-N-(a-carboxyphenethyl)succinamic acid N-methyl
ester; 3-amino-N-(a-methoxycarbonylphenethyl)succinamic
acid; APM;
Nonpropietary BP: Aspartame, PhEur: Aspartamum, USPNF: Aspartame
Names:
Chemical Name and N-a-L-Aspartyl-L-phenylalanine 1-methyl ester [22839-47-0]

CAS Registry No.:
Description: Aspartame occurs as an off white, almost odourless crystalline

powder with an intensely sweet taste.
Emperical Formula: C14H18N2O5.
Structural Formula:
.
Functional Sweetening agent.
categories:
Solubility: Slightly soluble in ethanol (95%); sparingly soluble in water.
Applications: Aspartame is used as an intense sweetening agent in beverage

products, food products, and table-top sweeteners, and in
pharmaceutical preparations including tablets, powder mixes,
and vitamin preparations. It is 180–200 times that of sucrose.
Storage: Aspartame is stable in dry conditions and should be stored in
a well-closed container, in a cool, dry place.

4.2.2.15 Talc
Table No. 4.2.2.15 Talc

Synonyms: Altalc; E553b; hydrous magnesium calcium silicate;
hydrousmagnesium silicate; Luzenac Pharma; magnesium
hydrogen metasilicate; Magsil Osmanthus; Magsil Star;
powdered talc; purified French chalk; Purtalc; soapstone;
steatite; Superiore.
Nonpropietary Names: BP: Purified talc, JP: Talc, PhEur: Talcum, USP: Talc
Chemical Name and Talc [14807-96-6]

CAS Registry No.:
Description: Talc is a very fine, white to greyish-white, odourless,

impalpable, unctuous, crystalline powder. It adheres readily to
the skin and is soft to the touch and free from grittiness.
Emperical Formula: Talc is a purified, hydrated, magnesium silicate,

approximating to the formula Mg6(Si2O5)4(OH)4. It may
contain small, variable amounts of aluminium silicate and
iron.
Functional categories: Anticaking agent; glidant; tablet and capsule diluent; tablet
and capsule lubricant.
Use: Used as dusting powder 90.0–99.0%, as a glidant and tablet
lubricant 1.0–10.0, tablet and capsule diluent 5.0–30.0
Solubility: Practically insoluble in dilute acids and alkalis organic
solvents, and water.
Applications: It is widely used as a dissolution retardant in the development
of controlled-release products. Talc is also used as a lubricant
in tablet formulations; in a novel powder coating for
extended-release pellets. Talc is used as a dusting powder,
Storage: Talc should be stored in a well-closed container in a cool, dry
place

Table No. 4.2.2.16 Sodium Stearyl Fumarate

Synonyms: Fumaric acid, octadecyl ester, sodium salt; Pruv; sodium
monostearyl fumarate.
Nonpropietary Sodium stearyl fumarate, PhEur: Natrii stearylis fumaras,
Names: USPNF: Sodium stearyl fumarate.
Chemical Name and 2-Butenedioic acid, monooctadecyl ester, sodium salt [4070-
CAS Registry No.: 80-8].
Description: Sodium stearyl fumarate is a fine, white powder with

agglomerates of flat, circular-shaped particles.
Emperical Formula: C22H39NaO4.
Structural Formula:
Functional Tablet and capsule lubricant.

categories:
Use: It is used as lubricant and also as a glident.
Solubility: Practically insoluble in acetone, chloroform, ethanol. Slightly

soluble in methanol. Solubility in water is 1 in 20 000 at
25°C, 1in10at80°C and 1 in 5 at 90°C,
Melting point: 224–245°C (with decomposition)
Applications: It is widely used as lubricant and also as a glident in tablet or
capsule formulations.
Storage: The bulk material should be stored in a well-closed container

4.3 INSTRUMENTS
Table No. 4.3 Instruments used for the research work

Sr. Instruments Manufacturer
No.
1. Electronic Weighing Balance (Model Essae-Teraoka Ltd

No. IND/09/2001/28)
2. UV-Vis Spectrophotometer (UV-1800) Shimadzu, Japan.
3. FTIR Spectrophotometer (8400S) Shimadzu, Japan.
4. Disintegration Test Apparatus ED-2L Electrolab.
5. Dissolution test apparatus TDT-08T Electrolab.
6. Digital Vernier Caliper Mitutoyo, Japan.
7. Digital pH meter 7007 Dgisun Electronics Hyderabad.
9. Test Sieve Scientific Engineering Corp. Delhi.
10. Hot Air Oven Servewell Instrument (P) Ltd,

Bangalore.
11. Stability Chamber Lab Control Equipment Co. Mumbai.
12. Friabilator USP EF-2 Electrolab.
13. Tablet punching machine, (Rimek mini Karnavati Engineering Ltd, Mehsana ,
press-1) 10- station Gujarat.
14. Monsanto Hardness Tester Ketan engineering Ltd, Mumbai
15. Tap density tester ETD 1020 Electrolab

4.4. STUDIES UNDER TAKEN
4.4.1 Preformulation studies
The goals of preformulation studies are to choose the correct form of the drug
substance, evaluate its physical and chemical properties, and generate a thorough
understanding of the material‘s stability under the conditions that will lead to the
development of a particular DDS. Preformulation is a science that serves as a big
umbrella for the fingerprinting of a drug substance or product both at the early and latter
stage of development in pharmaceutical manufacturing. The preformulation phase is a
critical learning time about candidate drugs. Typically, it begins during the lead
optimization phase and continues through prenomination and into the early phases of
development. Decisions made on the information generated during this phase can have a
profound effect on the subsequent development of those compounds.62
The goals of the preformulation study are:
 To establish the necessary physicochemical characteristics of a new drug
substance.
 To determine its kinetic release rate profile.
 To establish its compatibility with different excipients.
Hence, preformulation studies on the obtained sample of drug include colour, taste,
solubility analysis, melting point determination and compatibility studies.

4.4.1.1 Identification of Pantoprazole
4.4.1.1.1 Melting point determination
Melting point of Pantoprazole sodium was set to determine by open cup capillary
method.
4.4.1.1.2 Infrared absorption spectrum
The infrared absorption spectrum of Pantoprazole was recorded with a KBr disc
over the wave No. 4000 to 400 cm-1.
4.4.1.2 Preparation of standard calibration curve
4.4.1.2.1 Preparation of standard calibration curve of Pantoprazole sodium in 0.1 N

Hydrochloric acid
Procedure
1 gm of sodium bicarbonate was accurately weigh and transferred it in to 100 ml
amber coloured volumetric flask and dissolved in small quantity of 0.1 N HCl. To this a
solution 100mg of Pantoprazole sodium dissolved in approximately 2-5 ml of water was
added. The volume was made up with the 0.1 N HCl to get a conc. of 1000µg/ml
[Standard Stock -I (SS-I)].
From this 1ml was withdrawn and diluted to 100ml to get a conc. of 10µg/ml (SS-
II). From SS-II aliquots of 2ml, 4ml, 6ml, 8ml and 10ml were pipetted into 10ml
volumetric flasks. The volume was made up with 0.1 N HCl to get the final Conc. of 2, 4,
6, 8, 10 µg/ml respectively. When this solution was scanned in the UV range i.e. from
200nm to 800nm λmax was found to be 281.5 nm for Pantoprazole sodium in 0.1N HCl as
a blank in UV-Visible Spectrophotometer (UV-1800 Shimadzu). The absorbance (abs) of
each conc. was measured at 281.5 nm.

The same solution was stored at room temperature and abs of the solutions was
measured at 281.5 nm using UV-visible spectrophotometer after every half hour.
Beer’s range: 2- 100µg/ml.
The conc. was calculated using the following formula:
Conc =
4.4.1.2.2 Preparation of standard calibration curve of Omeprazole sodium in 0.1 N

Hydrochloric acid
Procedure
1 gm of sodium bicarbonate was accurately weigh and transferred it in to 100 ml
amber coloured volumetric flask and dissolved in small quantity of 0.1 N HCl. To this a
solution 100mg of Omeprazole sodium dissolved in approximately 2-5 ml of water was
added. The volume was made up with the 0.1 N HCl to get a conc. of 1000µg/ml
[Standard Stock -I (SS-I)].
From this 1ml was withdrawn and diluted to 100ml to get a conc. of 10µg/ml (SS-
II). From SS-II aliquots of 2ml, 4ml, 6ml, 8ml and 10ml were pipetted into 10ml
volumetric flasks. The volume was made up with 0.1 N HCl to get the final conc. of 2, 4,
6, 8, 10 µg/ml respectively. When this solution was scanned in the UV range i.e. from
200nm to 800nm λmax was found to be 301nm for Omeprazole sodium in 0.1N HCl as a
blank in UV-Visible Spectrophotometer (UV-1800 Shimadzu). The abs of each conc. was
measured at 301 nm.
The same solution was stored at room temperature and abs of the solutions was
measured at 301 nm using UV-visible spectrophotometer after every half hour.

Beer’s range: 2- 100µg/ml.
The conc. was calculated using the following formula:
Conc=
4.4.1.3 Compatibility studies of drug and polymers
4.4.1.3.1 FTIR Studies
Compatibility of the pantoprazole with superdisintegrants and other polymers
used to formulate ODTs where studied by FTIR analysis. FTIR spectral analysis of
pantoprazole sodium, superdisintegrants and excipients and combination of the
pantoprazole sodium and superdisintegrants and excipients were carried out to investigate
the changes in chemical composition of the drug after combining it with the excipients.
The compatibility study on IR was carried by Shimadzu 8400S IR spectra of pure
pantoprazole sodium, superdisintegrants, physical mixtures and optimized formulation
were obtained by adding potassium bromide 100 times the quantity of the sample to be
studied.
4.4.2. Post formulation Studies
4.4.2.1 Formulation of Orodispersible Tablets of Pantoprazole Sodium
Pantopraozle sodium ODT where prepared by using three approaches of Direct
Compression method.
Approach 1: Super disintigrant addition method.
Approach 2: Combination of different superdisintegrants method.
Approach 3: Sublimation method.

Approach 4: Combination of superdisintegrants and sublimationmethod.
Approach 5: Treated Natural gums used as superdisintegrants.
4.4.2.1.1 Preparation of Pantoprazole Orodispersible tablets using Superdisintegrant
addition method
Pantoprazole ODTs were prepared by direct compression. All the ingredients
were passed through 60# mesh sieve separately and collected. The drug was weighed
along with the other excipients and was mixed in geometrical order. This mixture was
shaken for few mins to ensure proper mixing of all the ingredients. The tablets were
compressed using flat face 16.4 X 8 mm flat oval shaped punch to get tablets of 1300 mg
weight using ten stations Rimek tablet compression machine (Karnavati Engineering Ltd.
Ahmadabad, India).
4.4.2.1.2 Preparation of Orodispersible tablets using combination of different

superdisintegrants method
In this approach pantoprazole Sodium ODTs were prepared by direct compression
using a combination of two different superdisintegrants in the ratio of 1:1. All the
ingredients were passed through 60# mesh sieve separately and collected. The drug was
weighed along with the other excipients and was mixed in geometrical order. This
mixture was shaken for few mins to ensure proper mixing of all the ingredients. The
tablets were compressed using flat face 16.4 X 8 mm flat oval punch to get tablets of
1300 mg weight using ten stations Rimek tablet compression machine (Karnavati
Engineering Ltd. Ahmadabad, India).

