Download Bahauddin Zakariya University Multan Pakistan.

FORMULATION DEVELOPMENT OF RANITIDINE
HYDROCHLORIDE CONTAINING WAFERS AND ITS
IN-VITRO KINETIC STUDIES
A thesis submitted
in partial fulfillment of the requirements for the degree
of
MASTER OF PHILOSOPHY
(Pharmaceutics)
By
RAUF-UR-REHMAN
04-PHP-S-14
Session: 2014-2016
Department of Pharmacy
Bahauddin Zakariya University
Multan
Pakistan.
I
II
IN THE NAME OF ALLAH
THE MOST GRACIOUS, THE MOST MERCIFUL
“...Say: ‘Are those equal, those who know and those who do not know?
It is those who are endowed with understanding that receive admonition.”
(Qur’an, 39:9)
Saying of Prophet Muhammad (PBUH)
“A believer is never satiated with gainful knowledge; he goes acquiring it till his
death and entry into Paradise.”
(Tirmidhi 222)
Saying of Prophet Muhammad (PBUH)
Teach! Make things easy! And do not make them complicated! Be
cheerful! And do not be Repulsive.”
III
Declaration
I, Rauf-ur-Rehman S/o Muhammad Siddique M. Phil (Pharmaceutics) Scholar of the Department
of Pharmacy, Bahauddin Zakariya University Multan, hereby declare that the research work
entitled “Formulation Development of Ranitidine Hydrochloride containing wafers and its
invitro kinetic studies” is done by me. I also certify that nothing has been incorporated in this
thesis work without acknowledgment and that to the best of my knowledge and belief that it does
not contain any material previously published or written by any other person or any material
previously submitted for a degree in any university where due reference is not made in the text.
Rauf-ur- Rehman S/o Muhammad Siddique
IV
Supervisor’s Declaration
It is hereby certified that work presented by Rauf-ur-Rehman in the thesis entitled
“Formulation Development of Ranitidine Hydrochloride containing wafers and its invitro
kinetic studies” is based on the result of research study conducted by candidate under my
supervision. No portion of this thesis work has formerly been offered for higher degree in this
university or any other institute of learning and to best of the author’s knowledge, no material
has been used in this thesis which is not his own work, except where due acknowledgement has
been made. He has fulfilled all the requirements and qualified to submit this thesis in partial
fulfillment for the degree of Master of Philosophy (MPhil. Pharmaceutics) in the Department of
Pharmacy, Bahauddin Zakariya University Multan.
Dr. Muhammad Hanif
Research Supervisor,
Assistant Professor,
Department of Pharmacy,
Bahauddin Zakariya University Multan
Pakistan.
V
Certificate
It is hereby certified that work presented by Rauf-ur-Rehman S/o Muhammad Siddique in the
thesis entitled “Formulation Development of Ranitidine Hydrochloride containing wafers and
its in-vitro kinetic studies” has been successfully presented and is accepted in its present form as
satisfying the requirement for the degree of Master of Philosophy (Pharmaceutics) in the
Department of Pharmacy, Bahauddin Zakariya University Multan.
Candidate
Rauf-ur-Rehman
Supervisor
Dr. Muhammad Hanif
Assistant Professor
Chairman
Department of Pharmacy
Bahauddin Zakariya University Multan.
VI
Dedication
To,
All family members, especially my Father and Mother, for their efforts in putting their children
to the pursuit of knowledge. Throughout my life, they have supported me in my determination to
find and realize my potential. Thanks for their unconditional love and support throughout the
course of this thesis. My brothers, and Late sister. Finally my most respected teacher Dr.
Muhammad Hanif and
truly loving friends who have always been a source of love, care and
strength for me.
VII
Acknowledgment
Words are bound and knowledge is limited to praise Almighty ALLAH, the Lord of words, the gracious,
most beneficent, the compassionate, and the merciful and with the blessings of whom the pavements of
my life became smooth. Countless blessings upon Holy Prophet HAZRAT MUHAMMAD‫ ﷺ‬who have
shown the right direction to humanity and thereby enlightening their ways with faith through his eternal
teachings.
My sincere gratitude to my worthy supervisor Dr. Muhammad Hanif, Assistant Professor of
Pharmaceutics, Faculty of Pharmacy Bahauddin Zakariya University, Multan, Pakistan for his
professional guidance, supportive attitude, and scientific advice throughout the research work
despite of his multifarious engagements. His inspiring help, consistent encouragement and
affectionate behavior during the entire study duration will ever be remembered.
I am grateful and feel highly privileged in Prof. Dr. Nazar Muhammad Ranjha (Chairman
Department of Pharmacy BZU Multan) who maintained discipline that acts as a bridge between
my target and accomplishment.
Appreciation goes to the teaching and non-teaching staff of the department of Pharmacy whose
encouragement contributed significantly to the successful completion of my work.
Words are inadequate to express my special thanks to my parents, brothers, sisters, my M.Phil.
Seniors, fellows especially my best friend and other junior research fellows whose nice
company, prayers for my success, moral support and special care encouraged me to achieve goal.
Rauf-ur-Rehman
VIII
Table of Contents
Supervisor’s Declaration .................................................................................................... ……….V
Certificate ............................................................................................................................ ………VI
Dedication ............................................................................................................................ ……..VII
Acknowledgment ................................................................................................................. ……..VIII
Table of Contents ................................................................................................................ ………IX
List of figures……………………………………………………………………….…..………XIII
List of Tables ....................................................................................................................... ……...XVI
List of abbreviation ............................................................................................................. ……..XVII
Abstract ................................................................................................................................ ……...XIX
1.
2.
Introduction ................................................................................................................. …………1
1.1.
Types of wafers ................................................................................................................ 2
1.2.
Polymers used in Wafers preparations ............................................................................. 4
1.3.
Hydroxypropyl methyl cellulose (HPMC) ....................................................................... 5
1.4.
Carboxy methylcellulose sodium (CMC) ........................................................................ 5
1.5.
Guar gum (GG) ................................................................................................................ 5
1.6.
Pectin (PC) ....................................................................................................................... 6
1.7.
Polyethylene Glycol (PEG 200) ....................................................................................... 6
Drug profile .................................................................................................................. ……..8
2.1.
Description ....................................................................................................................... 8
2.2.
Molecular formula ............................................................................................................ 8
2.3.
Chemical formula ............................................................................................................. 8
2.4.
Chemical name ................................................................................................................. 8
2.5.
Characteristics of Ranitidine hydrochloride:.................................................................... 9
2.6.
Solubility of Ranitidine .................................................................................................... 9
2.7.
Pharmacology ................................................................................................................... 9
2.7.1.
Pharmacokinetic ........................................................................................................ 9
IX
2.7.2. Volume of distribution ..................................................................................................... 10
2.7.3.
Metabolism and Excretion ...................................................................................... 10
2.7.4.
Pharmacodynamics ................................................................................................. 10
2.7.5.
Clinical indications ................................................................................................. 11
2.7.6.
Adverse effects........................................................................................................ 11
2.7.7.
Dosage and administration ...................................................................................... 11
2.7.8.
Contraindication ...................................................................................................... 12
2.7.9.
Cautions .................................................................................................................. 12
2.7.10.
Pregnancy category ................................................................................................. 12
2.7.11.
Toxicity signs and symptoms.................................................................................. 12
2.7.12.
Management of toxicity .......................................................................................... 13
3.
4.
Literature review ......................................................................................................... ……14
3.1.
Hydroxypropyl methylcellulose (HPMC) ...................................................................... 14
3.2.
Pectin wafers .................................................................................................................. 17
3.3.
Carboxy methyl cellulose wafers (CMC)....................................................................... 18
3.4.
Guar gum containing wafers .......................................................................................... 19
3.5.
Sodium alginate and gelatin wafers ............................................................................... 21
3.6.
Polyethylene glycol (PEG) wafers ................................................................................. 24
Material and Method................................................................................................... ……27
4.1
. Chemicals .................................................................................................................... 27
4.2
. Apparatus /equipment .................................................................................................. 27
4.3.
Experimental design (Box- Behnken) ............................................................................ 28
4.4.
Preparation of wafers ..................................................................................................... 29
4.5.
Characterization of wafers ............................................................................................. 30
4.5.1.
Physical parameters of wafers ................................................................................ 30
4.5.2.
Surface pH .............................................................................................................. 30
4.5.3.
Wafers thickness ..................................................................................................... 30
4.5.4.
Weight variation test ............................................................................................... 30
4.5.5.
Swelling index ........................................................................................................ 31
4.5.6.
Percentage moisture absorption (PMA) .................................................................. 31
X
4.5.7.
Percentage moisture loss (PML) ............................................................................. 31
4.5.8.
In-vitro mucoadhesion test ...................................................................................... 31
4.5.9.
Folding endurance ................................................................................................... 31
4.5.10.
Disintegration time.................................................................................................. 31
4.5.11.
Total dissolving time (TDT) ................................................................................... 32
4.6.
Morphological studies .................................................................................................... 32
4.6.1.
Scanning Electron Microscopy (SEM) ................................................................... 32
4.6.2.
Optical microscopy ................................................................................................. 32
4.7.
FTIR spectroscopy ......................................................................................................... 32
4.8.
Content uniformity ......................................................................................................... 33
4.9.
Stability studies .............................................................................................................. 33
4.10.
Dissolution study ........................................................................................................ 33
4.11.
Release kinetics .......................................................................................................... 33
4.11.1.
Zero order release ................................................................................................... 33
4.11.2.
First order release .................................................................................................... 34
4.11.3.
Higuchi model ......................................................................................................... 34
4.11.4.
Korsmeyer-peppas model ....................................................................................... 34
5.
Result and Discussion .................................................................................................. ……35
5.1.
Organoleptic evaluation ................................................................................................. 35
5.2.
Effects of excipients on various parameters of wafers formulations ............................. 35
5.3.
Physicochemical parameters .......................................................................................... 43
5.3.1.
Surface pH .............................................................................................................. 43
5.3.2.
Wafers thickness ..................................................................................................... 43
5.3.3.
Weight variation test ............................................................................................... 45
5.3.4.
Swelling index ........................................................................................................ 51
5.3.5.
Percentage moisture absorption (PMA) .................................................................. 53
5.3.6.
Percentage moisture loss (PML) ............................................................................. 54
5.3.7.
In-vitro mucoadhesion test ...................................................................................... 54
5.3.8.
Folding endurance ................................................................................................... 57
5.3.9.
Disintegration time.................................................................................................. 57
5.3.10.
Total dissolving time (TDT) ................................................................................... 59
XI
5.4.
Morphological studies .................................................................................................... 64
5.4.1.
Microscopic images of wafers ................................................................................ 64
5.4.2.
SEM of wafers formulations ................................................................................... 65
5.5.
FTIR studies ................................................................................................................... 65
5.6.
Content uniformity of wafers ......................................................................................... 68
5.7.
Stability studies .............................................................................................................. 68
5.8.
Preparation of standard /calibration curve ..................................................................... 69
5.9.
Dissolution studies ......................................................................................................... 70
5.9.1.
Kinetic models of formulations (FI-FIII) ................................................................ 72
5.9.2.
In-vitro kinetics of formulation (FIV-FVI) ............................................................. 78
5.9.3.
In-vitro kinetics of formulation (FVII-FIX) ........................................................... 84
5.9.4.
Kinetic models of formulation (FX-FXII) .............................................................. 91
5.10.
Discussion ................................................................................................................... 98
5.11.
Conclusion ................................................................................................................ 100
6.
Refrence ........................................................................................................................ …..101
XII
List of figures
Figure 1: Excipients effect on surface pH of Formulations (FI-FIII) ........................................... 36
Figure 2: Excipients effect on folding endurance of formulations (FI-FIII) ................................ 36
Figure 3: Excipients effect on mucoadhesion time of formulations (FI-FIII) .............................. 36
Figure 4: Excipients effect on percentage moisture loss of formulations (FI-FIII) ..................... 37
Figure 5: Effect of excipients on surface pH of formulations (FIV-FVI)..................................... 37
Figure 6: Effect of excipients on folding endurance of formulations (FIV-FVI) ......................... 38
Figure 7: Excipients effect on in-vitro mucoadhesion time of formulation (FIV-FVI) ................ 38
Figure 8: Excipients effect on percentage moisture loss of formulations (FIV-FVI) ................... 39
Figure 9: Excipients effect on surface pH of formulations (FVII-FIX)........................................ 39
Figure 10: Excipients effects on folding endurance of formulations (FIV-FVI) .......................... 40
Figure 11: Excipients effect on mucoadhesion time of formulations (FIV-FVI) ......................... 40
Figure 12: Excipients effect on moisture loss of formulations (FVII-FIX) .................................. 41
Figure 13: Excipients effect on surface pH of formulations (FX-FXII) ....................................... 41
Figure 14: Excipients effect on folding endurance of formulation (FX-FXII) ............................. 42
Figure 15: Excipients effect on in-vitro mucoadhesion of formulations (FX-FXII) .................... 42
Figure 16: Excipients effect on moisture loss of formulations (FX-FXII) ................................... 43
Figure 17: Thickness of wafers formulations FI-FIII (n=5) ......................................................... 44
Figure 18: Thickness of wafers formulations FIV-FVI (n=5) ...................................................... 44
Figure 19: Thickness of wafers formulations FVII-FIX (n=5) ..................................................... 45
Figure 20: Thickness of wafers formulations (FX-FXII) ............................................................. 45
Figure 21: Weight variation of wafers formulationF1 (n=20) ...................................................... 46
Figure 22: Weight variation of wafers formulation FII (n=20) .................................................... 46
Figure 23: Weight variation of wafers formulation FIII (n=20) ................................................... 47
Figure 24: Weight variation of formulation FIV (n=20) .............................................................. 47
Figure 25: Weight variation of formulation FV (n=20) ................................................................ 48
Figure 26: Weight variation of formulation (FVI) ........................................................................ 48
Figure 27: Weight variation of formulation FVII (n=20) ............................................................. 49
Figure 28: Weight variation of formulation FVIII (n=20) ............................................................ 49
Figure 29: Weight variation of formulation FIX (n=20) .............................................................. 50
Figure 30: Weight variation of formulation FX (n=20) ................................................................ 50
Figure 31: Weight variation of formulation XI (n=20)................................................................. 51
Figure 32: Weight variation of formulation XII (n=20) ............................................................... 51
Figure 33: Percentage radial swelling of formulations FI-FIII (n=5) ........................................... 52
Figure 34: Percentage radial swelling of formulations FIV-FVI .................................................. 52
Figure 35: Percentage radial swelling of formulations FVII-FIX (n=5)....................................... 53
Figure 36: Percentage radial swelling of formulations FX-FXII (n=5) ........................................ 53
Figure 37: In-vitro mucoadhesion time of wafers formulations FI-FIII ....................................... 55
Figure 38: In-vitro mucoadhesion time of wafers formulations FIV-FVI .................................... 55
XIII
Figure 39: In-vitro mucoadhesion time of wafers formulations FVII-FIX) ................................. 56
Figure 40: In-vitro mucoadhesion of wafers formulations FX-FXII ............................................ 57
Figure 41: Disintegration time of formulations (FI-FIII) ............................................................. 58
Figure 42: Disintegration time of formulations from FV-FVI...................................................... 58
Figure 43: Disintegration time of formulation (FVII-FIX)........................................................... 59
Figure 44: Total dissolving time of wafers formulations FI-FIII ................................................. 60