4.4.2.1.2 Preparation of Orodispersible tablets using sublimation method
Sublimating agents resulted in rapid disintegration of tablets due to the
phenomenon of sublimating which improves dissolution. Pantoprazole sodium ODTs
were prepared by direct compression.63 All the ingredients were passed through 60# mesh
sieve separately and collected. The drug was weighed along with the other excipients and
was mixed in geometrical order. This mixture was shaken for few mins to ensure proper
mixing of all the ingredients. The tablets were compressed using flat face 16.4 X 8 mm
flat oval size punches to get tablets of 1300 mg weight using ten stations Rimek tablet
compression machine (Karnavati Engineering Ltd. Ahmadabad, India). The tablets were
dried at 600 C in oven till constant weight was obtained.
4.4.2.1.4 Preparation of Orospersible tablets using combination of superdisintegrants

and sublimation method
Pantoprazole ODTs were prepared by direct compression. In this approach one
superdisintegrants and one sublimating agents where used. All the ingredients were
passed through 60# mesh sieve separately and collected. The drug was weighed along
with the other excipients and was mixed in geometrical order. This mixture was shaken
for few mins to ensure proper mixing of all the ingredients. The tablets were compressed
using flat face 16.4 X 8 mm flat oval shaped punch to get tablets of 1300 mg weight
using ten stations Rimek tablet compression machine (Karnavati Engineering Ltd.
Ahmadabad, India).

4.4.2.1.5 Treated natural gums used as superdisintegrants
Natural gums are getting a lot of importance due to their properties.
Treated agar gum (TAG) powder has shown having superdisintegration property.
Pantoprazole sodium ODTs using natural gums as superdisintegrants were prepared by
direct compression. The gums like agar, gaur gum, gum acacia etc where taken.
10gm of the gums was accurately weighed and added to 250 ml beaker containing
100 ml distilled water and then stirred for few minis. This was kept aside for 2 days and
then dried until it form dry powered. This mass was pulverised and pass throw 60# sieve.
All the other ingredients were also passed through 60# mesh sieve separately and
collected. The drug was weighed along with the other excipients and was mixed in
geometrical order. This mixture was shaken for few mins to ensure proper mixing of all
the ingredients. The tablets were compressed using flat face 16.4 X 8 mm flat oval size
punch to get a tablets of 1300 mg weight using ten station Rimek tablet compression
machine (Karnavati Engineering Ltd. Ahmadabad, India)

Table No. 4.4.2.1.1 Formulations of Orodispersible tablets using superdisintigrant addition method
Sr. Ingredients Quantity used in mg
No
F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 F13 F14 F15 F16
1. Pantoprazole 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20
2. CP - 13 39 65 - - - - - - - - - - - -
3. SSG - - - - 13 39 65 - - - - - - - - -
4. CCS - - - - - - - 13 39 65 - - - - - -
5. L-HPC - - - - - - - - - - 13 39 65 - - -
6. Pregelatinized Starch - - - - - - - - - - - - - 13 39 65
7. Treated Agar - - - - - - - - - - - - - - - -
8. Treated Gaur - - - - - - - - - - - - - - - -
9. Aspartame 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52
10. Mannitol DC 77.5 64.5 38.5 12.5 64.5 38.5 12.5 64.5 38.5 12.5 64.5 38.5 12.5 64.5 38.5 12.5
11. Talc 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26
12. SSF 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13
13. Sodium Bicarbonate 585 585 585 585 585 585 585 585 585 585 585 585 585 585 585 585
14. Potassium Bicarbonate 520 520 520 520 520 520 520 520 520 520 520 520 520 520 520 520
15. Flavour 6.5 6.5 6.5 6.5 6.5 6.5 6.5 6.5 6.5 6.5 6.5 6.5 6.5 6.5 6.5 6.5

Table No.4.4.2.1.2 Formulations of Orodispersible tablets using combination of

superdisintigrants
Sr. Chemical Used Quantity used in mg
No. F17 F18 F19 F20
1. Pantoprazole 20 20 20 20
2. CP - 32.5 32.5 32.5
3. SSG 32.5 32.5 - -
4. CCS 32.5 - 32.5 -
5. L-HPC - - - 32.5
6. Aspartame 52 52 52 52
7. Mannitol DC 12.5 12.5 12.5 12.5
8. Talc 26 26 26 26
9. SSF 13 13 13 13
10. Sodium bicarbonate 585 585 585 585
11. Potassium bicarbonate 520 520 520 520
12. Flavour 6.5 6.5 6.5 6.5
Table No 4.4.2.1.3 Formulations of Orodispersible tablets using subliming agent.

Quantity used in mg
Sr.No. Chemical used
F21 F22 F23
1. Pantoprazole 20 20 20
2. Camphor 65 - -
3. Menthol - - 65
4. Thymol - 65 -
5. Aspartame 52 52 52
6. Mannitol DC 12.5 12.5 12.5
7. Talc 26 26 26
8. Sodium steryl fumerate 13 13 13
9. Sodium bicarbonate 585 585 585
10. Potassium bicarbonate 520 520 520
11. Flavour 6.5 6.5 6.5

Table No. 4.4.2.1.4 Formulations of Orodispersible tablets using a combination of

Quantity used in mg
Sr. No. Chemical used
F24 F25
1. Pantoprazole 20 20
2. CP 32.5 32.5
3. Camphor 32.5 -
4. Menthol - 32.5
5. Aspartame 52 52
6. Mannitol DC 12.5 12.5
7. Talc 26 26
8. Sodium steryl fumerate 13 13
9. Sodium bicarbonate 585 585
10. Potassium bicarbonate 520 520
11. Flavour 6.5 6.5
Table No. 4.4.2.1.5 Formulations of Orodispersible tablets using Natural gums as

superdisintegrants.
Quantity used in mg
Sr. No. Chemical used
F26 F27
1. Pantoprazole 20 20
2. Gum Agar - 32.5
3. Gaur gum 32.5 -
5. Aspartame 52 52
6. Mannitol DC 12.5 12.5
7. Talc 26 26
8. Sodium steryl fumerate 13 13
9. Sodium bicarbonate 585 585
10. Potassium bicarbonate 520 520
11. Flavour 6.5 6.5

4.5 EVALUATION OF TABLETS
4.5.1 Pre-compression Parameters
4.5.1.1 Angle of Repose ()
Angle of repose is defined as the maximum angle possible between the surface of
a pile of the powder and horizontal plane. If more material is added to the pile, it slides
down the sides until the mutual friction of the particles, producing a surface at an angle 
is in equilibrium with the gravitational force; the tangent of the angle of repose is equal to
the coefficient of friction, µ, between the particles. The frictional force in a loose powder
or granules can be measured by using this angle of repose.
tan  = h / r
 = tan-1 (h/r)
Where,  is the angle of repose
h is height of pile
r is radius of the base of pile64
Different ranges of flow ability in terms of angle of repose are given in table no.4.5.1.1
Table No 4.5.1.1 Relationship between Angle of Repose () and flow properties.
Angle of Repose () (degrees) Flow
<25 Excellent
25=30 Good
30-40 Passable
>40 Very poor

Method
A funnel was filled to the brim and the test sample was allowed to flow smoothly
through the orifice under gravity. From the cone formed on a graph sheet was taken to
measure the area of pile, thereby evaluating the flowability of the granules. Height of the
pile was kept constant to 2cm measured.
4.5.1.2 Bulk Density
Bulk density is defined as the mass of a powder divided by the bulk volume. The
bulk density of a powder depends primarily on particle size distribution, particle shape,
and the tendency of the particles to adhere to one another. The bulk density of a powder
depends on particle packing and changes as the powder consolidates. A consolidated
powder is likely to have a greater arch strength then a less consolidated one and may
therefore be more resistant to powder flow. The ease with which a powder consolidates
can be used as an indirect method of quantifying powder flow.65
Method
Both loose bulk density (LBD) and tapped bulk density (TBD) were determined by
tap density tester. A quantity of accurately weighed powder from each formula,
previously shaken to break any agglomerates formed was introduced into a measuring
cylinder. After the initial volume was observed, the cylinder was allowed to fall under its
own weight onto a hard surface from the height of 2.5 cm at 2 seconds interval. The
taping was continued until no further change in volume was noted. LBD and TBD were
calculated using following formula;
LBD= --------- (a)
Dept of Pharmaceutics, Nargund College of Pharmacy, Bangalore Page- 92 -

TBD= ---------- (b)
4.5.1.3 Carr’s Compressibility Index
The compressibility index of the granules was determined by Carr‘s
compressibility index. Grading of the powders for their flow properties according to CI is
given in Table 4.5.1.3
Table No 4.5.1.3 Grading of the powders for their flow properties according to
Carr’s Index
Consolidation Index (Carr’s %) Flow
5 – 15 Excellent
12-16 Good
18-21 Fair to passable
23-35 Poor
33-38 Very poor
>40 Very very poor
(%) CI can be calculated by using the following formula
CI (%) = x 100----------- (c)
4.5.1.4 Hausners Ratio:
Hausner found that the ratio bulk density by tapped density war related to
interparticle friction and, as such, could be used to predict powder flow property. He
showed that powders with low interparticle friction, such as coarse spheres, have ratios of
approximately 1.2. Where more cohesive, less free-flowing powders such as flakes have
Hausner ratios greater than 1.6.70

HR =
Table No 4.5.1.4 Grading of the powders for their flow properties according to
Hausners Ratio
HR Flow
<1.2 Free flowing powder
>1.6 Less free flowing
4.5.2 Post-Compression Parameters
4.5.2.1 Shape and colour
The tablets were examined under a lens for the shape of the tablet and colour by
keeping the tablets in light.
4.5.2.2. Uniformity of thickness
The crown thickness of individual tablet may be measured with a vernier caliper,
which permits accurate measurements and provides information on the variation between
tablets. Other technique employed in production control involves placing 5 or 10 tablets
in a holding tray, where their total crown thickness may be measured with a sliding
caliper scale. The tablet thickness was measured using vernier caliper.
4.5.2.3 Hardness test
Tablets require a certain amount of strength, or hardness and resistance to
friability, to withstand mechanical shocks of handling in manufacture, packaging and
shipping. The hardness of the tablets was determined using Monsanto Hardness tester. It

is expressed in Kg/cm2. Three tablets were randomly picked from each formulation and
the mean and standard deviation values were calculated.
4.5.2.4 Friability test
It is the phenomenon whereby tablet surfaces are damaged and/or show evidence
of lamination or breakage when subjected to mechanical shock or attrition. The friability
of tablets was determined by using Roche Friabilator. It is expressed in percentage (%).
Ten tablets were initially weighed [W (initial)] and transferred into friabilator. The
friabilator was operated at 25 rpm for 4 mins or run up to 100 revolutions. The tablets
were weighed again [W (final)]. The percentage friability was then calculated by,
F=
Table No. 4.5.2.4 Acceptable limit of Friability
Percent Friability Acceptable limit
<1 Acceptable
>1 Not acceptable
4.5.2.5 Weight variation test
The tablets were selected randomly from each formulation and weighed
individually to check for weight variation. The U.S Pharmacopoeia allows a little
variation in the weight of a tablet. The percentage deviation in weight variation is shown
in table no 4.5.2.5.