Figure 45: Total dissolving time of wafers formulation FIV-FVI ................................................ 60
Figure 46: Total dissolving time of wafers formulation FVII-FIX............................................... 61
Figure 47: Total dissolving time of wafers formulation FX-FXII ................................................ 61
Figure 48: Total dissolving time of wafers formulation FII, FV, FVIII and FXII ....................... 62
Figure 49: Total dissolving time of wafers formulation FV, FVIII .............................................. 62
Figure 50: Total dissolving time with agitation formulation FI-FIII ............................................ 63
Figure 51: Total dissolving time of wafers formulations FIV-FVI .............................................. 63
Figure 52: Total dissolving time of wafers formulations from FVII-FIX .................................... 64
Figure 53: Microscopic images wafers prepared with (HPMC) ................................................... 65
Figure 54: Microscopic images of wafers prepared with Pectin................................................... 65
Figure 55: FTIR spectra (A) Ranitidine HCL (B)Pectin ,(C) Pectin wafers ,(D) CMC wafers and
(E) HPMC wafers ......................................................................................................................... 67
Figure 56: Calibration curve of ranitidine .................................................................................... 70
Figure 57: Percentage drug release of wafers formulation FI-FIII ............................................... 70
Figure 58: Percentage drug release of wafers formulations FIV-FVI .......................................... 71
Figure 59: Percentage drug release of wafers formulations FVII-FIX ......................................... 72
Figure 60: Percentage release of wafers formulations FX-FXII ................................................... 72
Figure 61: Zero order release models of formulation FI............................................................... 73
Figure 62 : Higuchi release model of wafers formulation (FI) ..................................................... 74
Figure 63: Korsmayer-peppas model of wafers formulation (FI) ................................................. 74
Figure 64: Zero order release model of wafers formulation (FII) ................................................ 75
Figure 65: First order release model of wafers formulation (FII) ................................................. 75
Figure 66: Higuchi release model of wafers formulation (FII) ..................................................... 76
Figure 67: Korsmeyer-peppas release model of (FII) ................................................................... 76
Figure 68: Zero order release model of wafers formulation (FIII) ............................................... 77
Figure 69: First order release model of wafers formulation (FIII) ............................................... 77
Figure 70: Higuchi release model of wafers formulation (FIII) ................................................... 77
Figure 71: Korsmeyer-peppas model of wafers formulations (FIII) ............................................ 78
Figure 72: Zero order release model of wafers formulation (FIV) ............................................... 79
Figure 73: First order release model of wafers formulation (FV) ................................................ 79
Figure 74: Higuchi release model of wafers formulation (FIV) ................................................... 80
Figure 75: Korsmeyer-Peppas release model of wafers formulation (FIV) ................................. 80
Figure 76: Zero order release model of formulation (FV) ............................................................ 81
Figure 77: First order release model of wafers formulation (FV) ................................................ 82
XIV
Figure 78: Higuchi release model of wafers formulation (FV) .................................................... 82
Figure 79: Korsmayer-peppas release model of wafers formulation (FV). .................................. 82
Figure 80: Zero order release model of wafers formulation (FVI) ............................................... 83
Figure 81: First order release model of wafers formulation (FVI) ............................................... 83
Figure 82: Higuchi release model of wafers formulation (FVI) ................................................... 84
Figure 83: Korsmeyer-peppas release model of wafers formulation (FVI) .................................. 84
Figure 84: Zero order release model of wafers formulation (FVII).............................................. 85
Figure 85: First order release model of wafers formulation (FVII) .............................................. 86
Figure 86: Higuchi release model of wafers formulation (FVII) .................................................. 86
Figure 87: Korsmeyer-peppas model of wafers formulations (FVII) ........................................... 87
Figure 88: Zero order release model of FVIII .............................................................................. 87
Figure 89: First order release model of wafers formulation (FVIII) ............................................ 88
Figure 90: Higuchi release model of wafers formulations (FVIII) ............................................... 88
Figure 91: Korsmeyer peppas release model of formulation (FVIII) ........................................... 89
Figure 92: Zero order release model of wafers formulation (FIX) ............................................... 89
Figure 93: First order release model of wafers formulation (FIX) ............................................... 90
Figure 94: Higuchi release model of wafers formulation (FIX) ................................................... 90
Figure 95: Korsmeyer-peppas release model of wafers formulation (FIX) ................................ 91
Figure 96: Zero order release model of wafers formulation (FX) ................................................ 92
Figure 97: First order release model of wafers formulation (FX) ................................................ 92
Figure 98: Higuchi release model of wafers formulation (FX) .................................................... 93
Figure 99: Korsmeyer-peppas release model of wafers formulation (FX) ................................... 93
Figure 100: Zero order release model of wafers formulation (FXI) ............................................. 94
Figure 101: First order release model of wafers formulation (FXI) ............................................. 94
Figure 102: Higuchi release model of wafers formulation (FXI) ................................................. 95
Figure 103: Korsmeyer peppas release model of wafers formulation (FXI) ................................ 95
Figure 104: Zero order release model of wafers formulation (FXII) .......................................... 96
Figure 105: First order release model of wafers formulation (FXII) ............................................ 96
Figure 106: Higuchi release model of wafers formulation (FXII) .............................................. 97
Figure 107: Korsmeyer peppas release model of wafers formulation (XII) ................................. 97
XV
List of Tables
Table 1: Mucoadhesive strength of natural and synthetic polymers............................................... 4
Table 2: Mucoadhesive strength of natural and synthetic polymers............................................... 7
Table 3: Coded values of the variables of Box-behnken design for wafers formulation ............. 28
Table 4. Composition of formulations of Ranitidine hydrochloride 50mg wafers (All quantities
were given in %ages) .................................................................................................................... 29
Table 5: Evaluation of various physical parameters of ranitidine hydrochloride wafers ............. 54
Table 6: Stability studies of Ranitidine hydrochloride wafers...................................................... 69
Table 7: In-vitro drug release kinetics and its model dependent approaches (FI-FIII) ................ 73
Table 8: In-vitro drug release kinetics and its model dependent approaches (FIV-FVI) ............. 78
Table 9: In-vitro drug release kinetics and model dependent approaches (FVII-FIX) ............... 85
Table 10: In-vitro release kinetics model dependent approaches (FX-FXII) ............................... 91
XVI
List of abbreviation
GRDDS
Gastroretantive drug delivery system
NDDS
Novel drug delivery system
GIT
Gastrointestinal tract
SV
Surface to volume ratio
HPMC
Hydroxypropyl methyl cellulose
NaCMC
Sodium carboxymethyl cellulose
PVP
Polyvinyl pyrollidone
GG
Guar gum
PC
Pectin
PEG
Polyethylene glycol
FE
Folding endurance
GIF
Gastrointestinal fluid
SEM
Scanning Electron Microscopy
FTIR
Fourier Transform Infrared Spectroscopy
RNH
Ranitidine Hydrochloride
NZD
Nizatidine
XVII
ABA
Absolute bioavailability
SR
Sustained release
QID
Four times a day
PCM
Paracetamol
RSM
Response surface methodology
UV
Ultra Violet
TDT
Total dissolving time
PMA
Percentage moisture absorption
PML
Percentage moisture loss
CU
Content Uniformity
PM
Petri plate method
XVIII
Abstract
Aim of study was to develop the sustained release wafers by using solvent casting technique with
various concentration of natural and synthetic polymers, plasticizers and surfactant. Box
Benkhen design was applied to observe the effect of excipients on wafers formulations. Six
formulations of each polymer hydroxy propylmethyl cellulose, carboxymethyl cellulose (HPMC,
CMC, Pectin and Guargum) was designed by taking different concentrations of plasticizers and
surfactant. On the bases of physicochemical parameters like surface texture, surface pH, tack
test, weight variation wafers thickness, folding endurance, radial swelling, moisture loss,
percentage moisture absorption, invitro mucoadhesion time, disintegration time, total dissolving
time, content uniformity were applied and three among the six formulations of each polymer
were optimized. Ranitidine hydrochloride was used as model drug in selected wafer
formulations. FTIR analysis and stability studies were carried out to evaluate the excipient
interactions and there was no interaction observed. FTIR spectra of drug, polymers and prepared
wafers showed peaks at 3300cm-1, 1640cm-1, 1590cm-1 and 1051cm-1 due to –CH2 alkane group
stretching, C=O stretching, carboxylic group stretching and stretching vibration of C-0H group
respectively. Three months stability showed the stable formulations under 75% humidity and 40
± 2 0C while the content uniformity was observed up-to 85-98%. Dissolution studies showed that
formulation FV, FVIII were found to be most suitable for sustained release delivery out of 12
optimized formulations (FI-FXII) these formulations showed more than 85 % drug released after
8 hrs. In-vitro drug release data was analyzed by applying different kinetic models zero order,
first order, higuchi and korsmeyer-peppas to all formulations which showed observe value of R2
in case of first order was very close to 1 indicating concentration dependent release of drug.
First order release model results showed that R2 value of formulation FVIII was very close to 1
showed best release pattern out of all formulations. Korsmeyer –peppas model was applied
results showed n value of all formulation were observed to be less than 0.45 showed fickian
release pattern.
XIX
Keywords: Wafers; solvent casting method; mucoadhesion; in-vitro drug release; release kinetic
models; tackiness.
XX
1. Introduction
Various routes are used for adminstration of drugs to the human body these routes includes oral
parental, intrathecal and subcutaneous, however the oral route has gained much more importance
due to its ease of administration [1]. In oral dosage systems various oral dosage forms includes
liquids, solids and wafers are given much more importance. Pharmatechnologist have an urge to
develop such dosage forms which are used as conventional dosage systems [2].
Conventional dosage system employed for treatment of various diseases, tablet is preferred due
to its ease of administration ease of manufacturing process as compared to other dosage forms
however is not suitable for elderly patients and children.
Most recently pharmaceutical industry is going to divert their research from conventional dosage
forms to novel drug delivery system based on changing patient requirements and global
development. The novel micropartices, lozenges, wafers and films are being made during the last
couple of decades. Wafers are the one of most advance drug delivery system used for the
management of diseases. Wafers disintegrate or dissolute when they come in contact with the
oral mucosa or mucosa of the gastrointestinal tract.
Wafers have porous structure and a relatively more surface area as compared to the other dosage
forms therefore they also have more drug loading capacity. There are however certain limitations
for the development of wafers formulations which need considerable attention with respect to
solubility of drug, polymer mucoadhesive property which achieves efficient targeted delivery
and its bioavailability.
Wafers as novel drug delivery system shows certain benefits such as rapid disintegration,
controlled release, measured (accurate quantity) can be administered, improved patient
compliance, efficacy(E) and safety However, as controlled released drug delivery system can
also be used either as mucoadhesive wafers formulations or as gastroretantive drug delivery
system (GRDDS) thus enhance retention time in gastric fluid. Drugs that are less absorbed
through the intestine or those having the narrow therapeutic window. Therefore, to maintain the
therapeutic concentration of drug in a suitable range for the management of either acute or
chronic diseases, it becomes compulsory to administer drugs multiple times in a day, due to
1
which a significant variations takes place. For all categories of treatment, a major challenge is to
define the optimal dose, time, rate, and. Recent developments in drug delivery techniques make
it possible to control the rate of drug delivery to sustain the duration of therapeutic activity and
or target the delivery of drug to a special organ or tissue. Many investigations are still going on
to apply the concepts of controlled delivery for a wide variety of drugs.
Changes plasma concentration causes changes in steady state level which results in improved
therapeutic efficacy of drugs for sever conditions drug plasma concentration of highly potent
drugs improves drugs safety and efficacy. Utilization of maximum concentration of drugs
depends upon the administered dose sustained release drug delivery system has several
advantages reduction in the frequency toxicity of drugs is reduced there are so many
disadvantages of sustained release drug delivery which includes decreased in the retention time,
bioavailability is not predicted accurately disadvantages of sustained released drug delivery
system can be improved by increasing the retention time of formulations. Novel drug delivery
system (NDDS) is gaining interest in advance pharmaceutical techniques.
1.1. Types of wafers
Various types of the wafers were prepared with different release characteristics such as
mucoadhesive melt away, mucoadhesive sustained release and flash release wafers. Mostly made
by the good film forming agents that provides the good release characteristics and make the
consumers handling and transportation easily, also the manufacturing is almost easy because it
was prepared by simple means. These wafers release drug rapidly and showed rapid onset of
action complete drug releases within 30 seconds site of administration and absorption of these
types of drugs is oral, local or systemic effect is induced by these types of wafers[3]. These
wafers disintegrate rapidly within 1 mint they completely disintegrate and dissolute, the
absorption of the released drug occurs in the gastrointestinal tract (GIT), these shows systemic or
local effect on the body [4].
These wafers formulations releases drugs within 5-30 mints [5]. Drug released for several hours
absorption site is gastric mucosa or gum ,onset of action is delayed, such type of formulations
are suitable for prolonged systemic effect in the body [6].
2
In controlled release drug delivery system the term mucoadhesion was first time introduced in
1980 [7].Therefore, most of researcher start focusing on the phenomena of mucoadhesive
polymers with the mucus of the membrane, Mucoadhesive drug delivery system. Bio adhesion
was used which indicates attachment of molecules of the drug to the biological surface or tissue
of the epithelium, attachment of drug to the mucoadhesive membrane is referred to as
mucoadhesion [8]. Mucoadhesive polymers for sustained release drug delivery system provide
excessive advantage as compared to non mucoadhesive polymers enhanced absorption and
bioavailability of the drugs due to a high surface to volume (S/V) ratio, increase contact time to
mucus layer due to increase absorption of drug increases [8, 9]. Wafers due to
greater
mucoadhesive property at the gastric pH can attach to the surface of tissues of gastric mucosal
tissue due to which it provides systemic and local sustained release of drugs, for sustained
released formulations administration frequency is decreased and enhanced bioavailability
targeted drug delivery using hydrophilic mucoadhesive polymers is increased Mucoadhesion has
become an important issue for the various drugs as mucosa delivery system due to its optimal
potential of targeted delivery where its desired concentration reached at the target site
gastrointestinal mucosa or the buccal mucosa.
Mucosal drug delivery system is of significant importance and was widely used for the
administration of mucoadhesive formulations to the sites in the body such as buccal, gastric and
nasal mucosa, also applicable to the wound surface. The contact between the mucosal surface
and the dosage form may be either due to the physicochemical interactions which can plays an
important role in the absorption as well as bioavailability of the drugs. The drug containing
formulation wafers can bind to the mucosal surface which may be either due to the hydration and
swelling which leads to the inter penetration of chains of the polymeric material with the mucin
or mucosal surface. This may be suitable method for the administration of drugs as it reduces the
adverse effect, toxicity, also reduces the choking and pain caused by the parental dosage forms.
Mucoadhesive polymers can be categorized broadly into two classes’ i.e. Hydrophilic polymers
and hydrophobic polymers, based on their solubility and chemical nature. Based on their origin
polymers was categorized into three types, natural polymers, synthetic polymers, semisynthetic
polymers. Hydrophilic polymers which contain carboxylic acid (C=0) group shows efficient
adhesion on the mucosal surface e.g., hydroxypropyl cellulose (HPC), sodium carboxymethyl
3
cellulose (SCMC), methyl cellulose (MC), poly vinyl pyrollidone (PVP), and other cellulose
derivatives. Polymers which possess greater mucoadhesive strength, hydrophobic polymers
showed increased water absorption swelling and epithelial attachment [8].
Table 1: Mucoadhesive strength of natural and synthetic polymers.
Polymers
Mucoadhesive strength
Sodium alginate
+++
Carboxymethyl cellulose
+++
Tragacanth
++
Gelatin
++
Pectin
+
Good (+), very good (++), Excellent (+++)
During the selection of the mucoadhesive polymers it must be considered that it shows maximum
gastrointestinal absorption, degradation by products should be less toxic or nontoxic even in low
doses it must be completely eliminated from body within a short duration of time. It should be
nonirritant to the mucus membrane. It should preferably form a strong covalent bond with the
mucin–epithelial cell surfaces it should adhere quickly to most tissue and should possess some
site specificity. It should allow easy incorporation of the drug and should offer no hindrance to
its release. Polymers should not decomposed on storage or during the shelf life of the dosage
form. Cost of polymer should not be high so that the prepared dosage form remains competitive
in market.
1.2. Polymers used in Wafers preparations
Various polymers were mostly used in formulation preparation for the wafers. Mucoadhesive
polymers can be used either alone or in combination with other polymers. Hydrophilic polymers
were commonly used in wafers development. Various hydrophilic polymers includes HPMC,
sodium carboxymethyl cellulose, pectin, gelatin, hydroxypropyl ethyl cellulose and polyvinyl
pyrrolidone.
4
1.3. Hydroxypropyl methyl cellulose (HPMC)
HPMC use was started in the 1960,s as a US patent of Dow chemical company, however its use
on large scale was started in 1960,s to 1970,s. Hydroxypropyl methyl cellulose are ethers of
cellulose which can be used for manufacturing controlled released formulations. HPMC a
white, off-white granular or fibrous powders which is a synthetic modification of natural
polymers, it is prepared when wood pulp is treated with sodium hydroxide (NaOH), 18%
hydroxypropyl and hydroxymethyl groups are introduced using propylene glycol and methyl
chloride, number of the group added to the molecules give unique property to the polymer like
soluble in cold water, or hot water. HPMC is widely used in the research work due to its
properties such as it cannot interfere with disintegration time and bioavailability of the drug
molecules. Solubility in the aqueous ,organic solvent and gastrointestinal fluids (GIF), odorless,
tasteless, ability to incorporate other colors in to the films due to lack of interaction with
coloring materials [10].
1.4. Carboxy methylcellulose sodium (CMC)
Sodium carboxy methyl cellulose was first prepared in 1918 and introduced commercially in
1920,s by Germany, carboxy methyl cellulose was prepared by treating sodium hydroxide with
akali cellulose and sodium salt of monochlorooacetic acid in the presence of isopropanol or
ethanol as organic solvent [11]. CMC is a water soluble polymer, its viscosity is high in dilute
solutions, it is off-white –white powder having good film forming property, mucoadhesive
strength, thickening effect and Excellent colloids protection [12].
1.5. Guar gum (GG)
Guar gum was obtained from the seeds of the guar plants and exactly present in the endosperm
of the seeds, plant is cosmopolitan in nature and mostly cultivated in Pakistan and India, it is a
polysaccharides composed of β-D-mannopyrunasoyl and galactomannans molecular weight of
Guar gum lies in the range of 50,000-80,000,000[13]. Gaur gum powder is with free flowing
properties which is odorless yellowish white to white in appearance, polymer insoluble in hot
aquous and organic solvents, however it is soluble in cold water and forms a viscous gel, solution
5
has buffering capacity therefore stable at pH 4-10.5.gum is used as emulsifiers, stabilizers and
thickening agent in various dosage forms.
1.6. Pectin (PC)
Major constituents
of plants and citrus fruits, it has very good gelling property pectin
chemically composed of alpha 1-4 galacturonic with methylation of carboxylic groups it is
structurally divided into branched, smooth and hairy region [14]. Pectin is prepared from the
plant cell wall by esterification it was observed that pectin can decreases glucose ,cholesterol
level and also possess anticancer property, in adenocarcinoma patient apoptosis can be induced
by using pectin [15]. Cheapest as compared to other polymers due to low cost of production, also
nontoxic and availability is high, Pectin can be used for delivery of drugs through various routes
like nasally, orally and vaginally also patient compliance is good. Pectin is widely used in
pharmaceutical and food industry [16].
1.7. Polyethylene Glycol (PEG 200)
Plasticizer reduced the glass transition temperature (GT)of the film forming polymers and thus
increases mechanical properties of wafers such as percentage elongation, tensile strength, elastic
strength of wafers formulations, it improves the flexibility and thus reduces the brittleness of the
wafers formed[16]. Depending upon the nature of the solvent plasticizer was selected some most
commonly used plasticizers were Polyethylene glycol, Glycerol, Castor oil, Glycerin. Wafers
are not formed if excessive or low quantity of plasticizer is used [17].
FDC approved colors can be used, however the concentration of coloring material should be less
than 1%. Drug should not be bitter in taste. Solubility of drug should be maximum in water
Penetration in the oral and gastrointestinal tract (GIT) should be Maximum. Stability of drug in
water should be Maximum. Drug having extensive first pass metabolism.
6
Table 2: Mucoadhesive strength of natural and synthetic polymers
Serial No.
Excipients
Max % used
1
Polymer
0-45%
2
Plasticizer
0-20%
3
Colorant
˓˃1%
4
Surfactants
q.s
The main objective of study was development of sustained released (SR) mucoadhesive wafers
contain ranitidine hydrochloride as model drug.
 Due to shortest half-life of Ranitidine hydrochloride and avoid hepatic first pass
metabolism novel dosage form was developed by using various concentrations of natural
and synthetic hydrophilic polymers.
 Synthetic hydrophilic polymers used were hydroxypropyl methyl cellulose, sodium
carboxymethyl cellulose.
 Natural hydrophilic polymers used were Pectin and Guar gum.
 Effect of polyethylene glycols (PEG) different concentrations used in combination with
different concentrations of polymers.
 Effect of surfactant Tween 80 on the disintegration time and dissolution studies of wafers
formulations.
 Various parameters were evaluated such as weight variation, surface pH, folding
endurance (FE), total dissolving time disintegration time.
 In-vitro mucoadhesion, percentage moisture loss, uniformity of percentage moisture
absorption.
 Microscopic images and scanning electron microscopy (SEM).
 Dissolution studies, kinetic models were applied to study drug release mechanism such as
Zero, first order, higuchi, korsmayer-peppas models were applied to study drug release
7
2. Drug profile
In 1990
James black introduced selective H2 antagonist Ranitidine hydrochloride for the first
time. He got Nobel Prize for introducing selective receptors antagonists (selective H2 receptor
antagonist and beta blockers). Cimetidine was first approved H2 antagonist in united states (US)
in 1977, after this ranitidine hydrochloride (RNH) in 1983 and Nizatidine (NZD) in 1988.
2.1. Description
Ranitidine Hydrochloride is without out the imidazole ring and cyanoguanidine group which is
present in famotidine however RNH is an amino alkyl substituted furan
2.2. Molecular formula
350.87
2.3. Chemical formula
C13H22N4O3S.HCl
Melting point
134c˚
2.4. Chemical name
N-[2-[5-(Dimethylaminomethyl)-2furylsulphanyl]-N-methyl-2-nitro-ethane-1,1-diamine) [18].
8
2.5. Characteristics of Ranitidine hydrochloride:
Ranitidine exist in two forms, crystalline and amorphous. Ranitidine actually showed
polymorphism i.e. crystalline nature commonly known as form 2, (F2) form1(F1), and these
possess different pseudo polymorphic structure [19]. Polymorphs of ranitidine depends on type
and nature of crystallizing solvents, for example, when solvent used is ethyl acetate along with
the ethanolic solution crystallized form thus obtained is Form1, However when the isopropanol
Hydrochloride is used as for crystallization the crystals thus formed are form 2 [20]. Difference
in the solubility as well as the bioavailability of two forms were found [21, 22] ranitidine
showed two different forms which were considered to be the tautomeric to each other as
concerned to the manufacturing process form 1 is expensive and difficult to manufacture,
however, form 2 is easy to manufacture and cheapest GSK most commonly used the form 2 ,two
forms of ranitidine cannot be converted to each other [23].
2.6. Solubility of Ranitidine
Ranitidine hydrochloride a pale yellow white, off white crystalline powder having sulphur like
odor and slightly bitter taste. Solubility of the RNH in water is 660mg/ml and is considered
freely soluble in water, however at pH range 1 to 7.4 and methanol solubility lies upto 550mg/
solubility is at the temperature 37 ◦C in methanol, however it is sparingly soluble in 96% ethanol
[24].
2.7. Pharmacology
2.7.1. Pharmacokinetic
Ranitidine administered through oral route, however oral sustained release formulation releases
most of the drug at the colon, the drug showed its absorption either in the gastrointestinal tract or
colon. In first (initial) segment of small intestine ranitidine absorption occurs, due to which it
showed fifty percent (50%) absolute bioavailability (ABA [25]. Ranitidine metabolism occurred
in colon which is responsible for the poor bioavailability. Therefore RNH (ranitidine
hydrochloride) is not favored by the traditional approaches for the development of sustained
release delivery of drug [26]. Hence, conventional technology may not be successful for the
preparation of ranitidine hydrochloride. Ranitidine hydrochloride is rapidly absorbed oral,
9
almost 50%-60% bioavailability of ranitidine after single dose administration within 0.5-1.5hrs
first peak plasma concentration achieved and within 3-4hrs second peak appears [27]. Ranitidine
administered orally only fraction of drug (0.4%) is excreted through biliary pathway (biliary
excretion), when solution of drug was administered directly in to the colon. Plasma was analyzed
drug shows double peak which is still unclear why it occurs.
The bioavailability of ranitidine is relatively lower when administered as a solution directly to
the colon instead of stomach, ileum, or jejunum as tight junctions in colon are considerably less
permeable than those in the small intestine, main absorption site of ranitidine is small intestine,
where absorption takes place through paracellular mechanism, absorption of drug is not effected
by food items. Due to its short
biological half-life of ranitidine hydrochloride (2.5to 3hrs).
Suitable candidate for sustained release (SR) formulation. Delivery at the local site can increase
the bioavailability for receptors located on stomach wall, due to which there is tremendous
increase in the ability of drug to reduce the secretion of gastric acid. This principal may improve
local as well as the systemic delivery of ranitidine hydrochloride, this results in decreased the
gastric acid secretions [18].
2.7.2. Volume of distribution
Volume of distribution(Vd) of Ranitidine Hydrochloride (RNH) for the initial phase ranges from
1.16 to 1.187 liter per kilogram (L/kg) [28]. whereas the protein binding of RNH is very less
which is almost less than 15% [28].
2.7.3. Metabolism and Excretion
70-80% of ranitidine remains unchanged and excreted through urine following intravenous
administration however 30% of unchanged ranitidine excreted through urine when administered
orally. Ranitidine 10% is metabolized administered through intravenous route and 26% is
metabolized when administered orally, colonic metabolism of ranitidine is partial due to which
availability of drug is poor, however it is unclear whether ranitidine follows linear or nonlinear
pharmacokinetics.
2.7.4. Pharmacodynamics
Ranitidine is an histamine H2 receptor antagonist, it
bind to H2 receptors located on the
mucosal surface of gastric parietal (GP) on antiluminal surface of endothelial mucosa, thus it can
10
block secretion and production pathway of gastric acid, due to which it decreases the gastric acid
secretion. Important factor for the common use of ranitidine is its selectivity of H2 blockers, it
has lesser or negligible effect on H1 receptors, the H1 receptor antagonist are used for the
management of allergic reactions but has little effect on H2 receptors [29].
2.7.5. Clinical indications
Ranitidine hydrochloride is one of the most commonly prescribed histamine H2-receptor
antagonists [1].It has two polymeric forms which are used in the manufacture of commercial
tablets or dosage forms, commonly used in treatment
of gastroesophageal reflux disease
(GERD) [30]. Peptic ulcer disease (PUD), widely, used in the management of gastric ulcer,
erosive esophagitis, Zollinger ellison syndrome and active duodenal ulcers. In management of
hives ( allergic skin condition)in combination with antihistamines such as fexofenadine it shows
better treatment outcomes [31]. Scleroderma esophagitis an infection of oesophagitis.
2.7.6. Adverse effects
 Aplastic anemia
 Cholestasis
 Pancreatitis
 Granulocytopenia
 Alopecia
 Insomnia
 Bradycardia
 Dizziness
 Depression
 Hypersensitivity reactions
2.7.7. Dosage and administration
Daily recommended doses of ranitidine hydrochloride for adult is 150mg BD or 300mg OD
erosive esophagitis can be treated by administering 150mg of ranitidine four times a day (QID).
150mg of ranitidine inhibits the secretion of gastric acid upto 5 hours. 300mg of ranitidine
increased plasma drug level therefore ,sustained release formulation of Ranitidine required [32].
11
For management of Zollinger-Ellison syndrome a recommended dose up to 900 mg can be used
without any adverse effects [33].
2.7.8. Contraindication
Patient hypersensitive to H2 antagonist/Ranitidine
2.7.9. Cautions
 Pediatric patient
 Elderly patient
 Patient on ventilation
 Porphyria
 Used not for more than 18 months
 Hepatic impairment
 Renal impairment
 Mechanical ventilated patients
2.7.10. Pregnancy category
B
Animal trials showed no risk to fetus, however no adequate and well controlled studies were
carried out on pregnant women.
2.7.11. Toxicity signs and symptoms
 Meiosis
 Ear and mouth redness
 Excessive salivation
 Mucous membrane pallor
 Fast respiration
 Tremors in muscles tachycardia
 Thrombocytopenia (TCP)
 Leucopenia
 Agranulocytopenia
 Angioedema
12
 Elevated serum creatinine
2.7.12. Management of toxicity
After ingestion of ranitidine hydrochloride (RNH) administration of Charcoal decreases
absorption of (RNH), in severe condition hemodialysis can be done for the removal of drug from
patient plasma.
13
3. Literature review
3.1. Hydroxypropyl methylcellulose (HPMC)
Kiran Goutam et al., 2015 developed promethazine theoclate wafers, various grades of
hydroxypropyl methylcellulose were used for development. Solvent casting method was used for
prepration of formulation. Wafers were evaluated an antihistamine drug used in the treatment of
vomiting and nausea. Phosphate Buffer of 6.8pH is used as the dissolution medium and drug
showed better release pattern [34].
Jagadesh Kumar et al., 2014 prepared the buccal wafers of antihypertensive drug Labetalol
hydrochloride. The objective of development of films was to increase the bioavailability of the
drug. Polyvinyl pyrollidone (PVP), hydroxypropyl methylcellulose were used in combination for
film formation by using solvent casting method. FTIR analysis showed no polymer –drug
interaction formulation contain higher percentage of polymer shows good release (94.35)% is
considered to be optimized formulation [35] .
Pahoa et al., 2014 they developed the transdermal wafers of Glibenclaimide employing cellulose
polymers as film forming agent. In-vitro skin permeation study was conducted which showed
better results of penetration of EC/HPMC and EC/PVP shows good permeability. Prepared films
were smooth, uniform and flexible [36].
Shiaimaa N et al., 2014 prepared wafers of Flurbiprofen as model drug by using solvent casting
technique. Objective of formulation development was to relief pain within a short period. Wafers
were prepared by using hydroxypropyl methylcellulose as film forming polymers, polyethylene
glycol was used as plasticizers. Wafers (films) disintegrate within 30 seconds however, almost
77.5% of the drug released in 2 mints, therefore prepared Flurbiprofen formulation can be used
for the relief of pain [37].
Farhana Sultana et al., 2013 developed wafers formulations containing anhydrous Caffeine
using various concentrations of film forming polymers such as sodium alginate, white Kollicoat
and hydroxypropyl methylcellulose percentage released from formulations containing Kollicoat
polymer is 99% in 240 seconds and disintegration time is 12 s comparatively HPMC contain
14
formulation disintegrate within 13 seconds and 100% drug was released in 120 second so the
HPMC containing formulations were considered suitable for use [38].
Joshua Boateng et al., 2013 developed solvent casted films of paracetamol and Amoxicillin as
combination therapy by using combination of hydrophilic polymers such as carrageenan,
carboxymethyl cellulose and sodium alginate. Films were evaluated by various parameters such
as mucoadhesion, swelling index, content uniformity, SEM (scanning electron microscopy), XRD. Drug release occurred through erosion and diffusion process the %age for Amoxicillin
was 70.59% and paracetamol 84.65% [39].
P.Narayana Raju et al., 2013 prepared fast dissolving films of Loratidine an antihistaminic
drug by using film forming polymer hydroxypropyl methylcellulose in organic solvents such as
methanol and dichloromethane by using solvent casting technique. Sweetness were added to
mask the bitter taste of Loratidine. Casted films were evaluated for various physicochemical
parameters like disintegration time, surface pH, content uniformity, thickness and weight
variation test, disintegration time of the formulations lies in the range of 24-29 seconds. In-vitro
dissolution studies showed drug release for 5 mints completely. Fourier transformed
spectroscopy (FTIR) showed no incompatibility between polymer –drug molecules [40].
Patel et al., 2012 they carried out screening of the polymers that are most suitable for
formulation of oral fast dissolving film. Different polymers like HPMC- E3, HPMC- E5, HPMC
E6, HPMC- E15, Pullulan, Gelatin, Chitosan and PVA were used for the preparation of wafers.
Pullulan and HPMC- E series showed transparent appearance, fast disintegration and dissolution
time with good folding endurance good tensile strength [41].
Sane et al., 2012 they have developed fast dissolving film of Zolmitriptan by solvent casting
method. The effect of different concentration of polymers and plasticizers evaluated for film
forming capacity, appearance and disintegration time .Films with HPMC E3 in combination with
PVA, were found to be very transparent having least disintegration time and best film forming
capacity [9].
Nagar et al., 2011 described oral route considerations, film forming polymers, ideal
characteristics of a polymer to be selected. They classified polymers as natural and synthetic.
They described advantages and disadvantages of pullulan, its properties, chemical structure, etc.
15
was categorized as the best film forming polymer. Starch and modified starches, pectin, sodium
alginate, gelatin, Maltodextrin and description of each. Also described synthetic polymers like
HPMC, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol,
polyethylene oxide and their properties in detail. Quality control tests for all polymers were
discussed.
Pathan et al., 2010 they developed the mucoadhesive buccal wafers of salbutamol sulphate for
the systemic delivery using the HPMC -K15 and Eudragit –S100 as the film forming polymers
no physicochemical interactions were studied when FTIR spectroscopic analysis was carried out.
physical and chemical characterization of the drug was carried out for the evaluation of the drug
which includes swelling index ,mucoadhesive strength weight variation, pH of the Patch and invitro kinetic studies were performed developed films showed controlled release over a period of
6h and follow the zero order release kinetics [42].
Alagusundaram et al., 2009 employed solvent casting method for the development of
mucoadhesive buccal film using HPMC, PVP as film forming polymers. Dichloromethane and
ethanol is used as solvent and propylene glycol was used as plasticizers as well as penetration
enhancer. Swelling characteristics were determined the drug loaded films showed greater
swelling as compared to unloaded films. Content uniformity studies indicates that drug was
uniformly dispersed [43].
Mona et al.,2008 developed buccal film of Glipizide using cellulose polymers and Eudragit RL100.Films were evaluated for their weight variation ,thickness, surface pH ,in-vitro residence
time and, folding endurance. In-vivo studies and permeation studies showed better release of
drug over 6h. Film showed satisfactory swelling and maximum retention time in combination
with HPMC and CMC [44].
Gohel et al., 2007 prepared the taste-masked film of valdecoxib for oral use. Films were
prepared using eudragit and hydroxypropyl methylcellulose as a polymer. Polymers are soluble
in organic solvent and water respectively. The films were prepared by solvent casting method
and evaluated by hydration study folding endurance and dissolution. Glycerol played a critical
role in imparting flexibility to the film and improving the drug release [14].
16
Maseru et al., 2005 developed and evaluated a fast dissolving film of salbutamol sulphate. The
prepared films were clear, transparent with smooth surface and has an acceptable mechanical
characteristics and satisfactory % drug release, tmax for fast dissolving film was lower than that
of conventional tablets. A fast dissolving film of Salbutamol sulphate could be helpful for relief
of fast onset asthmatic attack and also provides a rapid mean of management of asthma [15].
3.2. Pectin wafers
Vivek Gupta et al., 2013 developed pectin based polymeric wafers for intestinal mucoadhesion
using combination of Pectin and other hydrophilic polymers such ethyl cellulose (EC), sodium
carboxymethyl cellulose and carbopol. Calcitonin salmon (polypeptide) was used as model drug.
Various parameters such as mucoadhesive strength, increased drug absorption and dissolution
were carried out, formulation showed 44 fold increased bioavailability as compared to injectable
dosage form [16].
Olga et al., 2012 developed the topical wafers of antimicrobials and antibiotic therapy for
treatment of wound infections using Pectin as polymeric material and polyethylene glycol was
used as plasticizers .Swelling behavior of the wafers was determined by using the analytical
methods and reweighed after the period of 24 hours. Contents were assayed using the diffusion
disc method [17].