Table No. 4.5.2.5 Percentage deviation in weight variation
Average weight of a tablet Percentage deviation
130 mg or less 10
More than 130 mg and less than 324 mg 7.5
324 mg and above 5
In all the formulations the tablet weight was above 324 mg and, hence 5% maximum
difference was allowed.
4.5.2.6 Drug Content Uniformity
The content uniformity test is used to ensure that every tablet contains the amount
of drug substance intended with little variation among tablets within a batch. Due to
increased awareness of physiological availability, the content uniformity test has been
included in the monographs of all coated and uncoated tablets intended for oral
administration where the range of size of the dosage form available includes 50 mg or
smaller sizes. For content uniformity test, representative samples of 30 tablets are
selected and 10 are assayed individually. At least 9 must assay within ± 15% of the
declared potency and none may exceed ± 25%.
The amount of active ingredient(s) is determined by the method described in
assay and amount of active ingredient is calculated. Since active ingredient of present
investigation is not official in any pharmacopoeia the following method was used for
determination of drug content.
Twenty tablets were weighed and powdered. The blend equivalent to 20 mg of
pantoprazole sodium was weighed and dissolved in sufficient quantity of 0.1N HCl. The
solution was filtered through Whatmann filter paper (No.41), suitably diluted with 0.1N

HCl and assayed at 281.5 nm, using a UV-Visible double beam spectrophotometer (UV-
1800 Shimadzu).
4.5.2.7 In vitro disintegration time

The process of breakdown of a tablet into smaller particles is called as
disintegration. The in vitro disintegration time of a tablet was determined using a
modified disintegration test used only for fast disintegrating agents.
Method
For a drug to be absorbed from a solid dosage form after oral administration, it
must first be in solution, and the first important step toward this condition is usually the
break-up of the tablet; a process known as disintegration.
The disintegration time of the water dispersible tablets was determined in
accordance with the official European Pharmacopoeia monograph ‗Dispersible tablets‘,
stating a maximum disintegration time of 3 min for dispersible tablets (European
Pharmacopoeia, 2001). The disintegration apparatus (Pharma Test, Hainburg, Germany)
had to be modified, since the standard glass tube is 21.5 mm in internal diameter and the
tested tablets have, however, a mean diameter of 25 mm.57 The disintegration was carried
out in a beaker consisting of a 200 ml medium. The medium consisted of water at a
temperature between 15 and 25°C. Only one tablet at a time was tested and considered
disintegrated when completely dispersed fragments were obtained.

F
ig. No. 4.5.2.7 Method used for the disintegration of the Orodispersible tablets
4.5.2.8 In vitro dissolution studies
In vitro release studies were carried out using a modified USP XXIII dissolution
test apparatus. Two objectives in the development of in vitro dissolution tests was to
show that,
i) Release of the drug from the tablet is as close as possible upto 100%.
ii) Rate of drug release is uniform from batch to batch and is the same as the release
rate from those proven to be bioavailable and clinically effective.

Modification:
The normal USP XXIII dissolution apparatus was chosen in which a beaker was
placed. This beaker is an elongated one generally used for TLC and other purpose.
Another modification was that basket was used in place of paddles because of the narrow
mouth opening of the beaker. Outside this beaker water was putted at a level till the
dissolution fluid in the beaker reaches. The temperature was validated and kept at 40.1°C
and the rotation of the basket was kept at 75 RPM. Only 190 ml dissolution fluid was
used. Summary of general in vitro dissolution conditions employed throughout the study
to determine the in vitro dissolution rate for all the formulation is given in the following
table.
Table No.4.5.2.8 Summary of general dissolution conditions

Sr. No. Parameter Specification
1. Dissolution medium 190 ml 0.1 N HCl
2. Temperature 40.1°C ± 5°C
3. Rotation speed 75 rpm
4. Volume withdrawn 5 ml every 30 seconds for 10 mins
5. max 281.5nm
6. Beer‘s range 2 – 100g/ml
7. Tablet taken 1 tab (known drug content)

Fig No. 4.5.2.8 Modification done in the dissolution apparatus

4.5.2.9 Stability studies:
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
specifications. Stability studies was conducted as per the specified ICH guidelines the
selected best formulation. The purpose of stability testing is to provide evidence on how
the quality of a drug substance or drug product varies with time under the influence of a
variety of environmental factors such as temperature, humidity and light and enables
recommended storage conditions, re-test periods and shelf lives to be established.
In the present study, the ODTs where packed in suitable packaging material and
stored under the following conditions for a period of 90 days at 40 ± 1 0C and RH 75 ±
5%
The tablets were withdrawn after period of 15, 45 and 90days and analyzed for
physical characterization (Visual defects, hardness, friability, disintegration, dissolution
etc) and drug content.
4.5.2.10 Similarity factor:
Moore and Flanner proposed two new indices (f 1 and f 2 ) to compare dissolution
profiles of a test and a reference formulations . The concept of similarity factor (f 2) has
been endorsed by Food and Drug Administration (FDA); therefore, it is widely adopted
in formulation and development and dossier preparation. The equation of similarity factor
proposed by Moore and Flanner is represented in Eqn
ƒ2 = 50 × log {[1 / (1 + (Σ (Rt - Tt) 2) / N)]1/2 × 100}
Where, N = Number of experimental data.

This is a widely used factor used to determine the similarity between two
formulations. It is widely used when you have to check your formulation is similar to that
of the marketed formulation. Values of ƒ2 between 50 and 100 can be considered as
superimposed dissolution profiles.66

6. RESULTS
The present study was aimed at formulating ODTs of PPIs. This is a novel
approach for increasing the patient compliance with a faster onset of action as compared
to the conventional formulation mainly used at present.
5.1 IDENTIFICATION OF PANTOPRAZOLE SODIUM
5.1.1 FTIR Studies
FTIR is one of the most widely used methods for checking the compatability
between substances and for the identification of the drug. Pantoprazole sodium,
excipients and the selected formulations where analysed using infrared
spectrophotometer (Shimadzu FTIR 8-400, S model).
All the samples were scanned at the resolution of 4 cm-1 over the wave number
region 4000-400 cm-1 using KBr disk method. This KBr disks are formed by taking drug
and KBr in a ratio of 1:100 respectively. Then this mixture was mixed well in mortar for
three to five mins. A very small amount of this mixture was uniformly spread and
sandwich between the pellets and pressed using KBr pellet press at a pressure of 20,000
psi for 1 mins. The pressure was then released and pellet was placed into the pellet holder
and thus scanned in the IR region.
The selected formulation shows the characteristics peak similar to that obtained in
the pure pantoprazole sodium indicating that there is no incompatability between the drug
and the excipients used.

Fig No. 5.1.1.1 FTIR scan of Pantoprazole sodium
Table no.5.1.1.1 Different IR peaks for Pantoprazole Sodium
Characteristic peak Observed peak

Functional
group
Stretching Bending Stretching Bending
3363.97cm-1 &
N-H 3500-3300 cm-1 1500 cm-1 1450 cm-1
3489.94 cm-1
C-N 1350-1000 cm-1 1303.92 cm-1
1585.54 cm-1
C=C 16000-1400cm-1
& 1469.81cm-1
823.63 cm-1&
AromaticC-H 3150-3050 cm-1 900-690 cm-1 3057.27 cm-1
806.37cm-1
C-O 1100-1300 cm-1 1166.97 cm-1
C-F 1400-1000 cm-1 1303.92 cm-1

Fig no. 5.1.1.2 FTIR scan of formulation code F4

Table no. 5.1.1.2 Different IR peaks for formulation code F4

Functional
group
N-H 3500-3300cm-1 1500 cm-1 3398.69 cm-1 1450.52 cm-1
1350-1000
C-N 1317.43 cm-1
cm-1
16000-
C=C 1535.39 cm-1
1400cm-1
900-690
AromaticC-H 3150-3050cm-1 3063.40 cm-1 833.28 cm-1
cm-1
C-O 1100-1300cm-1 1174.69 cm-1
C-F 1400-1000cm-1 1305.85 cm-1

Fig no. 5.1.1.3 FTIR scan of formulation code F3

Table no. 5.1.1.3 Different IR peaks for formulation code F3

Functional
group
N-H 3500-3300 cm-1 1500 cm-1 3398.69 cm-1 1452.45 cm-1
C-N 1350-1000 cm-1 1317.43 cm-1
C=C 16000-1400cm-1 1549.90 cm-1
Aromatic C-H 3150-3050 cm-1 900-690 cm-1 3084.28 cm-1 833.28 cm-1
C-O 1100-1300 cm-1 1188.19 cm-1
C-F 1400-1000 cm-1 1306.88 cm-1

5.2 STANDARD CALIBRATION CURVE
5.2.1 Standard calibration curve of Pantoprazole sodium
Table No. 5.2.1 Calibration Curve of Pantoprazole sodium in 0.1N Hydrochloric

acid
Sr. No. Concentration (µg/ml) Absorbance at 281.5 nm
1. 0 0
2. 5 0.1535
3. 10 0.32583
4. 15 0.505
5. 20 0.6525
6. 25 0.81783
* Absorbance shown as mean of 6 replicates

Fig. No. 5.2.1a Calibration Curve of Pantoprazole sodium in 0.1N Hydrochloric

Acid
Fig No. 5.2.1b Ultravoilet Scan of Pantoprazole sodium at 1.2 pH
5.2.2 Standard calibration curve of Omeprazole sodium
Omeprazole sodium was used for the determination of the standard curve. The
marketed product, “OMEZ INSTA” label claim states that it contains only omeprazole.
Therefore a correction with respect to the weight of sodium was performed and
omeprazole sodium used was expressed in terms of pure omeprazole alone,
Method:
Molecular weight of omeprazole: 345.4
Molecular weight of omeprazole sodium: 345.4+23= 368.4
Therefore, 368.4 gm of omeprazole sodium contains 345.4 gm of omeprazole.