Rubina P shakikh et al., 2012 developed lyophilized wafers of diphenhydramine an
antihistaminic agent, comparison of non-crosslinked pectin wafers and non-crosslinked pectin
wafers were carried out. Various parameters were evaluated such as porosity ,surface
morphology ,vibrational and transitional texture attributes in-vitro and thermal release studies
shows that 80% burst release was observed from non-crosslinked wafers, however cross linked
wafers showed
40% release in first 30 mints, study showed
that crossed linked wafers
formulations were suitable for antihistamine drug release [45].
Sevsagi Gangor et al., 2008 prepared transdermal films of hydrophilic polymer Pectin as
polymeric material in combination with polyvinyl pyrollidone (PVP) and propylene glycol (PG)
used as plasticizer, methane and eucalyptol was added to increase the permeability of skin for
rapid drug absorption. Using tail cuff method these patches were applied on rats and systolic
17
blood pressure was measured, within 30 mints a marked decrease in systolic blood pressure was
observed [34].
3.3. Carboxy methyl cellulose wafers (CMC)
Mura P et al., 2015 prepared sustained released econazole nitrate antifungal agent by freeze
drying method using carboxymethyl cellulose sodium (NaCMC) and pectin as polymeric
material developed formulations showed mucoadhesion for 88 mints. Dissolution studies showed
drug 5mg drug release for every hour which is suitable for the treatment of candida albicans [46].
Nq SF et al., 2014 prepared exudates absorbent wafers for healing wounds using freeze drying
(Lyophilization) method for the development of wafers. Cellulose polymers such as methyl
cellulose (MC) and carboxymethyl cellulose sodium (Na CMC) were used purpose of
development was to improve healing process and reduced healing time. Sulphacetamide (SCM)
silver nitrate (SN) and neomycin sulphate (NS) were used as active ingredient in various
formulations, which were evaluated physically such as hydration capacity, swelling index,
uniformity of content, %moisture loss, microscopic evaluation, antimicrobial activity and drug
release. Sodium carboxymethyl cellulose wafers showed better results compared to methyl
cellulose [47].
Noelle H.et al., 2013 developed the wafers formulations for treatment of wound infection by
lyophilization method, cationic antimicrobial peptides with natural polymeric combinations were
evaluated for their antimicrobial activity using disc diffusion method (DM). Prepared wafers
were used against bacteria such as Pseudomonas aeruginosa, Staphylococcus aureus and natural
polymers contain formulations showed efficient antimicrobial activity [48].
Stephen CB Lim et al., 2013 developed lyophilized (freeze dried wafers) by using amylogen
carboxymethyl cellulose sodium (NaCMC) as film forming polymers. Wafers were evaluated by
various parameters such as, percentage moisture content, friability, weight uniformity and
dissolution studies were performed. Morphology of wafers were evaluated by X-ray diffraction
and SEM (scanning electron microscopy. Wafers showed 53% absolute bioavailability in-vitro
dissolution studies showed 90 % drug released within 1 mint from wafers formulation [24].
18
Boateng JSet al., 2010 developed wafers using solvent casting and lyophilization method using
carboxymethyl cellulose and sodium alginate as polymeric material for oral and gastric mucosa
as well as wound surface. Paracetamol (PCM) was used as model drug. Hydration capacity and
morphology of wafers were evaluated with laser scanning microscopy (LCM) and SEM
(scanning electron microscopy). Lyophilized wafers had porous structure, thus high hydration
and drug loading capacity as compared to casted wafers, due to different mechanical and
physical properties, ease of hydration solvent casted wafers and lyophilized wafers showed
different mucosal application time [25].
Amit Khair nar et al., 2009 prepared solvent casted wafers using Aceclofenac as drug of
choice. Formulations were prepared by using carboxymethyl cellulose sodium(Na CMC ),
polyvinyl alcohol (PVA) and gelatin casted films were evaluated for various physicochemical
and chemical properties such as folding endurance (FE),%age entrapment efficiency ,weight
variation ,thickness ,mucoadhesion (in-vitro),% age elongation in-vitro dissolution and stability
studies were carried out. Formulation F5 was optimized with more than 88% release after 8hrs,
all parameters shows that F5 was best formulation [49].
Joshau Boateng et al., 2009 prepared Paracetamol (PCM) wafers for the immediate analgesic
effect by using solvent casting, freeze drying (lyophilization) methods. Carboxy methyl cellulose
(CMC) as hydrophilic polymer, morphology of prepared films by both methods were evaluated
by using scanning electron microscopy (SEM). Exchange cell was used for dissolution studies
release of drug was measured by ultraviolet spectrophotometer (UV) at (243 nm),release rate of
drug was better from wafers as compared to the films [50] .
3.4. Guar gum containing wafers
Ismail sait Dogan et al., 2015 prepared gluten free backed products using natural hydrophilic
polymers such as gaur gum, xanthan gum that gluten free product are suitable for healthy living
of celiac patients. Products improved health of patients 0.5% guar gum and 0.1% xanthan gum
formulations were considered to be optimized for patients who need gluten free products [28].
V Senthil et al., 2015 purpose of current study was development of the taste masked oral wafers
of Ambroxol hydrochloride and Levocetrizine dihydrochloride. Various polymers such as, Guar
19
gum, sodium alginate (SA), Pectin, Propylene glycol (PG), polyvinyl pyrollidone, hydroxypropyl
methyl cellulose (HPMC k15) and sodium Alginate were used in combinations in different
ratios. Wafers were prepared by using solvent casting technique and all the prepared
formulations were evaluated for their physical and chemical parameters formulations contain
HPMC K15 and pectin showed best release studies [51].
A.Deepthi et al., 2014 prepared Zolmitriptan wafers by solvent casting method using, Guar
gum, Sodium alginate, xanthan gum as polymeric material, polyethylene (400) was used as
plasticizers. No drug –polymer in compatibility was found by Fourier transformed infrared
spectroscopy (FTIR). Wafers were characterized by various physical and chemical parameters
such as total disintegration time folding endurance, tensile strength (TS), disintegration time,
uniformity of content and dissolution studies maximum drug released within 6 mints is 98.5%
[30].
Labvitidia et al., 2012 prepared wafers of cyclohexatriene digluconate for treatment of wounds
using Guar gum as film forming polymeric material. Wafers were prepared by using freeze
drying method. Wafers heals the wound by absorbing the exudates (fluid )from surface of wound
in-vitro kinetic studies showed that dug release through diffusion process which showed drug
release follows korsmayer-peppas release model [52].
Noelle H et al., 2012 developed Guar gum containing, antimicrobial peptide containing wafers
used for direct supplication to the skin for the potential treatment of skin wound. These wafers
were prepared by using the free drying process, it was observed that the topical delivery of drug
for the treatment of wounds by using wafers as drug delivery system was considered important
dosage system for the eradication of wound infection. Antimicrobial cationic peptide with Guar
gum natural polymer was considered to be important formulation for application on skin [32].
Olga Labvitidia et al., 2011 prepared antimicrobial wafers using Guar gum, xanthene gum and
sodium alginate, polymers were mixed. Polymeric material
and combination of various
antimicrobial agents that were silver sulphadiazene (SA), povidone iodine (PI), neomycin
sulphate (NS) and cyclohexatrienes, wafers were used against various microbes the results
showed [53].
20
3.5. Sodium alginate and gelatin wafers
J Boateng et al., 2015 prepared and characterized wafers containing silver sulphadiazene for
treatment of wound infection by using gelatin and sodium alginate based as polymeric materials
by changing the concentration of polymers. FTIR spectroscopic studies were used to determined
polymer drug interaction. Physical parameters such as surface pH, thickness weight variation,
and content uniformity and in-vitro kinetic studies were carried out [34].
Josaine Guanclaves et al.,2015 developed and characterized orally disintegrating films of
gelatin and collagen using the ethanol extract of propolis. Films were prepared by using solvent
casting technique. Physical parameters such as mucoadhesion, swelling index, in-vitro release
kinetics and FTIR were carried out, extract containing films were more resistant as compared to
the blank films containing gelatin and collagen alone. Extract containing films showed
antimicrobial activity and can be used for the treatment of diseases caused by the Staphylococcus
auras [35].
Yeole Shaiaka et al., 2015 they developed the herbal favors by using variety of various plants
due to their medicinal effect on the human body. Various plants and their parts used includes
Asparagus sativus which contains the steroidal saponins Lepidium sativum has the potential to
improves the growth and possess the lactogenic property. Morinaga oliefera can be used for the
treatment of malnutrition as it is rich in the constituents having proteins and micronutrients in the
excessive quantity [36].
Indranil Gangualy et al., 2014 developed formulation of promethazine hydrochloride an
antiemetic drug for the sublingual administration. Various polymers were used in different
concentrations such as methylcellulose, gelatin, xanthan gum and Beta-Cyclodextrin was added
to mask the bitter taste of promethazine HCL. FTIR analysis was carried out and no interactions
were found. Physical and chemical parameters were evaluated such as surface pH, uniformity of
contents, moisture uptake, moisture loss, disintegration. In-vitro drug release and Ex-vivo
permeation studies were carried out using the porcine membrane model. In-vitro drug release
studies were observed to be 98-100% within 6 hours. Stability studies showed that lyophilized
drug wafers with good stability and compatibility were obtained [54].
21
Boating et al., 2014 developed sodium Alginate and chitosan based wafers. Delivery of
macromolecules for buccal drug delivery by using the rolling drum method, differential scanning
calorimetric, a comparative study of drug loaded wafers were carried out. Various tests were
performed like mucoadhesion test, Hardness testing, swelling capacity and dissolution studies.
Swelling capacity of drug loaded wafers was observed to be greater as compared to blank wafers
[55].
René et al., 2013 they studied the in vitro, ex vivo and in vivo examination of buccal absorption.
Metoprolol TR146 cell culture, porcine buccal mucosa and Gottingen minifies, a significant
higher absolute bioavailability was obtained after buccal dosing (58–107%). Compared to oral
(3%) administration in Gottingen minifies. A very clear level C in vitro in vivo correlation (r2 =
0.98) was obtained between the observed in vitro permeability’s and the bioavailability observed.
[39].
Joshua Boateng et al., 2013 developed solvent casted films of paracetamol and Amoxicillin as
combination therapy by using combination of hydrophilic polymers such as Carrageenan,
Carboxy methyl cellulose and sodium alginate. Films were evaluated by parameters such as
mucoadhesion, swelling index, content uniformity ,SEM (scanning electron microscopy ) ,X-RD,
release of drugs occurs through erosion and diffusion process the %age for Amoxicillin was
70.59% and paracetamol 84.65% [39].
Gag et al., 2011 described novel approaches in fast dissolving oral drug delivery systems.
Authors described need, advantages, and disadvantages of oral films. Formulation considerations
included a typical composition of film, description of polymers, plasticizers, surfactants.
Authors stated manufacturing methods with advantages and disadvantages of each [41].
Cilurzo et al., (2010) evaluated feasibility of a fast dissolving film made of Maltodextrin
containing nicotine hydrogen tartrate(NHT) salt using solvent free hot-melt extrusion
technology. The bitterness and astringency intensity of NHT and the suppression effect of
several TMA were evaluated by a Taste-Sensing System. The addition of NHT and tastemasking agents affected film tensile properties, however, effect of addition of these components
can be counterweighted by modulating the glycerin content and MDX molecular weight [56].
Kunte et al., 2010 they developed a fast dissolving Oral film for the delivery of Verapamil. Thus
the patient-friendly dosage form of bitter drugs such as Verapamil can be successfully
22
formulated using this technology and it can be especially useful for geriatric, bedridden and noncooperative patient due to its ease of administration [57].
Vishw et al. 2010 have formulated and evaluated fast dissolving tablet of metoprolol tartrate
using semisolid casting. They compared the effect of various superdisintegrants on the drug
release. Sodium starch glycolate was found to be best superdisintegrants; however the other
superdisintegrants shows the poor property [44].
Sumitha et al., 2009 designed a taste masked
films of Ondansetron hydrochloride by rolling
drum method. Polymer carrier system and formulation of rapid-disintegrating films. Rapid
dissolving film containing taste masked Ondansetron hydrochloride showed acceptable
properties. Drug release profile indicated that it could be used for the oral delivery of
Ondansetron hydrochloride in chronic and acute post-operative or chemotherapy or radiotherapy
induced emesis, so it possesses good antiemetic property. Good correlation between in vitro
disintegration behavior and in the oral cavity was recognized, patient friendly dosage form has
been accomplished [45].
Verena et al. 2009 prepared films of Caffeine, gelatin, pullulan by solvent casting technique.
The film casting solution was prepared by dissolving the excipients in the solvent and heating up
to 60C˚. Films thickness, disintegration, dissolution, and texture analysis was carried out
thickness of wet films decreases about 86-97%.films also showed good endurance strength [49].
Dinge et al., 2008 formulated and evaluated fast dissolving films of triclosan. Various film
forming agents, film modifiers and polyhydric alcohols were evaluated for optimizing the
composition of fast dissolving films. The potential of poloxamer 407 and hydroxypropyl-βcyclodextrin (HPBCD) to improve solubility of TC was investigated. Fast dissolving films
containing hydroxypropyl methylcellulose (HPMC), xanthan gum, and xylitol were formulated.
Use of poloxamer 407 and HPBCD resulted in significant improvement in the solubility of TC.
Fast dissolving films containing TC-HPBCD complex and TC-Poloxamer 407 were formulated
and were evaluated [50].
23
3.6. Polyethylene glycol (PEG) wafers
Youhan Zhao et al., 2015 prepared meclizine hydrochloride wafers for treatment of motion
sickness. Polyethylene glycol (PEG) was used as plasticizer, wafers (films) were prepared by
using solvent casting technique. FTIR results showed no polymer drug interaction and
dissolution studies were carried out in 0.1N HCL and distilled water. Absorbance was measured
by using UV-spectrophotometer results showed more than 80% drug released within 5 mints.
Kianfar et al., 2014 prepared lyophilized (freeze dried) wafers using polyethylene glycol
(peg600) a water soluble plasticizers, poloxamer and carrageenan as film forming polymeric
materials. Wafers were evaluated by scanning electron microscopic, hydration, in-vitro
mucoadhesion studies were carried out which showed that hydration and mucoadhesion of
poloxamer (4%) carrageenan (2%) and PEG 600 (4.5%) showed wafers with best hydration
capacity and porous network for loading of drug properly [52].
Kianfar et al., 2013 developed wafers of ibuprofen and paracetamol (PCM) using Carrageenan
and Pouluric acid as film forming polymers. Polyethylene Glycol 1.8%w/w was used as
plasticizers to increase the elastic strength, formulation remains stable for up to six month,
mucoadhesive strength was observed using mechanical texture analyzer, drugs gradually releases
up to 2 hours results showed prepared wafers were suitable for mucosa of buccal cavity [58].
Gorakh et al.,2013 developed solvent casted wafers (oral films ) using polyethylene glycol
(PEG) as plasticizer, in combination with various film forming polymers such as hydroxypropyl
methyl cellulose (KM100), hydroxypropyl methylcellulose (E5),hydroxypropyl methyl cellulose
(cps3). Wafers formulations were evaluated by various parameters such as disintegration time
(DT), weight variation, folding endurance (FE), surface pH, dissolution and stability studies,
thickness of wafers was in the range of 0.22 to 0.33mm,maximum folding endurance 200
complete disintegration time was within 60seconds. 100% drug release was observed within 2
mints which showed formulation possess best release characteristic and suitable for immediate
effect [54].
Kumaragiri Sasi Deepthi et al., 2012 they developed fast dissolving oral wafers (films )using
plasticizer polyethylene glycol (PEG 400), sweating agent glycerin (GLY), film forming
24
polymers such as HPMC, tween (80) were used. FTIR results were evaluated no polymer drug
interaction was found. Physicl and chemical parameters were evaluated such as content
uniformity, disintegration, folding endurance, thickness, surface pH, weight variation and
dissolution studies. Tensile strength of all formulations were carried formulation (F8) showed
less tensile strength and optimum drug release [59] .
Irana Alexendra Paun et el., 2012 developed implantable wafers using indomethacin as model
drug. Polyethylene glycol, polylactide-co-glycodie were used as plasticizers and polymeric
material. Formulations were prepared using laser evaporation (LP) techniques. Sustained
released (SR) wafers of indomethacin for more than three weeks. Kinetic models were applied to
study drug release mechanism which showed that drug releases by diffusion mechanism and
follow higuchi model when phosphate buffer saline was used as dissolution medium [56].
Farinose et al., 2011 prepared Carrageenan wafers containing ibuprofen by constant stirring at
80 ◦C. Poloxamer 407 and polyethylene Glycol (PEG600) were used as plasticizers. Thick
viscous gel is casted for 24hrs in an oven films formed were analyzed for its tensile strength,
elasticity and percentage elongation. Drug dissolution and Release profile was determined by
using HPLC by using different media as deionized water of pH 5.6. Buffer solution of pH 6.5.XRay powder diffraction was determined to measure the nature of film ,kinetic property of drug
release of the film was evaluated by using korsmayer-peppas, Higuchi, zero order and first order
release model [60].