Using the above relationship, the concentration of omeprazole was calculated from the
actual obtained concentrations of omeprazole sodium, as recorded in the table 5.2.2a
below.
Table No. 5.2.2a Concentration of Omeprazole in Omeprazole sodium
Sr. No. Conccentration of Concentration of Omeprazole in

Omeprazole Sodium Omeprazole Sodium
1 0 µg/ml 0 µg/ml
2. 2 µg/ml 1.875 µg/ml
3. 4 µg/ml 3.750 µg/ml
4. 6 µg/ml 5.625 µg/ml
5. 8 µg/ml 7.501 µg/ml
6. 10 µg/ml 9.376 µg/ml
* Absorbance shown as mean of 6 replicates
Table No. 5.2.2b Calibration Curve of Omeprazole in 0.1N Hydrochloric acid
Sr. No. Concentration (µg/ml) Absorbance at 301nm
1. 0 0
2. 1.875 0.05275
3. 3.750 0.10575
4. 5.625 0.16025
5. 7.501 0.21125
6. 9.376 0.261

Fig. No. 5.2.2 Calibration Curve of Omeprazole in 0.1N Hydrochloric Acid

5.3 EVALUATION
5.3.1 Pre compression evaluation parameters
Table No. 5.3.1.1 Evaluation of powder blend prepared by superdisintegrants

addition method.
FC Angle of repose LBD(gm/cm3) TBD(gm/cm3) CI (%) HR
F1 25.82 0.71 0.81 12.84 1.15
F2 27.35 0.70 0.80 12.50 1.14
F3 24.28 0.72 0.81 11.32 1.13
F4 25.11 0.69 0.79 12.73 1.15
F5 29.05 0.69 0.81 14.53 1.17
F6 26.76 0.70 0.82 14.55 1.17
F7 25.12 0.68 0.78 12.50 1.14
F8 25.29 0.71 0.83 14.55 1.17
F9 29.51 0.69 0.80 14.29 1.17
F 10 26.76 0.70 0.81 12.73 1.15
F 11 25.12 0.70 0.81 12.73 1.15
F12 27.76 0.69 0.81 14.29 1.17
F 13 27.15 0.69 0.80 14.29 1.17
F 14 28.83 0.69 0.79 12.49 1.14
F 15 26.57 0.71 0.83 14.29 1.17
F 16 26.38 0.71 0.81 12.73 1.15

Table No. 5.3.1.2 Evaluation of different powder blend prepared by combination of

different superdisintegrants.
F 17 25.11 0.69 0.80 14.28 1.17
F 18 28.18 0.690 0.79 12.48 1.14
F 19 26.19 0.70 0.81 12.72 1.14
F20 23.50 0.67 0.78 14.54 1.17
Table No. 5.3.1.3 Evaluation of different powder blend prepared by sublimation

method.
F 21 24.44 0.70 0.82 14.54 1.17
F 22 0.70 1.14
27.35 0.80 12.50
F 23 24.12 0.70 0.80 11.33 1.13
Table No. 5.3.1.4 Evaluation of different powder blend prepared by combination of

superdisintegrants and sublimationmethod.
F 24 24.12 0.71 0.83 14.55 1.17
F 25 24.78 0.72 0.81 11.11 1.13
Table No. 5.3.1.5 Evaluation of different powder blend prepared by treated natural
gums used as Superdisintegrants.
FC Angle of repose LBD(gmc/m3) TBD(gm/cm3) CI (%) HR
F 26 25.46 0.70 0.81 12.73 1.15
F 27 24.94 0.70 0.81 12.72 1.15

5.3.2 Post compression evaluation parameters
Table No. 5.3.2.1 Evaluation of Orodispersible tablet formulations prepared by

using superdisintegrant addition method.
Uniformity of Hardness Weight

FC Friability %
Thickness(mm) (kg/cm2) Variation (mg)
F1 6.98±0.04 3.37±0.15 0.30±0.13 1303±65.15
F2 7.01±0.025 3.57±0.06 0.58±0.35 1315.5 ± 65.78
F3 6.89±0.32 3.43±0.06 0.44±0.43 1293.5 ± 64.68
F4 7.01±0.03 3.57±0.06 0.35±0.24 1295± 58.75
F5 6.89±0.071 3.77±0.06 0.30±0.08 1306.5±65.33
F6 6.86±0.04 4.2±0 0.61±0.34 1303.5±65.18
F7 6.95 ± 0.03 3.47±0.06 0.43±0.19 1309±65.45
F8 6.96±0.03 4.17±0.06 0.52±0.19 1296.5±64.83
F9 6.96±0.03 4.23±0.06 0.17±0.11 1316.5±70.58
F 10 6.95±0.05 3.83±0.06 0.15±0.077 1298.5±64.95
F 11 6.97 ± 0.01 3.7±0.54 0.56±0.31 1304.5±65.25
F12 7.03±0.05 3.4±0 0.21±0.045 1297±69.6
F 13 7.04 ± 0.03 3.4±0.1 0.39±0.28 1301.5±65.08
F 14 6.95 ± 0.04 3.13±0.06 0.45±0.09 1288.5±69.18
F 15 7.00±0.02 3.23±0.12 0.64±0.42 1296±64.8
F 16 6.94±0.01 3.47±0.06 0.51±0.42 1299±60

* All the parameters shown above are based on 3 replicates and are expressed as Mean ±
S.D


using combination of different superdisintegrants.
FC Friability %
F 17 0.38±0.20 1307.5±65.38
7.03±0.01 3.3±0.1
F 18 7±0.01 3.5±0 0.39±0.20 1299.5±64.98
F 19 1303.5±65.18
7.05±0.01 3.47±0.06 0.33±0.09
F20 6.99±0.01 3.27±0.06 0.355±0.11 1306.5+65.38
* All the parameters shown above are based on 3 replicates and are expressed as Mean
±S.D

using Sublimation method.
Uniformity of Weight
FC Hardness (kg/cm2) Friability %
Thickness(mm) Variation (mg)
F 21 6.96±0.03 3.37±0.058 0.30±0.07 1308.5±65.43
F 22 7.01±0.01 3.43±0.058 0.51±0.19 1305±65.25
F 23 7.04+ 0.03 3.53±0.058 0.20±0.048 1308±65.4
±S.D

using combination of superdisintegrants and sublimationmethod.
Uniformity of Weight
FC Hardness (kg/cm2) Friability %
Thickness(mm) Variation (mg)
F 24 6.99±0.02 3.3±0.1 0.46±0.24 1308±65.4
F 25 6.98±0.01 3.3±0 0.38±0.22 1308±65.4
±S.D

Fig. No. 5.3.2.5 Evaluation of Orodispersible tablet formulations prepared by using

formulations using treated natural gums used as Superdisintegrants.
FC Friability %
F 26 7.02±0.012 3.3±0.1 0.55±0.17 1310.5±65.53
F 27 6.98±0.01 3.3±0.1 0.45±0.18 1299.5±64.98
±S.D
5.3.3 Disintegration test
Disintegration plays an important role for ODTs as the drug release and its pattern
purely depends on the disintegration time. For ODTs shortest disintegration time is
desired as the dosage form should be capable of being immediately absorbed with the
disintegrated portion reaching the gastric fluid in seconds without the requirement of
water, for ingestion.
Disintegration time of 3 min (180 sec) was fixed as the upper limit for branding
formulations as ODTs as specified by European Pharmacopoeia. Therefore, formulations
having disintegration time greater than 180 sec were not selected for further studies such
as drug content, in vitro dissolution etc.
Approaches such as sublimation methods, combination of superdisintegrants and
subliming agents, and treated natural gums to be used as superdisintegrants did not yield
favourable results with respect to the disintegration test.

Table No. 5.3.3 In vitro Disintegration Time

In- vitro disintegration time
FC Approach
(Seconds)
F1 Superdisintegrants addition Above 180 sec
F2 Superdisintegrants addition 96.67 ± 5.03
F3 Superdisintegrants addition 56.33 ±5.03
F7 Superdisintegrants addition 87 ± 3.06
F 10 Superdisintegrants addition 115.67 ± 4.04
F 11 Superdisintegrants addition Above 180 sec
F 12 Superdisintegrants addition Above 180 sec
F16 Superdisintegrants addition 166 ± 5.03
F17 Combination of different superdisintegrants 149.67 ± 1.53
F21 Addition of Sublimating agent Above 180 sec
Combination of superdisintegrants and
F24 Above 180 sec
sublimation method
Combination of superdisintegrants and
F25 Above 180 sec
sublimation method
Addition of treated natural gums used as
F26 Above 180 sec
superdisintegrants
Addition of treated natural gums used as
F27 Above 180 sec
superdisintegrants
±S.D

5.3.4 Drug content
Table No. 5.3.4 Drug Content

FC Approach Drug content in mg
`F2 Superdisintegrants addition 18.88 ± 0.38
F 16 Superdisintegrants addition 18.69 ± 0.33
F 17 Combination of different superdisintegrants 19.71 ± 0.67
±S.D
No limits for the drug content are presently available in the pharmacopoeias for
PPI prepared as ODTs. Therefore, IP 2010 limits of 90 to 110% for enteric coated tablets
were used in this study as a standard for comparison.
The drug content in the selected formulation was found to be in the range of
90.94% to 100.94% with a standard deviation of ± 0.18 to ± 0.60. This lies within the IP
limits for enteric coated pantoprazole tablets.

5.3.5 Drug dissolution profile :
Drug dissolution profile is one of the important aspects in development of all the
dosage forms. In this research project dissolution time of 10 min was chosen since the
expected dissolution time for ODT was around 5 min. In addition, IP has prescribed a
dissolution time of 10 min for Ondansetron DTs. Certain modification where done as
explained in the 4.5.2.8 In vitro dissolution studies under the topic called methodology.
All the formulation which passed the in vitro disintegration where subjected to in
vitro dissolution studies. This study also plays an important part in the selection of the
best formulation among all.

5.3.5.1 Dissolution drug profile of ODT formulations prepared by superdisintegrant addition method
Table No. 5.3.5.1 Cumulative percent drug release from Orodispersible tablets prepared by superdisintegrant addition method
Time
F2 F3 F4 F6 F7 F9 F10 F13 F16
(mins)
0 0±0 0 ±0 0 ±0 0 ±0 0 ±0 0 ±0 0 ±0 0 ±0 0 ±1.523
0.5 33.03 ± 3.18 87.65 ±2.17 95.35 ±0.72 20.69 ±5.73 40.91 ±2.78 37.18 ±1.57 47.00 ±1.78 3.97 ±1.93 8.10 ±1.5
1 44.52 ±1.40 93.59±2.10 102.52±0.23 31.06 ±2.24 75.77 ±3.26 60.45±5.28 67.64 ±4.05 7.60 ±1.70 11.81 ±1.96
1.5 73.11 ±3.35 97.34 ±.084 102.12±0.60 45.14±1.89 87.96 ±2.64 78.42 ±3.78 82.74 ±4.63 18.46 ±1.94 25.22 ±1.01
2 82.14 ±3.06 98.87 ±1.25 101.80±0.70 52.25 ±2.55 98.64 ±1.06 89.76 ±5.01 84.84 ±5.58 24.82 ±3.82 30.80 ±1.10
2.5 87.26 ±1.82 92.99 ±0.91 100.46±0.91 59.28 ±2.99 102.18±3.13 94.51±2.40 84.55 ±1.37 20.62±10.88 40.71 ±2.52
3 90.35 ±1.61 88.14 ±1.55 99.81 ±1.49 69.67 ±3.40 99.71 ±3.21 89.42 ±2.49 85.54 ±2.22 23.57±12.65 46.10 ±2.26
3.5 92.75 ±1.63 83.57 ±2.13 98.39 ±2.06 80.87 ±6.78 98.65 ±1.98 87.58 ±3.50 85.76 ±3.42 34.84 ±3.90 51.36 ±2.70
4 91.93 ±0.58 76.23 ±2.95 97.12 ±3.10 94.17 ±1.48 98.05 ±0.65 86.52 ±2.27 83.47 ±2.57 38.41 ±3.99 59.99 ±3.07
4.5 92.69 ±0.85 71.00 ±1.27 96.30 ±3.27 97.06 ±0.91 97.99 ±1.46 85.75 ±2.15 81.51 ±4.41 42.42 ±3.66 66.20 ±2.96
5 91.60 ±2.51 68.99 ±1.67 93.97 ±3.27 96.42 ±1.95 97.80 ±1.13 85.35 ±1.86 79.53 ±2.82 48.94 ±1.04 82.70 ±8.15
5.5 90.03 ±2.72 66.43 ±1.40 92.41 ±2.75 95.70 ±1.28 97.16 ±0.85 85.71 ±1.66 79.32 ±3.31 54.28 ±2.28 85.37 ±3.37
6 90.73 ±1.95 63.66 ±2.15 89.92 ±2.82 94.99 ±1.19 96.37 ±0.84 84.52 ±1.82 78.98 ±2.83 59.95 ±2.29 84.72 ±4.68
6.5 88.97 ±2.16 61.16 ±1.78 87.61 ±2.46 94.13 ±1.44 97.37 ±1.69 84.64 ±2.31 79.11 ±3.62 66.11 ±0.99 89.73 ±1.08
7 88.52 ±2.18 58.49 ±2.10 84.96 ±1.57 92.95 ±2.40 95.62 ±2.08 85.90 ±1.69 77.94 ±2.36 70.70 ±1.55 92.11 ±1.15
7.5 88.64 ±2.35 55.34 ±3.18 85.06 ±1.34 91.36 ±2.14 95.10 ±1.68 85.53 ±1.43 77.89 ±2.35 75.89 ±1.57 90.38 ±1.78
8 89.20 ±2.81 53.65 ±2.15 84.04 ±1.14 90.33 ±1.60 94.29 ±2.64 84.85 ±1.30 77.21 ±1.79 82.56 ±1.46 92.20 ±2.76
8.5 87.92 ±2.87 51.47 ±2.95 83.30 ±1.56 90.18 ±1.87 93.33 ±2.71 84.36 ±0.98 75.72 ±1.36 84.30 ±2.35 90.04 ±1.95
9 88.68 ±2.36 49.30 ±3.27 82.10 ±1.50 88.63 ±1.80 93.39 ±4.62 85.20 ±1.27 75.80 ±1.78 84.93 ±3.79 90.41 ±3.76
9.5 88.16 ±2.61 47.55 ±3.49 81.14 ±0.86 87.63 ±3.29 92.55 ±5.36 85.46 ±1.59 74.88 ±2.17 84.79 ±3.03 87.39 ±4.20
10 88.224±2.72 45.27 ±3.78 80.56 ±1.21 87.76 ±4.44 90.88 ±4.58 85.06 ±1.68 75.99 ±2 86.52 ±3.12 84.34 ±3.43
* Here n=6 for F3 and F4 formulations and n=4 for rest of all formulations (F2, F6, F7, F9, F10, F13, F16

Fig No. 5.3.5.1 Cumulative percentage drug released from Orodispersible tablet
formulations prepared by superdisintegrant addition method
5.3.5.2 Dissolution profile study of Orodispersible tablet formulations prepared by

combination of different superdisintegrants
Table No. 5.3.5.2 Cumulative percent drug released from Orodispersible tablet
formulations prepared by combination of different superdisintegrants
Time
F17 F18 F19 F20
(min)
0 0 ±0 0 ±0 0 ±0 0 ±0
0.5 2.79±1.29 33.09 ±0.97 22.96 ±4.28 36.15 ±2.25
1 34.49 ±2.70 57.63 ±5.58 43.03 ±2.2 50.01 ±1.11
1.5 49.86 ±1.56 79.65 ±3.99 80.96 ±3.39 77.28 ±7.86
2 61.99 ±0.42 85.95 ±2.52 92.70 ±1.95 86.85 ±2.30
2.5 72.60 ±1.57 90.60 ±3.19 98.08 ±2.20 93.134 ±2.50
3 81.64 ±1.73 92.57 ±2.74 98.14 ±0.86 94.53 ±1.68
3.5 88.01 ±1.50 95.17 ±1.09 98.37 ±1.36 95.42 ±1.08

4 84.10 ±2.72 94.65 ±1.42 96.26 ±1.39 94.98 ±0.97

4.5 89.14 ±1.30 93.25 ±3.31 94.34 ±0.80 95.19 ±1.75
5 89.30 ±1.73 92.57 ±2.99 94.21 ±0.91 96.41 ±1.28
5.5 89.78 ±1.47 92.21 ±2.91 93.57 ±0.78 95.99 ±1.73
6 90.82 ±1.30 92.68 ±4.43 92.70 ±0.95 95.01 ±2.70
6.5 91.85 ±1.22 92.31 ±6.21 92.45 ±1.85 94.77 ±3.03
7 92.32 ±1.47 91.15 ±4.54 91.15 ±1.74 94.95 ±2.51
7.5 93.05 ±1.45 90.63 ±4.68 91.14 ±2.83 94.36 ±2.73
8 93.68 ±1.26 90.22 ±3.83 90.55 ±2.99 93.31 ±3.09
8.5 94.20 ±2.93 89.92 ±3.63 91.03 ±3.30 93.47 ±2.40
9 94.38 ±1.74 88.99 ±3.22 91.19 ±3.08 91.33 ±3.19
9.5 93.93 ±2.17 89.30 ±3.12 91.31 ±3.41 91.27 ±3.86
10 93.71 ±1.84 90.62 ±4.10 91.47 ±3.30 90.85 ±3.79
*Here n=4 replicates for formulation F17, F18, F19 and F20
Fig No. 5.3.5.2 Cumulative percentage drug released from Orodispersible tablet
formulations prepared by combination of different superdisintegrants

Based on the disintegration time and the release patterns, formulations coded F4
and F3 were selected as the optimum formulations which fulfil best the criteria for ODTs.
5.3.5.3 Dissolution profile of reference marketed product
OMEZ INSTA was used as a reference for the evaluation of the similarity in
drug release of the reference and the selected formulations.
Table no. 5.3.5.3 Dissolution profile of OMEZ INSTA

Time (mins) Cumulative percent drug release*
0 0 ±0
0.5 89.90 ±3.43
1 98.11 ±2.71
1.5 100.27 ±1.29
2 101.95 ±1.92
2.5 101.57 ±1.58
3 101.12 ±0.84
3.5 100.36 ±1.57
4 101.42 ±0.98
4.5 100.36 ±2.14
5 100.53 ±2.13
5.5 99.22 ±3.13
6 99.07 ±3.22
6.5 98.62 ±2.4
7 98.89 ±2.65
7.5 98.40 ±2.25
8 98.26 ±2.77
8.5 97.12 ±2.53
9 96.39 ±3.56
9.5 93.98 ±5.64
10 90.15 ±2.70
* Here for Omez Insta n=6 replicates

Fig No. 5.3.5.3 Cumulative percent drug release of OMEZ INSTA
5.3.5.4 Comparison of dissolution profile between selected F4 and F3 formulations

with marketed OMEZ INSTA
Table No.5.3.5.4 Comparative table showing cumulative percent drug release of the
selected formulations F4 and F3 with marketed formulation OMEZ INSTA
Standard
Time (mins) F3 F4
Formulation
0 0 ±0 0 ±0 0 ±0
0.5 87.65 ±2.17 89.90 ±3.43 95.35 ±0.72
1 93.59±2.10 98.11 ±2.71 102.52±0.23
1.5 97.34 ±.084 100.27 ±1.29 102.12±0.60
2 98.87 ±1.25 101.95 ±1.92 101.80±0.70
2.5 92.99 ±0.91 101.57 ±1.58 100.46±0.91
3 88.14 ±1.55 101.12 ±0.84 99.81 ±1.49
3.5 83.57 ±2.13 100.36 ±1.57 98.39 ±2.06
4 76.23 ±2.95 101.42 ±0.98 97.12 ±3.10
4.5 71.00 ±1.27 100.36 ±2.14 96.30 ±3.27
5 68.99 ±1.67 100.53 ±2.13 93.97 ±3.27

5.5 66.43 ±1.40 99.22 ±3.13 92.41 ±2.75

6 63.66 ±2.15 99.07 ±3.22 89.92 ±2.82
6.5 61.16 ±1.78 98.62 ±2.4 87.61 ±2.46
7 58.49 ±2.10 98.89 ±2.65 84.96 ±1.57
7.5 55.34 ±3.18 98.40 ±2.25 85.06 ±1.34
8 53.65 ±2.15 98.26 ±2.77 84.04 ±1.14
8.5 51.47 ±2.95 97.12 ±2.53 83.30 ±1.56
9 49.30 ±3.27 96.39 ±3.56 82.10 ±1.50
9.5 47.55 ±3.49 93.98 ±5.64 81.14 ±0.86
10 45.27 ±3.78 90.15 ±2.70 80.56 ±1.21
* n=6 replicates for all the 3 formulations
Fig No. 5.3.5.4 table showing cumulative percent drug release of the selected
formulation F4 and F3 and marketed formulation OMEZ INSTA

5.3.6 Similarity factor
Table No 5.3.6 similarity factor of formulation F3 and F4

Similarity factor with respect to standard formulation “OMEZ INSTA”
F3 F4
50.6033 72.0016
Since the similarity factors of the formulations F3 and F4 are both greater than 50,
as per the USP guidelines, both these formulations are similar to the reference
formulation.
5.4 STABILITY STUDIES
Results of the stability studies are tabulated in table 5.4
Table No. 5.4 Stability studies.
Parameters
FC Time Hardness Drug DT
CPDR Friability Appearance
(Kg/cm2) content (sec)
F3 15 days 3.47 19.58 93.08 53.33 0.56 Same as Day 0
F3 45 days 3.4 19.22 93.25 55 0.39 Same as Day 0
F3 90 days 3.53 18.75 94.68 53.67 Same as Day 0

0.33
F4 15 days 3.53 19.79 100.8 25 Same as Day 0
0.35
F4 45 days 3.57 19.58 101.27 25.67 0.21 Same as Day 0
F4 90 days 3.47 19.54 102.40 26 0.39 Same as Day 0
* Here n=3 replicates for all the above parameters
Thus the selected formulations pass the stability test since none of the examined
parameters are outside the respective acceptance limits prescribed by ICH guidelines..