Isaac et al., 2011 prepared wafers by lyophilization of aqueous gels of the polymers using
various concentration of polyethylene glycol as plasticizers and D- manifold as cytoprotectant.
SEM was carried out with stereoscan-s-360. Phase separation study was carried out using the
DSC at different speeds. The drug loading capacity of formulation was determined by using the
assayed content and the initial loading of drug .Drug loading was observed upto 90%.
Mishra et al., 2011 developed wafers of cetirizine hydrochloride using different concentrations
of polyethylene glycol 400 as plasticizers and pullulan was used as film forming polymer.
Optimized batch of pullulan showed satisfactory thickness and mechanical properties. It showed
stability for six months under specified conditions. Films were prepared by using semisolid
25
casting. Prepared films showed better in-vitro and in-vivo disintegration time within 20-30s
[61].
Hiroyoshi Shimoda et al., 2009 prepared dexamethasone wafers (films) using polyethylene
glycol as plasticizer and hydroxypropyl methylcellulose was used as film forming polymers.at
75% humidity and 40 0C, formulation was stable within 5mints. 90% dexamethasone was
released however films disintegrate completely within 15 seconds. Treatment of emesis caused
by anticancer drugs dexamethasone oral wafers were used as drug of choice [62].
26
4. Material and Method
4.1. Chemicals
 Ranitidine Hydrochloride was gifted from (Ferozsons Pharmaceutical Karachi Pakistan)
 Hydroxypropyl methylcellulose (HPMC- E5) Sigma Aldrich Germany
 Carboxy methylcellulose (CMC) sigma Aldrich (Germany)
 Pectin purchased from (Dae-Jung chemicals and Metals CO.LTD Korea)
 Guar gum purchased Sigma Aldrich (Germany )
 Polyethylene glycol (PEG 200) E-Merck Dermastad (Germany)
 Amaranth coloring dye ( Dae-Jung chemicals and Metals CO.LTD Korea)
 Tween 80 (Dae-Jung chemicals and Metals CO.LTD Korea)
 Potassium dihydrogen phosphate (KH2PO4) Sigma Aldrich (Germany)
 Sodium hydroxide (NaoH) Sigma Aldrich (Germany)
4.2. Apparatus /equipment
 Glass petriplates (Pyrex)
 Electrical weighing balance (Eutect instruments)
 Hot plate stirrer ( Dahan Lab tech co.ltd)
 Measuring cylinder Beakers (Pyrex)
 Hot air Oven (Memmert Germany )
 Soni-cator (FAD Instruments Lab Lahore Pakistan)
 Micrometer screw gauge (Hitech Karachi Pakistan)
 Optical light microscopy (Germany )
 Vernier caliper (Hitech Karachi Pakistan)
 Disintegration apparatus (Erweka Germany)
 Dissolution apparatus (USP type II) ( Digiteck instruments Lahore Pakistan )
 FTIR spectrophotometer (Agilent Karachi Pakistan)
 UV-spectrophotometer (Perkin Almer Germany)
 PH meter (510 Eutech instrument)
27
 Aluminium foil (Zamas international FZCO, U.A.E.)
4.3.
Experimental design (Box- Behnken)
Response surface methodology is the technique used to develop the relationship between
quantitative and qualitative data of the experiment. In present study three factors evaluated at 2
levels offer advantages in the form of proposed formulations [63]. A standard (RSM) of boxbehnken design was used to study the variable concentration of polymers, plasticizers and
surfactant. Box-behnken design is a three factors .Variable with minimum (-1) and the
maximum(+1) was observed [64]. As shown in equation 1, 2 and 3.
(1)
-1 =
(2)
0=
(3)
Alpha (α) a constant value which is (1.68), min and max are the lowest and highest values of the
variables used, +1, 0, -1 are the maximum average and minimum value of variables as shown in
table3.
Table 3: Coded values of the variables of Box-behnken design for wafers formulation
Independent
variables
Level
High
Medium
Low
Code
+1
0
-1
Polymer
33.58
30.64
27.7
Plasticizer
20
18.81
17.63
Surfactant
1.79
1.49
1.20
28
4.4.
Preparation of wafers
Solvent casting method was used for preparation of Ranitidine wafers. Accurately weighed
polymer, plasticizer and ranitidine were dissolved in 15-30ml of water and stirred at 500rpm to
make clear solution at temperature 55-600C. Solution was poured in petri dish and allowed to dry
in an oven. After 2h hours removed the wafers from oven and wrapped in an aluminum foil and
stored in air tight glass container [65].
Table 4. Composition of formulations of Ranitidine hydrochloride 50mg wafers (All quantities
were given in %ages)
Class
Polymer
Formulation
HPMC
CMC
Pectin
Guar
gum
PEG
Tween
Water
FI
27.7
-
-
-
17.02
1.20
5.0
FII
33.58
-
-
-
17.02
1.50
6.76
FIII
33.58
-
-
-
20
1.20
4.0
FVII
-
27.7
-
-
17.02
1.20
5.0
FVIII
-
33.58
-
-
17.02
1.50
6.76
FIX
-
33.58
-
-
20.
1.20
4.0
FIV
-
-
27.7
-
17.02
1.20
5.0
FV
-
-
33.58
-
17.02
1.50
6.76
FVI
-
-
33.58
-
20
1.20
4.0
FX
-
-
-
27.7
17.02
1.20
5.0
FXI
-
-
-
33.58
17.02
1.50
6.76
FXII
-
-
-
33.58
20
1.20
4.0
Code
Synthetic
HPMC
Polymer
CMC
Natural
Polymer
Pectin
Guar
gum
29
4.5.
Characterization of wafers
Physicochemical parameters such as surface texture, transparency, tackiness, surface pH,
thickness, weight variation, swelling index, percentage moisture absorption and percentage
moisture loss were calculated. Mucoadhesion, folding endurance, disintegration time and
dissolving time were performed on wafers. Morphological studies of wafers were performed by
optical microscopy. Drug and polymer interaction were studied by Fourier transform infrared
spectroscopy (FTIR). Cumulative percent drug release was studied by dissolution and in-vitro
kinetic were studied by applying different kinetic models.
4.5.1. Physical parameters of wafers
Surface texture of wafers were evaluated by organoleptic method. A rectangular piece of each
wafer film was taken and placed on the internal side of spectrophotometer and transmittance was
measured at 600nm and transparency of film was calculated by using equation 4.
Transparency test (t) =
(4)
Where t is wavelength and b is the film thickness. Three films of each formulation were taken
and placed them on the piece of paper and tackiness was measured [65 and 66].
4.5.2. Surface pH
Three films of each formulation were taken at random and allowed to swell in agar plate for
about 2 hours. pH of wafers was measured by placing the pH paper on the swollen surface of the
wafers [43].
4.5.3. Wafers thickness
Thickness of wafers were measured by using the micrometer screw gauge at five different
position of the films i.e. the center and the four corners [67].
4.5.4. Weight variation test
Wafers were weighed accurately on the analytical weighing balance and average weight for each
formulation was measured, weight variation should be within the Pharmacopoeial limits ±10%
[54 and 68].
30
4.5.5. Swelling index
Swelling index of wafers was determined by measuring initial diameter of each wafer then
placed in agar petri dish at 37ºC. Diameter was again measured after 1hour [69]. Radial swelling
was calculated by using equation 5.
(5)
SD% means the percentage radial swelling, Dt is the diameter of swollen wafers and D0 is the
diameter of original wafers.
4.5.6. Percentage moisture absorption (PMA)
Physical stability was measured by using the 1-2cm weighed wafers in desiccator. Percentage
moisture absorption was calculated using following formula.
(6)
4.5.7. Percentage moisture loss (PML)
3-4cm of wafers film were cut, accurately weighed and kept in desiccator which contains fused
anhydrous calcium chloride. Films were removed after 72 hours and weighed. Average
percentage moisture loss of desiccated wafers was calculated using equation 7 [70].
(7)
4.5.8. In-vitro mucoadhesion test
In-vitro mucoadhesion test was carried out using the modified disintegration apparatus. A petri
dish cover was attached with the wall of disintegration apparatus. Everted sac technique was
used to evaluate mucoadhesion time, when it completely attached to the plate then wafers were
placed on the surface and move apparatus at 75rpm and time was measured at which wafers
detached from membrane [49].
4.5.9. Folding endurance
Folding endurance was evaluated by repeatedly folding wafers at same place until it breaks [71].
4.5.10. Disintegration time
31
Disintegration was carried out by using non agitation method (petriplate method) and agitation
(Beaker) method.
4.5.10.1. Beaker method (agitation method)
Three pieces of each wafers film were taken randomly and placed in a beaker containing 250 ml
of phosphate buffer 6.8 pH and placed on hot plate magnetic stirrer at 200 rpm and time was
noted until wafers start to disintegrate.
4.5.10.2. Petriplate method non-agitation method
Wafers samples were placed on a glass petri dish containing 10-20ml of distilled water and time
was noted which the wafers disintegrate.
4.5.11. Total dissolving time (TDT)
Three wafers of each formulation were placed in the Petriplate contain 15-20ml of phosphate
buffer pH 6.8 used as dissolution medium and time was noted at which the wafers completely
dissolves and becomes a solution [72].
4.6.
Morphological studies
4.6.1. Scanning Electron Microscopy (SEM)
SEM images of wafers were obtained at a magnification of 100um and spot size of 320A◦ carried
out to study the surface morphology of wafers [60].
4.6.2. Optical microscopy
Optical microscopy was carried out to study the surface morphology of drug loaded and
unloaded wafers by using low and high resolution of optical microscope [47].
4.7.
FTIR spectroscopy
FTIR spectra of ranitidine, polymers and drug loaded and unloaded wafers were recorded at
4000-400 cm-1 by using FTIR spectrophotometer (Agilent, USA) [51].
32
4.8.
Content uniformity
Content uniformity was determined by dissolving wafers in water to prepare solution of
ranitidine. Solution was filtered through 0.45um filter and was analyzed at 323nm by UV-visible
spectrophotometer. Each experiment was performed three times (n=3) [42].
4.9.
Stability studies
Stability studies were performed at 400C ±0.50C and humidity of about 75% for 3 months. After
three months wafers were again evaluated for surface pH, folding endurance, drug content,
uniformity of weight and in-vitro drug release [73].
4.10. Dissolution study
Drug release studies were performed by using USP type II dissolution paddle apparatus by using
phosphate buffer pH 6.8. Temperature of dissolution medium was maintained at 37± 0.50C and
peddle was rotated at 75rpm. Wafers were fixed on glass slide and placed in the dissolution
medium. Sink condition was maintained throughout the experiment. Sample was analyzed at
323nm [43 and 74]
4.11. Release kinetics
The mechanism drug release kinetics from wafers was analyzed by using various kinetic models
such as zero order, higuchi model, first order and korsmeyer-peppas model.
4.11.1. Zero order release
When drug release is not dependent on its concentration is referred as zero order release
mechanism and is calculated by following equation.
(9)
Where Ft is fraction of drug release at time t and Ko is rate constant for zero order release.
33
4.11.2. First order release
When drug release pattern depends upon concentration, it is referred as first order release
mechanism and calculated by following equation.
(10)
F is drug release in time t and K1 is first order release constant
4.11.3. Higuchi model
Higuchi model shows time dependent diffusion process from insoluble matrix. It is based on
Fick’s law of diffusion and calculated by following equation.
(11)
F is fraction of drug release in time t and K2 is Higuchi constant
4.11.4. Korsmeyer-peppas model
Korsmeyer-peppas equation is as follows.
Mt is amount of drug release at time t, M∞ is amount of drug release at infinity and n is diffusion
coefficients.
34
5. Result and Discussion
Pakistan is an under developed country where almost 51 % of population is living below poverty
line, it is difficult for people to purchase costly medicine. A dosage form, more effective having
less cost is much needed. Ranitidine hydrochloride (RNH) is commonly recommended drug for
management of erosive esophagitis, gastric ulcer (GU), Zollinger –Ellison’s syndrome, duodenal
ulcer, Ranitidine is recommended ranging from 150mg twice daily (BD). A novel drug delivery
system (NDDS) sustained released wafers of RNH was prepared by solvent casting technique
using various natural and synthetic polymers.
5.1.
Organoleptic evaluation
Natural polymer (Pectin and Gaur gum) containing wafers showed the smooth surface while the
synthetic polymers (HPMC) containing wafers showed slightly rough texture. CMC containing
wafers had the crystalline texture. All the prepared formulations showed maximum transparency
when observed in the cube cell of the spectrophotometer. Prepared formulations of natural
polymer were evaluated for their Stickiness and dryness characteristics at the surface of the paper
were found to be some stickiness while the lack stickiness was observed in synthetic polymers
containing wafers.
5.2.
Effects of excipients on various parameters of wafers formulations
Effect of excipients on surface pH and folding endurance of formulation FI-FIII was evaluated as
variables using box behnken design which showed that increasing the concentration of polymer
showed no marked variations in surface pH, however increasing concentration of polymer and
decreasing plasticizer concentration showed increased folding endurance of formulation as
shown in figure 1 and 2.
35
Figure 1: Excipients effect on surface pH of Formulations (FI-FIII)
Figure 2: Excipients effect on folding endurance of formulations (FI-FIII)
Mucoadhesion time and % moisture loss of formulation FI-FIII was study and was found to be
increased concentration of polymer enhanced mucoadhesion time and reduces percentage
moisture loss as shown in figures 3 and 4 respectively.
Figure 3: Excipients effect on mucoadhesion time of formulations (FI-FIII)
36
Figure 4: Excipients effect on percentage moisture loss of formulations (FI-FIII)
Effect of Pectin polyethylene concentration was observed on surface pH and folding endurance
of formulations FIV-FVI. No significant effect on surface pH was observe, however increasing
effect on folding endurance was observed with increasing polymer concentration and decreasing
plasticizer concentration as shown in figures 5 and 6 respectively.
Figure 5: Effect of excipients on surface pH of formulations (FIV-FVI)
37
Figure 6: Effect of excipients on folding endurance of formulations (FIV-FVI)
Effect of excipients on mucoadhesion time and %moisture loss of formulations FIV-FVI was
observed which showed that formulations contaning higher polymer concentration with more
mucoadhesion and less moisture loss as shown in figures 7 and 8.
Figure 7: Excipients effect on in-vitro mucoadhesion time of formulation (FIV-FVI)
38
Figure 8: Excipients effect on percentage moisture loss of formulations (FIV-FVI)
Surface pH and folding endurance of wafers formulations (FVII-FIX) contain various
concentration of CMC, PEG were evaluated which showed that increasing concentration have
no significant effect on surface pH, however significant increase
folding endurance was
observed as shown in figures 9 and 10 respectively.
Figure 9: Excipients effect on surface pH of formulations (FVII-FIX)
39
Figure 10: Excipients effects on folding endurance of formulations (FIV-FVI)
CMC possess an excellent mucoadhesive strength due to which it showed increased
mucoadhesion time and less %moisture loss as shown in figures 11 and 12 respectively.
Figure 11: Excipients effect on mucoadhesion time of formulations (FIV-FVI)
40
Figure 12: Excipients effect on moisture loss of formulations (FVII-FIX)
Effect of excipients concentration on surface pH of formulations (FX-FXII) showed changing
concentrations had no effect on surface pH of formulations. However increasing polymer
concentration results in increasing folding endurance as shown in figure 13 and 14.
Figure 13: Excipients effect on surface pH of formulations (FX-FXII)
41
Figure 14: Excipients effect on folding endurance of formulation (FX-FXII)
Effect of excipients on percentage moisture loss of formulations containing Guar gum which
showed that increasing polymer concentration reduces % moisture loss of formulations however
when plasticizers concentration increased moisture loss increases. Polymer concentration showed
increased mucoadhesion.
Figure 15: Excipients effect on in-vitro mucoadhesion of formulations (FX-FXII)
42
Figure 16: Excipients effect on moisture loss of formulations (FX-FXII)
5.3.
Physicochemical parameters
5.3.1. Surface pH
Surface pH of wafers formulations was found to be within range of 6.52-6.56 ± 0.1 which was
suitable for absorption of drug at intestinal pH as shown in table 5.
5.3.2. Wafers thickness
Five wafers of each formulation were taken randomly and thickness of each wafer was
measured at five different positions and average thickness of wafers was upto 0.35mm as shown
in figures 17, 18 and 19 respectively.
43
Figure 17: Thickness of wafers formulations FI-FIII (n=5)
Figure 18: Thickness of wafers formulations FIV-FVI (n=5)
Thickness of various formulations contain various concentrations of excipients was evaluated
which shows that all formulations FVII-FXII were of uniform thickness which was less than
1mm and was found to be within limit as shown in figures 19 and 20.
44
Figure 19: Thickness of wafers formulations FVII-FIX (n=5)
Figure 20: Thickness of wafers formulations (FX-FXII)
5.3.3. Weight variation test
Twenty wafers of each formulation were randomly taken and weighed individually. Average
weight of twenty wafers was calculated variation of wafers were not found to be more then ±5±10%. Weight variation of each formulations is shown in graphs below. Weight variation of
Twenty wafers (films) of FI,FII and FII were taken randomly and weighed individually and
average weight was calculated which was found by 647mg ±3.56 and was found to be within
pharmacopoeial limits ,maximum weight of wafer was found to be 659 mg and minimum weight
643mg which lies within the limit. As shown in figure 21, 22 and 23 respectively.