6 DISCUSSION
In the present work, an attempt was made to prepare an ODTs of PPIs. ODTs have
an advantage over the conventional tablets in elderly, pediatric and patients with
dysphagia. Pantoprazole sodium was used as a model drug to represent the class of PPIs.
The main challenge of this research was to deal with the stability of the drug. All PPIs are
unstable at a pH below 5 and the project involved delivery of the drug into stomach with a
pH of 1.2. The degradation half life of the drug in the stomach is 1-2 min. No UV
spectrophotmetric method was reported to be developed in gastric stomach pH 1.2.
The pre and post compression parameters of all the formulation were evaluated.
The effect of formulation variables, such as different classes of superdisintegrants in
varying ratios on various pre and post parameters were evaluated using parameters such
as disintegration time, uniformity of weight, content uniformity, friability, hardness,
thickness and stability studies..
6.1 IDENTIFICATION OF PANTOPRAZOLE SODIUM
6.1.1 Melting Point Determination
Melting point of pantoprazole sodium was to be determined by open cup capillary
method. However, pure pantoprazole sodium degrades at higher temperatures, which is a
specific characteristic of PPIs. A similar observation was also made in this set of
experiments confirming the well known degradation of PPIs at higher temperatures.
Thus, determination of the melting point of pantaprazole sodium was not possible as
expected.

6.1.2 Solubility
Pantoprazole sodium was found to be soluble in ethanol, water, and in phosphate
buffer of 6.8 and 7.4. pantoprazole sodium shows a clear solution in stimulated gastric
pH 1.2 but also show a characteristic yellow coloration when PPIs are dissolved in acidic
pH. The coloration intensifies as the pH decreases. Thus this yellow coloration could
possibly be associated with degradation in the acidic medium.
Fig. no 6.1.2 Solubility of Pantoprazole Sodium in different medium
6.2 STANDARD CALIBRATION CURVE
Although seemingly easy, preparation of standard calibration curves is a very
tricky and complex procedure for PPIs. Many methods were tried but the main problem
associated with the standard curve preparation was its stability. As stated in the
introduction, to discussion (Section 6), the degradation half-life of pantoprazole sodium
is just 1 to 2 mins. Therefore, as soon as the drug was added into the acidic medium

degradation sets in. Thus it was contemplated to add buffer along with it but then a new
problem arose. When buffer was dissolved in1.2 pH the drug was not getting solubilized
even after sonication for 1 hr. A different method was adopted by adding of 5 ml of
purified water into 100 ml of solution of HCl, pH 1.2. The pH of the solution remained
unchanged around 1.2; within the expected limits. Thus a method involving dissolution
of the drug in 5ml of the purified water, followed by addition of this solution to the
bicarbonate dissolved in 1.2 pH, and further making up the volume to 100 ml using 1.2
pH HCl (SS-I) was followed. Other stock solutions were prepared by dilution of SS-I
using 1.2 pH HCl solutions.
6.2.1 Standard Calibration Curve of Pantoprazole sodium
The scanning of drug solution was done in the UV region (200–400 nm) to find
out the wavelength of maximum absorption (λ max) in the gastric fluid pH 1.2. The λ max
was found to be at 281.5 nm. The standard calibration curve of pantoprazole sodium was
developed at this wavelength. The calibration curve was linear between 1–100 µg/ml
conc. ranges. The standard calibration was obtained by plotting absorbance against conc.
at 281.5 nm, and it follows the Beer‘s law. Results were tabulated in Table No.5.1.2 and
plotted in Fig. no.5.1.2 The r2 was found to be 0.9994 and slope was found to be 0.032 in
0.1 N HCl.
6.2.2 Standard Calibration Curve of Omeprazole sodium
The scanning of drug solution was done in the UV region (200–400 nm) to find
out the wavelength of maximum absorption (λ max) in the gastric fluid pH 1.2. The λ max
was found to be at 301 nm. The standard calibration curve of omeprazole sodium was

developed at this wavelength. The standard calibration was obtained by plotting
absorbance against conc. at 301 nm, and it follows the Beer‘s law. Results were tabulated
in Table No.5.1.3 and plotted in Fig. no.5.1.3 The r2 was found to be 0.9998 and slope
was found to be 0.028 in 0.1 N HCl.
6.3 COMPATABILITY STUDIES
6.3.1 FTIR Studies
Drug- excipient interactions play a crucial role with respect to the stability and-
potency of the drug. FTIR techniques have been used here to study the physical and
chemical interaction between drug and excipients used.
Compatibility studies were performed using FTIR spectrophotometer. The IR
spectrum of pure pantoprazole sodium and physical mixture of drug and polymers were
studied. The FTIR scan shows characteristic absorption peaks of pantoprazole sodium at
3363.97 cm-1, 1450.52 cm-1 (N-H stretching and bending vibrations); 1303.92 cm-1 (C-N
stretching vibration); 1589.40 cm-1 and 823.63 cm-1 (C=C stretching vibration);
3057.27cm-1 (Aromatic C-H stretching and bending vibrations), 1041.60 cm-1 (S=O
stretching vibration) respectively.
The FTIR spectrum of pure drug and different excipients and the tablet formulation
where studied and is tabulated in table no. 5.1.1.1 to 5.1.1.3.

The peaks obtained in the spectra of the pure drug have a correlation with the
peaks obtained when the drug and excipients were scanned together, thus indicating that
the drug was compatible with the formulation excipients.
Based on this study it was concluded that there is no chemical interaction between
drug and the excipients used and thus it can be safely used in the formulations.
6.4 PRECOMPRESSION PARAMETERS
6.4.1 Loose Bulk Density
LBD of the formulation blend plays an important role in the compression of the
powder the LBD of the formulation was found to be in the range of 0.679 g/cm3 to
0.719 g/cm3.
6.4.2 Tapped Bulk Density
TBD also plays an important role in knowing the compressibility of the
formulation blend it was found to be in the range of 0.69g/cm3 to 0.83 g/cm3. It was noted
that the TBD of all the formulation where greater than their respective LBD thus
indicating that all the powder formulation had a good compressibility.
6.4.3 Angle of Repose (θ).
The angle of repose for the formulated blend was carried out and the results were
shown in Table no. 5.2.2.1 to 5.2.2.5. It was concluded that the entire formulations blend
were in the range 230491' to 29⁰511' thus falling in the official limit range of 250 to 300
which indicates that all the formulation blend have good flow property.

6.4.4 Carr,s Index
CI was calculated on the basis of the LBD and TBD and the results were shown in
table 5.2.2.1 to 5.2.2.5. It was found to be in the range of 11.32% to 14.55% which lies in
the official limits i.e. 5% to 15%, indicating the granules blend has excellent flow
property for compression.
6.4.5 Hausners Ratio
HR was calculated on the basis of the LBD and TBD. It is an ratio between TBD
and LBD and was found to be in the range of 1.127 to 1.17 thus indicating that
formulation blend have free flowing property which is ideal for ODTs.
6.5 FORMULATION OF ORODISPERSIBLE TABLETS
For the formulation of ODTs the most easy and economical method direct
compression, was selected. This is one of the most widely used methods. Five
approaches were designed to be used for this research work: superdisintegrant addition,
combination of different superdisintegrants, sublimation method and combination of both
superdisintegrants and sublimation methods and using treated natural gums as
superdisintegrants. Thus a wide variety of superdisintegrants were used for the
preparation of ODTs. Mannitol DC, SSG and other excipients were chosen based on the
review done for ODTs.
Due to the use of high amount of buffer which is always associated with bad taste,
Orange DC100 was incorporated as a flavour in the concentration of 0.5% to mask this

effect. All the superdisintegrants were used in the concentration of 2%, 3%, and 5%
respectively.
Blending time was carefully controlled since SSF was used. Long mixing times can
result in the formation of hydrophobic powder beds which do not disperse easily.
Therefore, SSF was added and mixed for a period of only 2 to 5 minutes. An increase in
the coefficient of variation of mixing and a decrease in the dissolution rate have been
observed following long mixing periods of SSF with a tablet powder. Tablet dissolution
rate and crushing strength is decreased as the time of blending is increased; and SSF may
also increase tablet friability.
The uniform blends of tablet were directly compressed by keeping tablet press
setting constant for all the formulations. Proper lubrication of powder blends was
essential for ease of ejection of compressed tablets as well as for free movement of lower
punch during compression cycle. The tablets were compressed using flat face 16.4 X 8
mm flat oval size punches to get tablets of 1300 mg weight using ten stations Rimek
tablet compression machine (Karnavati Engineering Ltd. Ahmadabad, India). The
hardness for the tablets was set at a lower level of 3 Kg/cm2.
6.6 MODIFICATION OF THE DISSOLUTION APPARATUS
During the course of this research, a lot of questions arose due to various
perspectives of this research work. First the traditional method was considered for
performing the dissolution in 900 ml of dissolution media, but the results were
unsatisfactory. The quantity of buffer used was then considered. Further review showed
that in IP 2010 in the assay for Ondansetron orally disintegrating tablets dissolution was

performed in 500 ml of dissolution medium. Based on this information it was decided to
use 500 ml of dissolution medium. The percentage of drug released using 500 ml of
dissolution medium was more than that obtained using 900 ml, although the cumulative
percent released was less than 72%. Further review of the literature revealed that a
marketing pamphlet existed for ―OMEZ INSTA‖ which quoted that the marketed product
will increase the pH of the stomach above 6.
Fig. no 6.5 Study performed in 500 ml of 1.2 pH of OMEZ INSTA, F4 and F3
Thus based on back calculation it was determined that 190 ml of acid should be
present to increase the pH above 6. Further it was seen that good similarity existed

between the dissolution profiles obtained with the test formulations and the marketed
formulation of OMEZ INSTA when both 900 ml and 500 ml of dissolution medium was
used. The temperature was validated and kept at 40.1°C and the rotation of the basket
was kept at 75 RPM.
The photograph shown above (fig. 6.5) of the dissolution study done in 500 ml
dissolution medium for OMEZ INSTA clearly shows the yellow colouration indicating
that it may be due to the degradation.
6.7 QUANTITY OF BICARBONATES
A combination of two buffers i.e. Sodium and potassium bicarbonate were used
for stabilizing agents so that the level of sodium will be maintained. The quantity of 1.1
gm of the buffer mixture consisting of sodium and potassium bicarbonate was arrived at
by a series of in vitro dissolution tests. The least amount of buffer mixture required to
prevent the drug from degradation was selected.
Comparison of the three formulations, F3, F4 and OMEZ-INSTA clearly indicates
that the intensity of the yellow colouration is minimal with both the F3-CP 3% and F4-
CP 5% as compared to OMEZ INSTA. This could be explained by possible decreased
degradation of PPIs indicating the correct choice of the optimum amount of buffer.