45
Figure 21: Weight variation of wafers formulationF1 (n=20)
Figure 22: Weight variation of wafers formulation FII (n=20)
.
46
Figure 23: Weight variation of wafers formulation FIII (n=20)
Weight variation of twenty wafers FIV,FV and VI was determined by taking five wafers of each
formulation which was found to be
647.20mg ±3.39 and
was found to be within
pharmacopoeial limits ,maximum weight of wafer was found to be 656mg and minimum weight
644mg which lies within the limit as shown in figures 24 ,25 and 26 respectively.
Figure 24: Weight variation of formulation FIV (n=20)
47
Figure 25: Weight variation of formulation FV (n=20)
Figure 26: Weight variation of formulation (FVI)
Weight variation of twenty wafers (films) of FVII, FVIII and FIX were taken randomly and
weighed individually and average weight was calculated which was found by 647.700mg ±3.74
which was found to be within pharmacopoeial limits, maximum weight of wafer was found to be
656mg and minimum weight 639mg which lies within the limit as shown in figure 27, 28 and 29
48
Figure 27: Weight variation of formulation FVII (n=20)
Figure 28: Weight variation of formulation FVIII (n=20)
49
Figure 29: Weight variation of formulation FIX (n=20)
Weight variation of twenty wafers of FX, FXI and FXII were taken randomly and weighed
individually and average weight was calculated which was found to be 647mg ±3.56 which was
found to be within Pharmacopoeial limits, maximum weight of wafer was found to be 656 mg
and minimum weight 639 mg which lies within the limit as shown in figures 30, 31and32
respectively.
Figure 30: Weight variation of formulation FX (n=20)
50
Figure 31: Weight variation of formulation XI (n=20)
Figure 32: Weight variation of formulation XII (n=20)
5.3.4. Swelling index
Five wafers of each formulation were randomly taken initial diameter and final was measured
percentage radial swelling of formulations FI-FVI was measured. Maximum radial swelling was
found to be 15 minutes as shown in figures 33and 34.
51
Figure 33: Percentage radial swelling of formulations FI-FIII (n=5)
Figure 34: Percentage radial swelling of formulations FIV-FVI
Percentage radial swelling of formulations FVII-FXII was determined and radial swelling of
formulations was found to be up to 30 mints as shown in figure 35and 36.
52
Figure 35: Percentage radial swelling of formulations FVII-FIX (n=5)
Figure 36: Percentage radial swelling of formulations FX-FXII (n=5)
5.3.5. Percentage moisture absorption (PMA)
Percentage moisture absorption of various formulations were carried out by taking three wafers
of each formulations initial weighed and then placed initially weighed and then placed in
desiccator containing calcium chloride solution after 72 hours these were taken out again
weighed , %moisture absorption was calculated for each formulation and shown in the table 5.
53
5.3.6. Percentage moisture loss (PML)
Percentage moisture loss of various formulations were carried out by taking three wafers of each
formulation
initial weighed and then placed in oven for 72 hours after specified time interval
these were taken out again weighed %moisture loss
was calculated for each formulation and
shown in the table 5.
Table 5: Evaluation of various physical parameters of ranitidine hydrochloride wafers
Class
Polymer
Formulat
ion
Surface
Folding
% moisture
% moisture
absorption
Swelling
index
Thickness
Conent
uniformty
pH
Endurance
loss
FI
6.51 ±0.08
116.42 ±3.20
1.84 ±0.63
1.08 ±0.36
7.81 ±3.10
0.31 ±0.02
93.52±7.22
FII
6.53 ±0.13
142.64±3.162
1.71 ±0.76
1.18 ±0.39
10.80±3.0
0.34 ±.015
92.19±8.32
FIII
6.56 ±0.11
107.36 ±3.54
1.58 ±0.10
1.060±0.42
11.61±2.5
0.32±0.011
95.38±3.84
FVII
6.59 ±0.25
289.81 ±2.25
1.344 ±0.38
1.50 ±0.39
8.74±1.83
0.35±0.021
95.81±3.07
FVIII
6.56 ±0.12
296.73±1.49
1.540 ±0.54
1.682±0.41
11.77±2.3
0.35±0.022
96.92±3.11
FIX
6.51 ±0.10
288.66 ±2.19
1.295 ±0.80
1.572 ±0.32
15.11±3.6
0.39±0.015
95.59±2.79
FIV
6.51 ±0.11
298.29 ±2.30
1.095 ±0.32
1.520 ±0.61
8.77±1.81
0.26±0.021
95.13±2.87
FV
6.53 ±0.10
298.33 ±1.49
1.56 ±0.46
1.40 ±0.50
12.14±2.4
0.33±0.015
97.22±3.07
FVI
6.53 ±0.12
292.03 ±2.18
1.33 ±0.49
1.23 ±0.13
8.571±2.1
0.352±0.02
95.30±2.90
FX
6.56 ±0.25
213.12 ±3.21
1.339±0.49
1.34 ±0.44
9.34±2.18
0.302±0.01
95.91±2.75
FXI
6.56 ±0.25
235.16 ±2.43
1.24 ±0.46
1.630 ±0.40
15.0±1.24
0.318±0.01
95.51±2.37
FXII
6.53 ±0.10
241.71±2.23
1.82 ±0.49
1.28 ±0.22
5.012±2.4
0.318±0.01
98.50±5.501
Code
Synthetic
HPMC
Polymer
CMC
Natural
Polymer
Pectin
Guar
gum
5.3.7. In-vitro mucoadhesion test
Mucoadhesion time of wafers formulations containing different concentrations of polymers,
plasticizers and surfactant which showed that formulation FI, FIII were found to be with less
mucoadhesion time 19.3 and 22.25 minutes however formulation FII showed maximum
mucoadhesion time 24 minutes as shown in figure 37.
54
Figure 37: In-vitro mucoadhesion time of wafers formulations FI-FIII
Wafers formulations FIV, FV and FVI were evaluated for mucoadhesion time. Mucoadhesion
time of formulations was found to be up to 25 minutes as shown in figure 38.
Figure 38: In-vitro mucoadhesion time of wafers formulations FIV-FVI
Mucoadhesion time of wafers formulations containing different concentrations of polymers,
plasticizers and surfactant which showed that formulation FVII, FIX were found to be with less
mucoadhesion time, however formulation FVIII showed maximum mucoadhesion which showed
that increasing concentration of polymer and lowering plasticizer results in more mucoadhesive
formulations as shown in figure 39.
55
Figure 39: In-vitro mucoadhesion time of wafers formulations FVII-FIX)
Mucoadhesion time of wafers formulations containing different concentrations of polymers,
plasticizers and surfactant which showed that formulation FX, FXII were found to be with less
mucoadhesion time, however formulation FXI shows maximum mucoadhesion which showed
that increasing concentration of polymer and lowering plasticizer results in more mucoadhesive
formulations.
Radial graph showed
mucoadhesion time of wafers formulations containing different
concentrations of polymers, plasticizers and surfactant which showed that formulation FII, FXI
were found to be with less mucoadhesion time, however formulation FV,FVIII shows maximum
mucoadhesion which showed that increasing concentration of polymer and lowering plasticizer
results in more mucoadhesive formulations as shown in figure 40.
56
Figure 40: In-vitro mucoadhesion of wafers formulations FX-FXII
5.3.8. Folding endurance
Three wafers of each formulation were taken and folded at the same place for several periods of
time until the films break the maximum limit at which film breaks is folding endurance; folding
endurance of various formulation as shown in table 5.
5.3.9. Disintegration time
Disintegration of five wafers of each formulation were carried out both by agitation and nonagitation method and average disintegration time of each formulation was calculated it was
found that disintegration time without agitation is more as compared to agitation as shown in
figures 41, 42,43 and 44 respectively.
57
Figure 41: Disintegration time of formulations (FI-FIII)
Figure 42: Disintegration time of formulations from FV-FVI
58
time mints
30
25
20
15
10
5
0
fixna
Fviia
Fviia
Fviina
Fviiia
fixa
Fviina
Fviiina
Fixa
Fix na
fviina
fviiia
Figure 43: Disintegration time of formulation (FVII-FIX)
5.3.10. Total dissolving time (TDT)
Three wafers of each formulation were placed in the Petriplate having 15-20ml of phosphate
buffer pH 6.8 and the time at which the wafers completely dissolved without agitation were
calculated. Solution formation after the agitation were also observed as shown in figure 45. Total
dissolving time along a single axis graph showed total dissolving time of three wafers
formulations FI-FIII, Figure showed that formulation FI and FIII, showed less total dissolving
time however FII showed maximum dissolving time as compared to FI,FIII so FII was
considered to be optimized formulation as compared to the other two formulations as shown in
figures 45 and 46.
59
Figure 44: Total dissolving time of wafers formulations FI-FIII
Total dissolving time along a single axis graph showed total dissolving time of three wafers
formulations FIV-FVI ,graph showed that formulation FIV,FVI showed less total dissolving time
however FV showed maximum dissolving time as compared to FIV, FVI so FV was considered
to be optimized formulation as compared to the other two formulations.
Figure 45: Total dissolving time of wafers formulation FIV-FVI
Total dissolving time along a single axis graph showed total dissolving time of three wafers
formulations FVII-FIX ,graph showed that formulation FVII,FIX showed less total dissolving
time however FVIII showed maximum dissolving time as compared to FVII, FIX so FVIII was
considered to be optimized formulation as compared to the other two formulations as shown in
figures 47 and 48 respectively.
60
Figure 46: Total dissolving time of wafers formulation FVII-FIX
Total dissolving time along a single axis graph showed total dissolving time of three wafers
formulations FX-FXII ,graph showed that formulation FX ,FII showed less total dissolving time
however FXI showed maximum dissolving time as compared to FX,FXII so FXI was considered
to be optimized formulation as compared to the other two formulations.
Figure 47: Total dissolving time of wafers formulation FX-FXII
Total dissolving time along a single axis graph showed total dissolving time of three wafers
formulations FII, FV, FVIII, FXI, graph showed that formulation FII,FXI showed less total
dissolving time however FV, FVIII showed maximum dissolving time as shown in figures 49
and 50.
61
Figure 48: Total dissolving time of wafers formulation FII, FV, FVIII and FXII
Figure 49: Total dissolving time of wafers formulation FV, FVIII
62
Figure 50: Total dissolving time with agitation formulation FI-FIII
Total dissolving time with agitation along a single axis graph showed total dissolving time of
three wafers formulations FIV-FVI ,graph showed that formulation FIV,FVI showed less total
dissolving time however FV showed maximum dissolving time as compared to FIV,FVI so FV
was considered to be optimized formulation as compared to the other two formulations.
Figure 51: Total dissolving time of wafers formulations FIV-FVI
Total dissolving time with agitation along a single axis graph showed total dissolving time of
three wafers formulations FVII-FIX ,graph showed that formulation FVII,FIX showed less total
63
dissolving time however FVIII showed maximum dissolving time as compared to FVII,FIX so
FVIII was considered to be optimized formulation as compared to the other two formulations as
shown in figure 51 and 52.
Figure 52: Total dissolving time of wafers formulations from FVII-FIX
5.4.
Morphological studies
Microscopic image analysis of wafers formulations containing different concentrations of
polymers and plasticizer and tween 80 were compared. Wafers formulation (FIII) showed crosslinked network like structure with uniform loading of drug concentration. Formulation FIV
contained pectin polymers was wrinkled in shape and showed agglomeration with drug
molecules. The difference was observed due to irregular mixing of excipients and drug
molecules in formulation. FV formulation containing 17% of plasticizer showed smooth surface
in texture and was easily inspected visually due to uniform distribution of drug particles. Wafers
formulations containing lesser concentration of polymeric material showed crystalline texture as
shown in figures 53 and 54.
5.4.1. Microscopic images of wafers
64
Figure 53: Microscopic images wafers prepared with (HPMC)
Figure 54: Microscopic images of wafers prepared with Pectin
5.4.2. SEM of wafers formulations
5.5.
FTIR studies
FTIR studies of pure Ranitidine hydrochloride (RNH) prepared wafers formulations containing
polymers such as HPMC, CMC, Pectin and Guar gum were evaluated ranging from 4000-400
cm. Pure drug showed peaks due to secondary diamine, furan ring alkene and nitro group
at2500cm-1 peak observed which is due to the presence of N+-H- bond protonated tertiary amine,
2nd peak was observed at the 1610cm-1which was due to stretching of acetonitrile group and third
peak of pure ranitidine was observed at 1460cm-1 for diamine contain group due to vibrational
65
motion of the molecules. Standard FTIR spectra of pure ranitidine was compared with the
spectra of formulations containing various polymers in different concentration along with
plasticizers and surfactants. FTIR spectra of tween 80 showed peaks at 3350 cm-1 and 1640 cm-1
due to stretching of CH2 alkane group and at 1640cm-1 due to C=O stretching as shown in Figure
56.FTIR spectra of pectin showed peaks at 1750cm-1, 1400cm-1, 1200cm-1,1050cm-1 and 980cm-1
due to ester carbonyl group ( C=O) stretching ,1400 cm-1 due to CH bonding (in –plane) and at
1200 cm-1 due to =C-H out –of –plane bending as shown in Figure55(A). FTIR spectra of pectin
wafers showed peaks at 3300cm-1, 1600cm-1, 1400cm-1, 1100cm-1 and 1000cm-1 due to C=O
stretching –CH bending and =C-H bending respectively as shown in Figure55(B). FTIR spectra
of CMC showed peaks at 3300cm-1,1590cm-1,1390cm-1,1240cm-1,1100cm-1, and 1000cm-1 due to
–OH stretching, carboxylic group stretching and stretching vibration of the C-OH group
respectively as shown in Figure 55(C). FTIR spectra of drug contain wafers showed peaks
at3300cm-1,2100cm-1 1564cm-11421cm-1,1321cm-1 and 1051cm-1 due to –OH stretching,
carboxylic group stretching and stretching vibration of C-OH group respectively as shown in
Figure60.FTIR spectra of Guar gum drug loaded wafers showed peaks at 2490cm-1,1616cm1
,1370cm-1,1220cm-1 and 1000cm-1 due to methyl C-H stretching, 1616 cm-1 due to=C-
Hstretching,1220cm-1 due to methylene twisting and 1000 cm-1 due to stretching vibration of COH group as shown in Figure55(D). No changes in the peaks were observed which shows that
the excipients shows compatibility with the all the excipients.as no changes in these peaks were
evaluated so no drug –excipients interactions were found as shown in figure (E).
66
Figure 55: FTIR spectra (A) Ranitidine HCL (B)Pectin ,(C) Pectin wafers ,(D) CMC wafers and
(E) HPMC wafers
67
5.6.
Content uniformity of wafers
Content uniformity test was carried out on various wafers formulation, contents of the
formulations were found to be within the limit. Content uniformity values of various
formulations were presented in table 5.
5.7.
Stability studies
Prepared wafers were placed in the stability chamber at humidity of about 75% and temperature
of the chamber was maintained at 400C for 3 months. After three months in the stability chamber
these formulations were again evaluated for surface pH, folding endurance, drug content,
uniformity of weight, results were presented in the table 6.
68
Table 6: Stability studies of Ranitidine hydrochloride wafers
Parame
ters
F1
F2
F3
F4
F5
Color
F6
F7
F8
F9
F10
F11
F12
Light red
Surface
pH
6.51±0.1
1
6.46±
0.11
6.41±
0.13
6.59±
0.25
6.56±
0.13
6.51±
0.10
6.51±
0.12
6.52±
0.10
6.53
±0.1
2
6.51
±0.1
4
6.53
±0.1
1
6.52
±0.1
3
Folding
endura
nce
116.4±3.
2
107.4
±3.5
142.6
±4.1
296.73
±2.81
289.8
±4.25
278.6
±1.48
292.04
±2.2
298.3
±2.3
298.
3±1.
5
262±
2.2
270±
2.7
276
Disinte
gration
time
10.2±0.5
7
18.7
5±
14.6
±0.9
6
17.4
±0.8
9
17.5
±0.8
9
94.6
8
95.5
4
95.6
15.5±
0.79
17.6±
0.41
12.8±
0.57
18.5±
0.79
18.6±
0.41
20±0.
79
20.65
±0.78
±1.5
0.79
Content
unifor
mity
5.8.
85.30±1
1.12
92.54
±8.91
89.50
1±17.
993
88.01
±5.14
94.6±
7.03
95.89
±12.7
91.12
±19.4
1
91.70
±14.5
4
92.6
7
Preparation of standard /calibration curve
The stock solution of Ranitidine hydrochloride was prepared in phosphate buffer pH 6.8 and
serial dilutions was prepared. Absorbance was measured by using UV-visible spectrophotometer
as shown in figure 56.
69
0.93
absorbance(nm)
1
y = 0.2629x + 0.0991
R² = 0.9985
0.8
0.491
0.6
0.4
0.2
0.213
0.156
0.143
0.303
0
0
0.5
1
1.5
2
2.5
3
3.5
Drug percentage
Figure 56: Calibration curve of ranitidine
5.9.
Dissolution studies
In-vitro release of wafers was studied by using modified USP type II dissolution apparatus.
Percentage drug release of three wafers formulation FI showed more than 85% drug release
within 3hours, FII showed more than 85 % release within 6 hours , however FII showed more
than 85% release after 6 hours which as shown in figure 57.
Figure 57: Percentage drug release of wafers formulation FI-FIII
70
Percentage drug release of wafers formulation FIV released more than 85% of ranitidine within
2 hours , FV showed more than 85% drug release after 8hours and FVI showed more than 85
% release after 6 hours as shown in figure 58.
Figure 58: Percentage drug release of wafers formulations FIV-FVI
Percentage drug release of formulation FVII showed more than 85% release within 4 hours,
FVIII showed more than 85% drug release after 8hours and FIX showed more than 85% release
within 6 hours as shown in figure 59.
71
Figure 59: Percentage drug release of wafers formulations FVII-FIX
Radial graph shows %age drug release along a single axis graph shows that %age drug release of
formulation FX showed more than 85% release within 6 hours, FXI shows more than 85% drug
release after 8hours and FIX showed more than 85 % release within 3 hours as shown in figure
60.
Figure 60: Percentage release of wafers formulations FX-FXII
Release kinetic models
Different kinetic models of release were applied to the 12 formulations of wafers to determine
drug follows which type of kinetic models.
5.9.1. Kinetic models of formulations (FI-FIII)
Four models zero order, first order, higuchi, and korsmeyer-peppas models were applied to the
formulations (FI-FIII) formulations values were shown in table 7.
72
Table 7: In-vitro drug release kinetics and its model dependent approaches (FI-FIII)
Kinetic model
FI
FII
FIII
-
R2
K(h-1)/n
R2
K(h-1)/n
R2
K(h-1)/n
Zero order
0.573
12.21
0.410
11.18
0.379
12.30
First order
0.947
0.402
0.816
0.408
0.809
1.152
Higuchi
0.376
37.44
0.516
33.20
0.556
38.00
Korsmeyer Peppas
0.860
0.255
0.977
0.329
0.923
0.208
Kinetic models i.e. zero order, first order, higuchi model and korsmeyer-peppas were applied to
the formulation (FI) values of R2 were upto 0.947 very close to unity(1) which shows that drug
release depends on concentration of drug in body as shown in figures 62,63 and 64.
Figure 61: Zero order release models of formulation FI
73
Figure 62 : Higuchi release model of wafers formulation (FI)
Korsmeyer-peppas release model was applied on formulation (FI) and n value was found to be
less than 0.255 which shows that drug release follows Fickian release as shown in figure 65.
Figure 63: Korsmayer-peppas model of wafers formulation (FI)
Various kinetic models such as zero order, first order and Higuchi were applied successfully on
formulation (FII) value of R2 was observed and incase of first order was 0.816 found close to
(1) indicating drug dependency release pattern as shown in figure 66,67 and 68.
74
Figure 64: Zero order release model of wafers formulation (FII)
Figure 65: First order release model of wafers formulation (FII)
75
Figure 66: Higuchi release model of wafers formulation (FII)
Observed n value was less than 0.329 which indicates that drug release follows Fickian kinetic as
shown in figure 69.
Figure 67: Korsmeyer-peppas release model of (FII)
Percentage release data of FIII formulation was fitted in to various kinetic models i.e. zero order,
first order and higuchi and observed R2 value in first order model 0.809 which was near to unity
which indicates that drug release is concentration dependent as shown in figure 70,71 and 72.
76
Figure 68: Zero order release model of wafers formulation (FIII)
Figure 69: First order release model of wafers formulation (FIII)
Figure 70: Higuchi release model of wafers formulation (FIII)
77
Korsmeyer peppas model was applied to formulation FIII and n value was observed and found to
0.208 which shows drug release follow Fickian model as shown in figure 73.
Figure 71: Korsmeyer-peppas model of wafers formulations (FIII)
5.9.2. In-vitro kinetics of formulation (FIV-FVI)
Four models zero order, first order, Higuchi and korsmeyer-peppas were applied to the
formulations (FIV-FVI) formulations of wafers as shown in table 8.
Table 8: In-vitro drug release kinetics and its model dependent approaches (FIV-FVI)
Kinetic model
FIV
FV
FVI
-
R2
K(h-1)/n
R2
K(h-1)/n
R2
K(h-1)/n
Zero order
.704
12.66
0.824
11.17
0.325
11.29
First order
0.882
1.889
0.847
0.577
0.885
0.339
Higuchi
0.361
39.81
0.320
33.801
0.881
32.76
Korsmeyer Peppas
0.796
0.159
0.901
0.244
0.896
0.431
Drug release data of (FIV) was analyzed by Appling zero, first order and higuchi release model
and observed R2 of first order 0.882 was very close to 1 in first order which indicates drug release
dependents on concentration as shown below in figure 74,75 and 76 respectively.
78
Figure 72: Zero order release model of wafers formulation (FIV)
Figure 73: First order release model of wafers formulation (FV)
79
Figure 74: Higuchi release model of wafers formulation (FIV)
Korsmeyer-peppas release FIV release was analyzed n value 0.402 which indicates drug release
follow Fickian kinetic.as shown in figure 77.
Figure 75: Korsmeyer-Peppas release model of wafers formulation (FIV)
Kinetic release models i.e. zero, first. Higuchi were applied on drug release data of formulation
FV and observed R2 value of first order was 0.847 found to close to unity indicating
concentration dependent release pattern as shown in figure 78,79 and 80.
80
Figure 76: Zero order release model of formulation (FV)
81
Figure 77: First order release model of wafers formulation (FV)
Figure 78: Higuchi release model of wafers formulation (FV)
Observed n value of korsmeyer-peppas was found to be 0.244 which showed Fickian release of
FV formulation as shown in figure 81.
Figure 79: Korsmayer-peppas release model of wafers formulation (FV).
82
Kinetic models i.e. zero, first and higuchi were applied successfully to FVI formulations.
Results of R2 of first order was found to be 0.885 very close to 1 indicating drug concentrating
dependent release pattern as shown in figures 82, 83, 84 and 85 respectively.
Figure 80: Zero order release model of wafers formulation (FVI)
Figure 81: First order release model of wafers formulation (FVI)
83
Figure 82: Higuchi release model of wafers formulation (FVI)
Figure 83: Korsmeyer-peppas release model of wafers formulation (FVI)
5.9.3. In-vitro kinetics of formulation (FVII-FIX)
Four models zero order, first order, higuchi and korsmeyer-peppas were applied to the
formulations (FVII-FIX) formulations of wafers as shown in table 9.
84
Table 9: In-vitro drug release kinetics and model dependent approaches (FVII-FIX)
Kinetic model
FVII
FVIII
FIX
-
R2
K(h-1)/n
R2
K(h-1)/n
R2
K(h-1)/n
Zero order
0.130
11.60
0.476
10.71
0.447
10.84
First order
0.977
0.454
0.964
0.950
0.967
0.312
Higuchi
0.846
34.29
0.945
30.92
0.946
31.36
Korsmeyer Peppas
0.887
0.393
0.949
0.452
0.953
0.454
Drug release data of (FVII) was applied to various kinetic models i.e. zero order ,first order and
higuchi and R2 of first order was 0.977 very close to unity (1) indicating concentration depends
release as shown in figure 86, 87 and 88.
Figure 84: Zero order release model of wafers formulation (FVII)
85
Figure 85: First order release model of wafers formulation (FVII)
Figure 86: Higuchi release model of wafers formulation (FVII)
Korsmeyer-peppas release model of wafers formulation (VII) was applied and n value was found
to be 0.393 shows Fickian release as shown in figure89.
86
Figure 87: Korsmeyer-peppas model of wafers formulations (FVII)
Kinetic models zero, first and higuchi were applied successfully R2 value was 0.950 indicating
drug release depends on concentration i.e. follow first order release kinetics as shown in figure
90, 91 and 92.
Figure 88: Zero order release model of FVIII
87
Figure 89: First order release model of wafers formulation (FVIII)
Figure 90: Higuchi release model of wafers formulations (FVIII)
Fickian release was observed by applying drug release data in to kinetic models as value of n
was 0.452 shown in figure 93.
88
Figure 91: Korsmeyer peppas release model of formulation (FVIII)
Percentage drug release data of formulation (FIX) was fitted in to kinetic models and R 2 was
observed which showed that first order value 0.967 is close to unity (1) indicates concentration
dependent drug release as shown in figure 94, 95 and 96 respectively.
Figure 92: Zero order release model of wafers formulation (FIX)
89
Figure 93: First order release model of wafers formulation (FIX)
Figure 94: Higuchi release model of wafers formulation (FIX)
Korsmeyer peppas release model shows drug release value R2 0.454 follows Fickian release
kinetics as shown in figure 97.
90
Figure 95: Korsmeyer-peppas release model of wafers formulation (FIX)
5.9.4. Kinetic models of formulation (FX-FXII)
Four models such as zero order, first order, Higuchi and korsmeyer-peppas were applied to
formulations (FX-FXII) formulations of wafers as shown in table 10.
Table 10: In-vitro release kinetics model dependent approaches (FX-FXII)
Kinetic model
FX
FXI
FXII
-
R2
K(h-1)/n
R2
K(h-1)/n
R2
K(h-1)/n
Zero order
0.456
11.29
0.621
10.15
.5760
11.99
First order
0.971
0.344
0.974
0.245
0.910
0.692
Higuchi
0.922
32.68
0.989
28.96
0.542
36.45
Korsmeyer Peppas
0.926
0.362
0.989
0.399
0.908
0.276
Drug release data of formulations (FX) was fitted in to kinetic models i.e. zero first order and
higuchi models observed results are 0.977 showed that drug release is dependent on
concentration of drug as shown in figure 98,99 and 100.
91
Figure 96: Zero order release model of wafers formulation (FX)
Figure 97: First order release model of wafers formulation (FX)
92
Figure 98: Higuchi release model of wafers formulation (FX)
Korsmeyer-peppas release model of wafers formulation (FX) was applied successfully and drug
release was observed which shows that n value is 0.393 thus it follows fickian mechanism as
shown in figure101.
Figure 99: Korsmeyer-peppas release model of wafers formulation (FX)
Zero order, first order and higuchi release kinetics models were applied to formulation (FXI) R2
value was observed which was found to be 0.967 and close to unity in first order as compared to
zero and higuchi so drug release dependent on drug concentration as shown in figure 102,103
and 104.
93
Figure 100: Zero order release model of wafers formulation (FXI)
Figure 101: First order release model of wafers formulation (FXI)
94
Figure 102: Higuchi release model of wafers formulation (FXI)
Korsmeyer-peppas release model of wafers formulation (FXI) was successfully applied and it
was observed n value was 0.362 that drug release follows fickian mechanism as shown in figure
105 .
Figure 103: Korsmeyer peppas release model of wafers formulation (FXI)
Percentage drug release data was analyzed by applying drug release mechanism R2 was found to
be 0.974and it depends on drug concentration as shown in figure 106,107 and 108.
95
Figure 104: Zero order release model of wafers formulation (FXII)
Figure 105: First order release model of wafers formulation (FXII)
96
Figure 106: Higuchi release model of wafers formulation (FXII)
Korsmeyer peppas release model of wafers formulation n values was 0.276 (FXII) shows that
drug release follows fickian release as shown in figure109.
Figure 107: Korsmeyer peppas release model of wafers formulation (XII)
97
5.10. Discussion
Ranitidine hydrochloride (RNH) is commonly recommended for the management of erosive
esophagitis, gastric ulcer, Zollinger –Ellison’s syndrome and duodenal ulcer. RNH. Various
problems are associated with conventional formulations used in the colon [25]. In the present
study a novel drug delivery system (NDDS) such as sustained released wafers of RNH was
prepared by solvent casting technique by using two natural and two synthetic polymers. Wafers
were evaluated for surface texture which was found to be smooth for pectin, guar gum and
HPMC, however crystalline texture was observed for CMC wafers formulation was reported by
Shaima et al.,2014 [37] . Wafers of 5×4cm2 were placed on piece of paper and was evaluated for
tackiness. All prepared wafers showed non-tackiness already reported by Komaragiri et al.,2012
after preparing the fast dissolving wafers of atenolol [59]. Surface pH of all wafers formulations
(FI-FXII) was found to be ranging from 6.52-6.62±0.41. The similar studies were already
reported by M.Alagus Undrum et al., 2009 [43]. Thickness of wafer was evaluated at five
different positions using screw gauge and was observed uniform thickness ranges 0.31-0.35±0.22
mm which was found to be less than 1mm. Pathan et al., 2011 also reported the similar findings
[42]. All formulations showed constant values of the thickness due to solubility of exact amount
of drug in all the preparations. Garsuch et al.,2013 reported the similar finding after observing
the texture, and drug loading of the different compositions of wafers [75]. Twenty films of each
formulation were selected and weighed accurately using analytical weighing balance all the
formulations showed weight in the range of 647.5-650.5 ±0.025mg which showed that the
method used is suitable for development of wafers also reported by Semalty et al.,2008 [44].
Folding endurance of all wafers formulations were calculated by repeatedly folding the wafers at
the same place the order of folding endurance is as CMC>Pectin>Gaur gum>HPMC that showed
that nature and concentration of polymer effects the folding endurance that was already reported
by Devi et al., 2003 that he developed hydroxypropyl methylcellulose oral films using different
concentrations of hydroxypropyl methylcellulose [76]. Formulations were evaluated using
modified disintegration apparatus. In-vitro mucoadhesion time showed similar results reported
by Ayensu et al., 2012 prepared chitosan and thioglycolic acid lyophilized wafers formulations
[77]. Percentage moisture loss of prepared wafers formulations was measured by initially
weighing the three wafers of each formulation and placed in an oven for 72 hours, after 72 hour’s
wafers were reweighed and percentage loss in weight was calculated percentage. Weight loss of
98
formulations was in the order of CMC<Pectin<Guar gum< HPMC showed similar results were
reported by Joshu S Boetang et al., 2009, moisture loss was increased by increasing the contents
of plasticizers [78]. Disintegration time of various formulations were evaluated using Petriplate
and beaker methods showed that disintegration time was more in non-agitation method as
compared agitation method reported by N Jummat et al., 2014 [47]. Percentage moisture
absorption of wafers formulations were evaluated to check the stability of wafers in the humid
conditions which showed moisture absorbance less than 1.06±0.42-1.68±0.62%. Mathews et al.,
2008 evaluated the same by using this technique and found that humidity upto 14% could not
affect the stability of wafers formulations [79]. Total dissolving time of wafers were determined
by agitated and non-agitated method and it was found that wafers dissolve completely in agitated
as compared to non-agitation method reported by Sasi Deepthi et al., 2012 [59]. Morphological
studies of formulations were evaluated by optical microscopy and some formulations showed
smooth appearance however, other formulations showed the wrinkled network like appearance.
Gurcsh et al., 2009 evaluated oral films by using same evaluation technique [80]. Scanning
electron microscopy of wafers showed that drug was uniformly distributed throughout the wafers
Paola Mura et al., 2015 evaluated upper and lower surface morphology of films using SEM [46].
FTIR analysis of pure ranitidine hydrochloride, excipients and prepared wafers showed no
incompatibilities or interactions were reported. Dissolution studies were carried out using USP
typeII dissolution apparatus using phosphate buffer 6.8pH as dissolution medium absorbance
was measured by using spectrophotometer. It was revealed that by increasing the concentration
of polymer, release of drug was retarted from formulations. Patil et al., 2010 also found
inprepared floating tablets of ranitidine hydrochloride [81]. Rajesh Kaza et al., also reported that
increasing concentration of HPMC retards the release of drug which is suitable polymer for the
prepration of controlled released formulations [82]. Polyethylene glycol (PEG200) was used as
penitratration enhancer and plasticers used ranging from 17-19% study reveiled that formulations
containing 17% plasticizers concentration showed best release. Naryan et al., 2014 prepared the
Glibinclamide sustained released release transdermal wafers formulations and reported similar
findings [36]. Carboxy methylcellulose containg wafers were evaluated for in-vitro kinetic
studies which showed that the formulation containing higher CMC concentration showed better
results for controlled released as compared to the less quantity of CMC. K Regurum et al., 2003
also reported that increasing concentration of CMC retards the drug release for several hours
99
[83]. Boetnge et al., 2009 also reported that increasing CMC concentration retards release rate of
drug [78]. Wafers were prepared using PEG as plasticizers as well as penetration enhancer it was
observed that formulations containing increased polymer concentration and 17% plasticizer
retard drug release upto several hours. Kinetic models were applied to drug release data of
wafers formulations are shown in tables 7, 8, 9 and 10 respectively. R2 values of all the
formulations were observed which was found to be 0.977 indicates the formulation followed the
first order. Values of n was 0.442 which was less than 0.45 indicates fickian drug release
mechanism [84].
5.11. Conclusion
Ranitidine hydrochloride wafers were prepared successfully using solvent casting. Drug release
was studied upto 12 hours, results showed that CMC containg formulations showed best
sustained release effect up to 12 hours various kinetic models were applied to the drug release
data which showed that the drug through the wafers follows first order and fickian drug release
mechanism.
100
6. Refrence
1.
Raval, K.M., Overview on oral strip. Journal of drug discovery and therapeutics, 2013.
1(03).
2.
Jangra, P.K., S. Sharma, and R. Bala oral , International journal of universal Pharmacy
and Biosciences fast dissolving oral films , 2014.(3) 1,6
3.