6.8 EVALUATION OF TABLETS
6.8.1 Shape of the tablets
All the tablets have common flat oval shape.
6.8.2 Colour of the tablets
The colour of the tablet was white and formulation prepared by addition of treated
natural gums shows specific brown to black colouration depending on the colour of the
dried treated gum powder.
6.8.3 Thickness
Thickness of all the tablets was found to be between 6.86 mm to 7.05.
6.8.4 Tablet Hardness
The crushing strength of the tablets of each batch ranged between 3.13 to 4.23
kg/cm2. This ensures good handling characteristics of all batches.
6.8.5 Friability Test
The values of friability test were in the range from 0.21 to 0.64% the percent
friability of all the formulation was less than 1% ensuring that the tablets were
mechanically stable.
6.8.6 Weight Variation Test
The percentage weight variations for all formulations were done. All the
formulated tablets passed weight variation test as the percent weight variation was within

the pharmacopoeial limits as the formulation blend of all the formulations have a good
flow thus the percent weight deviation was in between 5% of the average weight. The
weights of all the tablets were found to be uniform with low standard deviation values.
6.8.7 Drug Content Uniformity
The percentage of drug content for all formulation was found to 91.98% to
100.94% which lies in the IP limit for enteric coated formulation of 90 to 110% which
was taken into consideration as ODTs of pantoprazole sodium is not official in any
pharmacopoeia.
6.9 IN VITRO DISINTEGRATION TEST
This is the most important test with respect to ODT formulations. Five
superdisintegrants, three subliming agents and, two treated gums were used for these
studies. Among all CP was selected as the best superdisintegrant as it gave the least in
vitro disintegration time. It was noted that no superdisintegrant was able to give the in
vitro disintegration time with in 180 sec at a cocn. of 2% except CP. As the cocn. of CP
was increased in vitro disintegration time reduced; least in vitro disintegration time was
obtained at a concn. of 5%.
When the combination of different superdisintegrants were used it had a little
effect on in vitro disintegration time only when CP was used. Sublimation method totally
failed the disintegration test perhaps due to the cocn. used (5%) and the size and weight
of tablet. When superdisintegrants were combined with subliming agents it was strange to

see that even when the concentration of CP used was 2.5% it did not give the in vitro
disintegration time with in the specified limit of 3 mins. At the start of the test some part
of the tablet disintegrated quickly possibly due to the presence of CP on the surface, but
not the whole tablet. Thus we can conclude that 2.5 to 5% of subliming agents are not
sufficient for proper disintegration suggesting that combination of CP and subliming
agents yield unsatisfactory results.
Natural gums like Acacia and Gaur were selected as they gave a proper dried
mass after the treatment. However, they failed to give in vitro disintegration time with in
the specified limit thus indicating that 5% of the treated natural gums are not sufficient
for proper disintegration
6.10 IN VITRO DISSOLUTION STUDIES
All the selected formulations which passed the in vitro disintegration test were
subjected to in vitro release studies using modified USP dissolution apparatus II in 0.1N
HCl pH 1.2.
Depending on the in vitro disintegration test, in vitro dissolution test and the
similarity factor formulation F3 and F4 were selected as optimised formulation.
Formulation F3 released the maximum amount of drug. (98.86 ± 1.24) within 2
mins and for the formulation F4 the maximum drug release (102.52 ± 0.23) was found
within 1 minute. These results are in tune with those obtained for the disintegration time
for the respective formulations.

6.11 ACCELERATED STABILITY STUDY
The selected formulation were subjected to accelerated stability studies and the
formulations where evaluated for appearance, hardness, friability, drug content, in vitro
disintegration time and in vitro dissolution test. The formulations where stored at 40°C
±1°C and RH 75 ± 5%. All the formulation where analysed after every 15, 30, 45 and 90
days. All the formulations show no change in all the above parameters thus successfully
passes the accelerated stability study which was conducted for 90 days.

7. CONCLUSION
In this research work ODTs of PPIs were successfully formulated by direct
compression method using superdisintegration addition method, combination of different
superdisintegrants, sublimation method, combination of superdisintegrants and
sublimation method, and treated natural gums used as Superdisintegrants.
The in vitro disintegration test revealed that the tablets prepared with CP, and
mixture of superdisintegrants with CP show faster disintegration as compared to tablets
prepared with rest of superdisintegrants, subliming agent and treated natural gums used
as Superdisintegrants.
Even the dissolution studies confirmed that tablets prepared with CP, and its
mixture show faster drug release as compared to tablets prepared with rest of
superdisintegrants, subliming agent subliming agent and treated natural gums used as
Superdisintegrants.
The flow properties of the formulation powder have good flow property which is
an important aspect for the ODT formulations.
Direct compression method is the best method for the formulation of ODTs. This
method is also very economical and time saving. CP was found to be the best
superdisintegrant among all with 5 percent concentration yielding the best results. It was
also concluded that 1.1 gm of bicarbonate is required for the stability of the PPIs in acidic
conditions.
In vitro disintegration time and in vitro drug release shows that among all the
superdisintegrants used CP gives the least in vitro disintegration time and release the

maximum amount of drug within 1-3 mins. The results show that an increase in CP level
leads to a decreases in the in vitro disintegration time and thus decrease in the in vitro
drug release time. Thus formulation F4 and F3 were selected as best formulations among
those examined.
Stability studies reviled that the formulation F3 and F4 i.e. formulation with 3%
and 5% CP have good stability in accelerated stability testing.

8. SUMMARY
Mankind has lived with peptic ulcers since ancient times. Perhaps the first
description of this malady is the one inscribed on the pillars of the temple of Aesculapius
of Epidaurus from around fourth century B.C.
PPIs are the most potent suppressors of gastric acid secretion and are inhibitors
of the gastric H+/K+-ATPase. The usual dose of pantoprazole is 20 to 40 mg. In typical
doses, these drugs diminish the daily production of acid (basal and stimulated) by 80% to
95%. PPIs are widely used for treating acid induced inflammation, ulcers of the stomach
and duodenum, GERD, erosive esophagitis, heartburn, upper gastrointestinal bleeding in
critically ill patients, and Zollinger-Ellison Syndrome. They are also used in combination
with antibiotics for eradicating H. pylori infection of the stomach.
Administration of conventional tablets of PPIs has been reported to exhibit
longer lag time as they are enteric coated and fluctuations in the plasma drug levels,
resulting either in reduction in drug cocn. in the blood.
Thus ODTs can act as a dosage form which can nullify all the drawbacks and
problems related to conventional enteric coated formulation with additional advantages of
increased patient compliance and quick relief.

FURTHER AVENUES FOR EXPLORATION:
Present work was an attempt in designing ODTs for a drug which have
degradation in acidic pH.
 The system can be further worked upon to give a more specific release by using
different superdisintegrants.
 In-vivo study can be carried out in animals for better prediction of in vivo
behaviour using models such as pyloric ligation method, chemical induced ulcer,
stress induced ulcers etc.
 Despite using a modified dissolution apparatus to overcome practical issues in
conducting the dissolution tests, accurate in vivo in vitro correlation is expected
since the in vivo conditions have been mimicked.
 Relative bioavailability studies can be conducted to assess the bioavailabilty of
drug by the ODT product as compared to the conventional oral PPIs preparations.

9. BIBLIOGRAPHY
1. Edwards LD, Fletcher AJ, Fox AW. Principles and practice of pharmaceutical
medicine. 2nd ed. London: JohnWiley & Sons; 2007: p.7-61.
2. Lachman L, Liberman HA, Kaing JL. The theory and practice of industrial pharmacy.
3rd ed. Bombay: Varghese publishing house; 1987: p.293-335.
3. Liberman HA, Lachman L, Schwartz JB. Pharmaceutical dosage forms tablet volume
1. 2nd ed. New York: Marcel dekker inc; 2005 p. 75-7.
4. Ghosh TK, Pfister WR. Drug delivery to the oral cavity molecules to market. U.S.A:
Taylor and Francis group; 2005: p. 261-89.
5. Shukla D, Chakraborty S, Singh S, Mishra B. Mouth dissolving tablets I: An overview
of formunation technology. Sci Pharm 2009; 77: 309-26.
6. Bhowmik D, Krishnakanth CB, Chandira RM. Fast dissolving tablet: An overview. J.
Chem. Pharm. Res. 2009;1 (1): 163-77.
7. Kumaresan C. Orally disintegrating tablet-rapid disintegration, sweet taste, and target
release profile 2008; 6 (5).
8. Bhaskaran S, Narmada GV. Orally disintegrating tablets. Indian Pharmacist 2002; 1
(2): 9-12.
9. Swarbrick, J, Boylan J. Encyclopedia of Pharmaceutical technology, 2nd ed. New
York (NY): Marcel Dekker; 2002: p. 2623-38.
10. http://www.pharmpedia.com
11. Mishra DN, Bindal M, Singh SK, Kumar SGV. Rapidly disintegrating tablets of
Valdecoxib. Indian Drugs 2005; 42: 685-7.

12 Hirwaiker AA, Ramesh M, Fast disintegrating tablets of Atenolol by dry granulation
method. Indian J. Pharm. Sci 2004; 66: 422-6.
13. Devi VK, Asha AN, et al. Oral dispersible Fluconazole tablets - preparation and
evaluation. Indian drugs 2006; 43 (7): 548-52.
14. Mahajan HS, Kuchekar BS, et al. Mouth dissolve tablets of Sumatriptan Succinate.
Ind. J. Pharm. Sci. 2004; 238- 40.
15. Kuchekar BS, Badhan AC, et al. Mouth dissolving tablets of Salbutamol Sulphate: a
novel drug delivery system. Indian drugs 2004; 41 (10): 592-8.
16. Nayak SM, and Gopalkumar P. Design and optimization of fast dissolving tablets for
Promethazine Theoclate. Indian drugs 2004; 41 (9): 554-6.
17. Patel DM, Patel NM, et al. Studies in formulation of ODTs of Rofecoxib. Ind. J.
Pharm. Sci. 2004; 66 (5): 621-5.
18. Desai SA, Ferade SV. Orodissolving tablets of Promethazine Hydrochloride. Ind. J.
Pharm. Edu. Res. 2006; 40 (3): 172-4.
19. Patel MM, and Patel DM. Fast dissolving Valdecoxib tablets containing solid
dispersion of Valdecoxib. Ind. J. Pharm. Sci 2006; 68 (2): 222-6.
20. Poornima D, Anita R, et al. Patient compliant dosage form for Roxithromycin. Ind. J.
Pharm. Sci. 2004; 670- 3.
21. Gilman AG. The Pharmacological basis of therapeutics. 10th ed. NewYork: McGraw-
Hill; 2001: p.1005-20.
22. Tripathi KD. Essential of Medicinal Pharmacology 6th ed. New Delhi: Jaypee
brothers medical publishers (P) ltd; 2008: p. 627-38.

23. Wilson, Gisvold, Block JH. Textbook of organic medicinal and pharmaceutical
chemistry. 11th ed. Philadelphia: Lippincott Williams and Wilkins; 2004: p. 722-27.
24. Tortora GJ, Grabowski SR. Principles of anatomy and physiology. U.S.A : John
Wiley & sons; 2003: p.866-70.
25. http://www.cims.com
26. Guyton AC, Hall JE. Textbook of Medical Physiology. Singapore: Harcourt Brace
and company; 1998: p.793-851.
27. Jungnickel PW. Pantoprazole: A new proton pump inhibitor clinical therapeutics
2000; 22 (11): 1268-93.
28. Bell W, Staar U and Sewing KF. Pantoprazole: a novel H+/K+-ATPase inhibitor with
an improved pH stability. Eur. J. of Pharmacol. 1992; 218: 265-71.
29. Li XQ et al. Comparison of inhibitory effects of the proton pump inhibiting drugs
Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole, and Rabeprazole on human
cytochrome p450 activities. The Amer. Soc. for Pharmacol. and Expt. Therap. 2004;
32 (8): 821-7.
30. Tutuian R et al. Dose-dependent control of intragastric pH by Pantoprazole, 10, 20 or
40 mg, in healthy volunteers. Aliment Pharmacol Ther. 2002; 16: 829–36.
31. Raghunath AS et al. a review of the clinical and economic impact of using
esomeprazole or lansoprazole for the treatment of erosive esophagitis. Clin.
Therap. 2003; 25 (7): 2088-101.
32. Numans ME et al. Short-term treatment with proton-pump inhibitors as a test for
gastroesophageal reflux disease. Ann. Intern. Med. 2004; 140: 518-27.

33. Ren S et.al. Effect of pharmaceutical excipients on aqueous stability of Rabeprazole
sodium. Int. J. Pharma. 2008; 350: 197–204.
34. Armstrong D. Oral Esomeprazole vs. intravenous Pantoprazole: a comparison of the
effect on intragastric pH in healthy subjects. Aliment. Pharmacol. Ther. 2003; 18:
705–711.
35. Wahbi AAM et al. Spectrophotometric determination of Omeprazole, Lansoprazole
and pantoprazole in pharmaceutical formulations. J. Pharm. Biomed. Ana. 2002; 30:
1133-42.
36. Moustafa AAM. Spectrophotometric methods for the determination of Lansoprazole
and Pantoprazole Sodium Sesquihydrate. J. Pharma. Biomed. Ana. 2000; 22: 45–58.
37. Ramakrishna NVS et al. High-performance liquid chromatography method for the
quantification of Pantoprazole in human plasma. J. Chroma. B 2005; 822: 326–29.
38. Rajic KK, et al. First-order UV-derivative spectrophotometry in the analysis of
omeprazole and pantoprazole sodium salt and corresponding impurities. Journal of
Pharmaceutical and Biomedical Analysis 2003; 32: 1019-27.
39. Farinha A. Bioequivalence evaluation of two omeprazole enteric-coated formulations
in humans. European Journal of Pharmaceutical Sciences 1999; 7: 311–5.
40. Choi HG, Kim CK, et al. Development of omeprazole buccal adhesive tablets with
stability enhancement in human saliva. Journal of Controlled Release 2000; 68: 397-
404.
41. Choi HG, Jung JH, et al. Formulation and in vivo evaluation of omeprazole buccal
adhesive tablet. Journal of Controlled Release 2000; 68: 405–12.

42. Gohel MC, Mehta PR, Dave RK, Bariya NH. A more relevant dissolution method for
evaluation of floating drug delivery system. Dissolutiontechnologies.2004;22-5.
43. Garcia CV, et al. Development and validation of a dissolution test for rabeprazole
sodium in coated tablets. Journal of Pharmaceutical and Biomedical Analysis 2004;
41: 833-7.
44. Bladh N, et al. A new esomeprazole packet (sachet) formulation for suspension: in
vitro characteristics and comparative pharmacokinetics versus intact capsules/tablets
in healthy volunteers. Clinical Therapeutics 2007; 29(4): 640-9.
45. F. Baldi, et al. Lansoprazole fast disintegrating tablet: a new formulation for an
established proton pump inhibitor. Digestion 2003; 67: 1–5.
46. Silver DI, et al. Lansoprazole orally disintegrating tabets. US 2007/0202169 A1.
47. Kundu S and Sahoo PK. Recent trends in the developments of orally disintegrating
tablet technology. Pharma Times 2008; 40(4): 11-20.
48. Bhowmik D, et al. Fast dissolving tablet: an overview journal of chemical and
pharmaceutical research 2009; 1(1): 163-77.
49. Hirani JJ, et. al. Orally disintegrating tablets: a review. Tropical Journal of
Pharmaceutical Research 2009; 8 (2): 161-72.
50. Fu Y, et al. Orally fast disintegrating tablets: developments, technologies, taste-
masking and clinical studies. Therapeutic Drug Carrier Systems 2004; 21(6): 433–75.
51. Fini A, et al. Fast dispersible/slow releasing ibuprofen tablets. European Journal of
Pharmaceutics and Biopharmaceutics 2008; 69: 335–41.
52. Schiermeier S. and Schmidt PC. Fast dispersible ibuprofen tablets. European Journal
of Pharmaceutical Sciences 2002; 15: 295–305.

53. Venkatesh GM. et. al Orally disintegrating tablets of atomoxetine. US2006/0057199
A1.
54. Puttewar TY. et al. Formulation and evaluation of orodispersible tablet of taste
masked doxylamine succinate using ion exchange resin. Journal of King Saud
University (Science). Science direct 2010 article in press.
55. Okuda Y, et al. A new formulation for OrDTsusing a suspension spray-coating
method. International Journal of Pharmaceutics 2009; 382: 80–7.
56. Shoukri RA, et al. In vitro and in vivo evaluation of nimesulide lyophilized orally
disintegrating tablets. European Journal of Pharmaceutics and Biopharmaceutics 2009;
73: 162–71.
57. Kuno Y, et al. Evaluation of rapidly disintegrating tablets manufactured by phase
transition of sugar alcohols. Journal of Controlled Release 2005; 105: 16–22.
58. Goverment of India ministry of health and family welfare. The Indian Pharmacopoeia
commission Vol-3. Ghaziabad ;Controller of publications 2010; p.1813-9; 1856-8.
59. http://www.rxlist.com/protonix-drug.htm
60.http://en.winkipedia.org/winki/pantoprazole_sodium
61. Rowe RC, Sheskey PJ and Owen SC. Handbook of Pharmaceutical Excipients. 5th
ed. Chicago: Pharmaceutical press; 2006: p. 14-704.
62. Niazi SK. Hand book of preformulation. New York; informa health care; 2007: p. 1-
7.
63. Patel DM. et al. Optimization of fast dissolving Etoricoxib tablets prepared by
sublimation technique. Journal of Pharmaceutical Science 2008; 70: 71-6.

64 Sinko PJ. Martin‘s Physical Pharmacy and Pharmaceutical Sciences. 5th ed.
Philadelphia.: Lippincott Williams & Wilkins; 2006: p. 558.
65. Aulton ME. Pharmaceutics the science of dosage form design. 2nd ed. Philadelphia:
Churchill livingstone; 2005: p. 201-7.
66. Gohel MC, Sarvaiya KG, Shah AR, Brahmbhatt BK. Mathematical approach for the
assessment of similarity factor using a new scheme for calculating weight. Indian J
Pharm Sci 2011; 71: 142-4.

10. ANNEXURES

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FORMULATION DEVELOPMENT AND

CHAUDHARI JITESH JAGDISH

Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore,

In partial fulfillment of the requirements for the degree of

Under the guidance of

Dr. GOPAL MURALIDHARAN

DECLARATION BY THE CANDIDATE

I hereby declare that the matter embodied in the

DATE: Mr. CHAUDHARI JITESH JAGDISH

This is to certify that the dissertation entitled

DATE: Dr. GOPAL MURALIDHARAN

This is to certify that the dissertation entitled

DATE: Mr. HARISH JAIN

This is to certify that the dissertation entitled “Formulation

DATE: Dr. C. S. R. LAKSHMI

This is to certify that the dissertation entitled “Formulation

DATE: Dr. L .V. G. NARGUND

DECLARATION BY THE CANDIDATE

I hereby declare that the Rajiv Gandhi University

DATE: Mr. CHAUDHARI JITESH JAGDISH

© Rajiv Gandhi University of Health Sciences, Karnataka.

λmax : Lambda max

ACH : Acetyl choline

AMP : Adenosine mono phosphate

AUC : Area under curve

CCS : Croscarmellose sodium

CNS : Central nervous system

CPDR : Cumulative percent drug release

DDS : Drug delivery system

et al. : and others

FDA : Food and Drug administration

FDT : Fast dispersible tablets

FTIR : Fourier transformed infrared spectroscopy

GERD : Gastroesophageal Reflux disease

HCL : Hydrochloric acid

HPLC : High performamce liquid chromatography

KBr : Potassium bromide

KHCO3 : Potassium bicarbonate

L-HPC : Hydroxy propyl cellulose low substituted

LBD : Lose bulk density

LFDT : Lansoprazole fast disintegrating tablet

Mannitol DC : Directly compressible Mannitol

MDDDS : Mouth dissolving drug delivering system

NaHCO3 : Sodium bicarbonate

ODDs : Oral drug delivery system

OrDTs : Orally disintegration tablets

pH : Negative logarithm of hydrogen ion concentration

PhEur : European Pharmacopoeia

PPIs : Proton pump inhibitors

rpm : revolutions per minute

RDGs : Rapid disintegrating granules

SSF : Sodium steryl fumerate

SSG : Sodium starch glycolate

TAG : Treated agar powder

t½ : Time required to reduce the amount to its half

TBD : Tapped bulk density

USP : United States of Pharmacopoeia

BACKGROUND AND OBJECTIVE:

pump (K+/H+ -ATPase) in the parietal cell secretory membrane.