Patil, P. and S. Shrivastava, Fast dissolving oral films: An innovative drug delivery
system. Structure, 2012. 20(70): p. 50-500.
4.
Vibhooti, P. and K. Preeti, wafers technology a new approch to smart drug delivery
system. . Indian Journal of Research in Pharmacy and Biotechnology, 2013. 1(3): p. 428.
5.
Khatoon, N., N.R. Rao, and B.M. Reddy, Overview on fast dissolving oral films. Int J
Chem Pharm Sci, 2013. 1(1): p. 63-75.
6.
Bala, R., Parven p,Shushil khana and Redupa R , Orally dissolving strips: A new
approach to oral drug delivery system. International journal of pharmaceutical
investigation, 2013. 3(2): p. 67.
7.
Peggs, K. and S. Mackinnon, Imatinib mesylate-the new gold standard for treatment of
chronic myeloid leukemia. New England Journal of Medicine, 2003. 348(11): p. 10481048.
8.
Jyotsana, M., B. Sagar, and D. Mahesh, fast dissolving fims of chlorpromazine www.
ijrap. net.2009
9.
Madan, J.,Avachat A,Bandode S and Dangi M, Formulation and evaluation of a bilayer
floating drug delivery system of Nizatidine for nocturnal acid breakthrough. 2012.
10.
Ghosal, K., S. Chakrabarty, and A. Nanda, Hydroxypropyl methylcellulose in drug
delivery. Der pharmacia sinica, 2011. 2(2): p. 152-68.
11.
Heinze, T. and K. Pfeiffer, Studies on the synthesis and characterization of
carboxymethylcellulose. Die Angewandte Makromolekulare Chemie, 1999. 266(1): p. 3745.
12.
Barba, C. Montane, D. Rinado, M and Ferrori, X. , Synthesis and characterization of
carboxymethylcelluloses (CMC) from non-wood fibers I. Accessibility of cellulose fibers
and CMC synthesis. Cellulose, 2002. 9(3-4): p. 319-326.
101
13.
Bhagat, S., R. Gaikwad, and A. Warade, Guar Gum Products, Its Research & Uses in
Chemical Industries.
14.
Mishra, R., A. Banthia, and A. Majeed, Pectin based formulations for biomedical
applications: a review. Asian Journal of Pharmaceutical and Clinical Research, 2012.
5(4): p. 1-7.
15.
Olano-Martin, E. Willat, G. and Mikalson, D. Pectin and pectic-oligosaccharides induce
apoptosis in in vitro human colonic adenocarcinoma cells. Anticancer research, 2002.
23(1A): p. 341-346.
16.
Yamada, H., Contribution of pectins on health care. Progress in biotechnology, 1996. 14:
p. 173-190.
17.
Ms, A. and P.M. Amin, Oral Film Technology: Challenges and Future Scope for
Pharmaceutical Industry.
18.
Patel, D.M., Bhatt A., Floating granules of ranitidine hydrochloride-gelucire 43/01:
formulation optimization using factorial design. AAPS PharmSciTech, 2007. 8(2): p.
E25-E31.
19.
Madan, T. and A. Kakkar, Preparation and characterization of ranitidine-HC1 crystals.
Drug development and industrial pharmacy, 1994. 20(9): p. 1571-1588.
20.
Crookes, D. Crystalline ranitidine hydrochloride and pharmaceutical composition
containing it. in Chem Abstr. 1982.
21.
Shen, J., D. Lee, and R. Mc Keag, Bioequivalence of two forms of ranitidine. New
Zealand Pharmacy Oct, 1995: p. 24-25.
22.
Bawazir, S., et al., Comparative bioavailability of two tablet formulations of ranitidine
hydrochloride in healthy volunteers. International journal of clinical pharmacology and
therapeutics, 1998. 36: p. 270-274.
23.
Wu, V., T. Rades, and D. Saville, Stability of polymorphic forms of ranitidine
hydrochloride. Die Pharmazie, 2000. 55(7): p. 508-512.
24.
Stosik, A. Patil ,Savile D, Biowaiver monographs for immediate release solid oral
dosage forms: Metoclopramide hydrochloride. Journal of pharmaceutical sciences, 2008.
97(9): p. 3700-3708.
102
25.
Patel, R., Kumar K, Thakre, K. Vionade, M., Formulation and optimization of floating
matrix tablet of ranitidine hydrochloride. International Journal Comprehensive
Pharmacy, 2011. 2: p. 36-45.
26.
Oates, J.A. Feldman. M,Burtan. M ., Histamine2-receptor antagonists: standard therapy
for acid-peptic diseases. New England Journal of Medicine, 1990. 323(24): p. 16721680.
27.
Basit, A.W. and L.F. Lacey, Colonic metabolism of ranitidine: implications for its
delivery and absorption. International journal of pharmaceutics, 2001. 227(1): p. 157165.
28.
Bogues, K.,Roberts C . Pharmacokinetics and bioavailability of ranitidine in humans. in
British Journal of Pharmacology. 1981: .
29.
Brunton, L.L., Goodman & Gilman's the pharmacological basis of therapeutics. Vol. 12.
2011: McGraw-Hill Medical New York.
30.
Yadav, S., K. Kavita, and T. Tamizhamani, Formulation and evaluation of floating
tablets of ranitidine hydrochloride using natural and synthetic polymers. Int J pharm
Tech Res, 2010. 2(2): p. 1513-1519.
31.
Chowdhury, M.E.H. and M. Pathan, Preparation and evaluation of floating matrix
tablets of Ranitidine Hydrochloride. The Pharma Innovation, 2012. 1(7).
32.
HCL, R., Journal of Drug Discovery and Therapeutics 1 (7) 2013, 42-45. Journal of drug
discovery and therapeutics, 2013. 1(7): p. 42-45.
33.
Brogden, R. Carmine, A. Avery GS, ., Ranitidine: a review of its pharmacology and
therapeutic use in peptic ulcer disease and other allied diseases. Drugs, 1982. 24(4): p.
267-303.
34.
Kiran Goutam, R.G., Ajay Sharma, Ajay Singh, Pooja Sharma, Shriya Formulation and
evaluation of oral fast dissolving films of promethazine theoclate (25mg):, 2015. 5((8): p.
2536-2544.
35.
Kalluri, J.K.Y., Fabrication and Assessment of fast Dissolving Buccal Films of Labetalol
Hydrochloride for Hypertension. International Journal of Medicine and Pharmaceutical
Research, 2014. 2(1): p. 462-467.
36.
Yadav, P.N., P. Bhat, and S. Soni, Glibenclamide fabricated transdermal wafers for
therapeutic sustained delivery systems. 2014.
103
37.
Abd-Alhammid, S.N. and H.H. Saleeh, Formulation and Evaluation of Flurbiprofen Oral
Film. Iraqi J Pharm Sci, 2014. 23(1): p. 53-59.
38.
Sultana, F., M. Arafat, and S.I. Pathan, Preparation and evaluation of fast dissolving oral
thin film of caffeine. Int. J. Pharm. Biol. Sci, 2013. 3: p. 153-161.
39.
Boateng, J., J. Mani, and F. Kianfar, Improving drug loading of mucosal solvent cast
films using a combination of hydrophilic polymers with amoxicillin and paracetamol as
model drugs. BioMed research international, 2013.
40.
Raju, P.N, Kumar. M,Ravishkanar k and Reddy. Ch ., Formulation and Evaluation of
Fast Dissolving Films of Loratidine by Solvent Casting Method. The Pharma Innovation,
2013. 2(2).
41.
Pallavi Patil.1, S.K.S., Fast Dissolving Oral Films: An Innovative DrugDelivery System.
(2012):.
42.
Pathan, A.M.,Mahhaduhri.A , Chandewar V and Bakade V ., 5. Development and in vitro
evaluation of salbutamol sulphate mucoadhesive buccal patches. Int J Pharm Pharm Sci,
2011. 3(2): p. 39-44.
43.
Alagusundaram, M.,Ramkanth. k,Cuhdna.C and Madu. C, ., Formulation and evaluation
of mucoadhesive buccal films of ranitidine. International journal of pharmtech research,
2009. 1(3): p. 557-563.
44.
Semalty, M., A. Semalty, and G. Kumar, Formulation and characterization of
mucoadhesive buccal films of glipizide. Indian journal of pharmaceutical sciences, 2008.
70(1): p. 43.
45.
Shaikh, R.P. Vinas. P ,Nadesno. K, Kumar. P, ., The application of a crosslinked
pectin‐based wafer matrix for gradual buccal drug delivery. Journal of Biomedical
Materials Research Part B: Applied Biomaterials, 2012. 100(4): p. 1029-1043.
46.
Mura, P, Kosalec. I, Orlanedi S and Mario. J ., Amidated pectin-based wafers for
econazole buccal delivery: Formulation optimization and antimicrobial efficacy
estimation. Carbohydrate polymers, 2015. 121: p. 231-240.
47.
Ng, S.-F. and N. Jumaat, Carboxymethyl cellulose wafers containing antimicrobials: a
modern drug delivery system for wound infections. European Journal of Pharmaceutical
Sciences, 2014. 51: p. 173-179.
104
48.
Noelle H. O’Driscoll, O.L., K.H.M. T. P. Tim Cushnie, and D.K.M.A.J. Lamb,
Production and Evaluation of an Antimicrobial Peptide-Containing Wafer Formulation
for Topical Application. 2013.
49.
Khairnar, A., Jain. D, Bavishkar. D, Jain. P, , Developmement of mucoadhesive buccal
patch containing aceclofenac: in vitro evaluations. Int J Pharm Tech, 2009. 1: p. 978981.
50.
Boateng, J.S., Mathews.KH,and Auffret.AD ., In vitro drug release studies of polymeric
freeze-dried wafers and solvent-cast films using paracetamol as a model soluble drug.
International journal of pharmaceutics, 2009. 378(1): p. 66-72.
51.
Senthil, V, Rizwana. B, Venkatta. T, and Rahti v., ., Levocetirizine dihydrochloride and
ambroxol hydrochloride oral soluble films: Design, optimization, and patient compliance
study on healthy volunteers. International Journal of Health & Allied Sciences, 2013.
2(4): p. 246.
52.
Labovitiadi, O., A.J. Lamb, and K.H. Matthews, Lyophilised wafers as vehicles for the
topical release of chlorhexidine digluconate—Release kinetics and efficacy against
Pseudomonas aeruginosa. International journal of pharmaceutics, 2012. 439(1): p. 157164.
53.
Olga Labovitiadia, b., Andrew J. Lamba, Kerr H. Matthewsa, Lyophilised wafers as
vehicles for the topical release of chlorhexidine digluconate—Release kinetics and
efficacy against Pseudomonas aeruginosa Olga Labovitiadia,b, Andrew J. Lamba, Kerr
H. Matthewsa. 2012) p. 157– 164.
54.
Ganguly, I.,., Development of Fast Dissolving Sublingual Wafers of Promethazine
Hydrochloride. Iranian Journal of Pharmaceutical Sciences, 2014. 10(1): p. 71-92.
55.
Boateng, J. and D. Areago, Composite Sodium Alginate and Chitosan Based Wafers for
Buccal Delivery of Macromolecules. Austin J Anal Pharm Chem, 2014. 1(5): p. 1022.
56.
Cilurzo, F.,Bhurrati.S,Selmini. F, Nicotine fast dissolving films made of maltodextrins: a
feasibility study. AAPS PharmSciTech, 2010. 11(4): p. 1511-1517.
57.
Kunte, S. and P. Tandale, Fast dissolving strips: A novel approach for the delivery of
verapamil. Journal of pharmacy and bioallied sciences, 2010. 2(4): p. 325.
105
58.
Kianfar, F., Lyophilized wafers comprising carrageenan and pluronic acid for buccal
drug delivery using model soluble and insoluble drugs. Colloids and Surfaces B:
Biointerfaces, 2013. 103: p. 99-106.
59.
Deepthi, K.S, Goutam.K,Sharma. A, and Khushal. S, , Formulation and Characterization
of Atenolol Fast Dissolving Films. Indian Journal of Pharmaceutical Science & Research,
2012. 2(2): p. 58-62.
60.
Kianfar, F., ., Formulation development of a carrageenan based delivery system for
buccal drug delivery using ibuprofen as a model drug. Journal of Biomaterials and
Nanobiotechnology, 2011. 2(05): p. 582.
61.
Mishra, R. and A. Amin, Formulation development of taste-masked rapidly dissolving
films of cetirizine hydrochloride. Pharmaceutical technology, 2009. 33(2): p. 48-56.
62.
Shimoda, H., et al., Preparation of a fast dissolving oral thin film containing
dexamethasone: a possible application to antiemesis during cancer chemotherapy.
European Journal of Pharmaceutics and Biopharmaceutics, 2009. 73(3): p. 361-365.
63.
Ferreira, S.C., Burns R.E,Brando. G,and Suza .A, e, Box-Behnken design: An alternative
for the optimization of analytical methods. Analytica chimica acta, 2007. 597(2): p. 179186.
64.
Ismail, A.M., ., Early Post Trabeculectomy Hypotony is a Risk Factor for Glaucoma
Failure. Liver, 2012. 70: p. 73.
65.
Sakhare, A.V., Effect of Glycerin as Plasticizer in Orodissloving Films of Losartan
Potassium.
66.
Fulzele, S., P. Satturwar, and A. Dorle, Polymerized rosin: novel film forming polymer
for drug delivery. International journal of pharmaceutics, 2002. 249(1): p. 175-184.
67.
Garsuch, V. and J. Breitkreutz, Novel analytical methods for the characterization of oral
wafers. European Journal of Pharmaceutics and Biopharmaceutics, 2009. 73(1): p. 195201.
68.
El-Nabarawi, M.,Rehab. A,Taley. s, ., Development and characterization of ketorolac
tromethamine (KT) orobuccal films. Int. J. of Pharmacy and Pharm. Sci, 2012. 4(4): p.
186-193.
106
69.
Chakraborty, P, Shurjet Dey,Versha. P, ., Design expert supported mathematical
optimization and predictability study of buccoadhesive pharmaceutical wafers of
loratadine. BioMed research international, 2013. .
70.
Kusum Devi, V., ., Design and evaluation of matrix diffusion controlled transdermal
patches of verapamil hydrochloride. Drug development and industrial pharmacy, 2003.
29(5): p. 495-503.
71.
Semalty, M., Beshant. S, Shree. V , Development of mucoadhesive buccal films of
glipizide. International journal of pharmaceutical sciences and nanotechnology, 2008.
1(2): p. 184-190.
72.
Bansal, S., M. Bansal, and G. Garg, Formulation and evaluation of fast dissolving film of
an antihypertensive drug. Int. J. of Pharmaceutical, Chemical and Biological Sciences,
2013. 3(4): p. 1097-1108.
73.
Patel, A.R., D.S. Prajapati, and J.A. Raval, Fast dissolving films (FDFs) as a newer
venture in fast dissolving dosage forms. International journal of drug development and
research, 2010. 2(2): p. 232-246.
74.
Sakuda, Y., .,Yushira.M,Sastu. M, Preparation and evaluation of medicinal carbon oral
films. Chemical and Pharmaceutical Bulletin, 2010. 58(4): p. 454-457.
75.
Chakraborty, P.,Vercha. P, Goash A, ., Mathematical optimization and characterisation
of pharmaceutically developed novel buccoadhesive wafers for rapid bioactive delivery
of Loratadine. Journal of Pharmaceutical Investigation, 2013. 43(2): p. 133-143.
76.
VK Devi, S.S., GR Maria, PU Deepti. Drug Dev. Ind. Pharm, 2003, 29, 495–503.
77.
Ayensu, I. and J. Boateng, Development and evaluation of lyophilized thiolated-chitosan
wafers for buccal delivery of protein. Journal of Science and Technology (Ghana), 2012.
32(2): p. 46-55.
78.
Boateng, J.S., Mathews K, Development and mechanical characterization of solvent-cast
polymeric films as potential drug delivery systems to mucosal surfaces. Drug
development and industrial pharmacy, 2009. 35(8): p. 986-996.
79.
Matthews, K., Boeatng S.j,., Formulation, stability and thermal analysis of lyophilised
wound healing wafers containing an insoluble MMP-3 inhibitor and a non-ionic
surfactant. International journal of pharmaceutics, 2008. 356(1): p. 110-120.
107
80.
Garsuch, V., Preparation and characterization of fast-dissolving oral films for pediatric
use. 2009.
81.
Patil, V., Kumar k sunail. V and shunil D., Formulation and evaluation of floating matrix
tablet of locally acting h2-antagonist. International Journal of Pharmacy & Technology,
2010. 2(3): p. 528-540.
82.
Kaza, R., Arvind. K, Gupta P and Chawla ., Design and Evaluation of Sustained release
Floating tablets for the treatment of Gastric Ulcers. J Pharm Sci Res, 2009. 1(4): p. 8187.
83.
Reddy, K.R., S. Mutalik, and S. Reddy, Once-daily sustained-release matrix tablets of
nicorandil: formulation and in vitro evaluation. AAPS pharmscitech, 2003. 4(4): p. 480488.
84.
V.F. Patel, N.M.P.a.P.G.Y., Studies on, f. floating matrix tablets international journal of
pharmaceutical sciences 2012 .,(3) 2
108