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FORMULATION AND VALIDATION OF ORGANOGELS AS CARRIERS FOR

TOPICAL DELIVERY OF TERBINAFINE HYDROCHLORIDE


By
HAJARATUMAR DODDAMANI
B. Pharm.
Reg. No. 10PQ580

Dissertation submitted to the


Rajiv Gandhi University of Health Sciences, Karnataka, Bengaluru

In partial fulfillment of the requirements for the degree of

MASTER OF PHARMACY
IN
QUALITY ASSURANCE

Under the guidance of

Prof. G M Sreenivasa, M. Pharm. Ph.D

P.G. Department of Quality Assurance


S.C.S. College of Pharmacy
Harapanahalli-583 131
Karnataka
2012
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BENGALURU.

DECLARATION BY THE CANDIDATE

I hereby declare that this dissertation entitled “FORMULATION AND


VALIDATION OF ORGANOGELS AS CARRIERS FOR TOPICAL DELIVERY OF
TERBINAFINE HYDROCHLORIDE” is a bonafide and genuine research work
carried out by me under the guidance of Prof. G M Sreenivasa, M. Pharm., Ph.D.
Department of Quality Assurance, S.C.S College of Pharmacy, Harapanahalli.
The work embodied in this dissertation is original and has not been submitted the
basis for the award of degree, diploma, associateship (or) fellowship of any other
university (or) institution.

Date:
Place: Harapanahalli Hajaratumar Doddamani
S.C.S COLLEGE OF PHARMACY
HARAPANAHALLI- 583 131

CERTIFICATE BY THE GUIDE

This is to certify that the dissertation entitled “FORMULATION AND


VALIDATION OF ORGANOGELS AS CARRIERS FOR TOPICAL DELIVERY OF
TERBINAFINE HYDROCHLORIDE” is a bonafide research work done by
Hajaratumar Doddamani in partial fulfillment for the award of the degree of
“Master of Pharmacy” in Quality Assurance by the Rajiv Gandhi University of
Health Sciences, Karnataka, Bengaluru.

Date: Prof. G M Sreenivasa. M.Pharm, Ph.D


Place: Harapanahalli
S.C.S COLLEGE OF PHARMACY
HARAPANAHALLI- 583 131

CERTIFICATE BY THE CO-GUIDE

This is to certify that the dissertation entitled “FORMULATION AND


VALIDATION OF ORGANOGELS AS CARRIERS FOR TOPICAL DELIVERY OF
TERBINAFINE HYDROCHLORIDE” is a bonafide research work done by
Hajaratumar Doddamani in partial fulfillment for the award of the degree of
“.Master of Pharmacy” in Quality Assurance by the Rajiv Gandhi University of
Health Sciences, Karnataka, Bengaluru.

Date: Dr. E. Jayachandran. M.Sc. (Ph.chem.), Ph.D

Place: Harapanahalli
S.C.S COLLEGE OF PHARMACY
HARAPANAHALLI- 583 131

CERTIFICATE BY THE H.O.D

This is to certify that the dissertation entitled “FORMULATION AND


VALIDATION OF ORGANOGELS AS CARRIERS FOR TOPICAL DELIVERY OF
TERBINAFINE HYDROCHLORIDE” is a bonafide research work done by
Hajaratumar Doddamani in partial fulfillment for the award of the degree of
“Master of Pharmacy” in Quality Assurance by the Rajiv Gandhi University of
Health Sciences, Karnataka, Bengaluru.

Date: Dr. R Nagendra Rao. M.Pharm, Ph.D


Place: Harapanahalli
S.C.S COLLEGE OF PHARMACY
HARAPANAHALLI- 583 131

ENDORSEMENT BY THE PRINCIPAL

This is to certify that the dissertation entitled “FORMULATION AND


VALIDATION OF ORGANOGELS AS CARRIERS FOR TOPICAL DELIVERY OF
TERBINAFINE HYDROCHLORIDE” is a bonafide research work done by
Hajaratumar Doddamani Submitted in partial fulfillment for the award of the
degree of “Master of Pharmacy” in Quality Assurance by the Rajiv Gandhi
University of Health Sciences, Karnataka, Bengaluru,. This work was carried
out by him in the library and laboratories of S.C.S College of Pharmacy,
Harapanahalli, under the guidance of Prof. G M Sreenivasa, M. Pharm., Ph.D.,
Department of Quality Assurance, S.C.S College of Pharmacy, Harapanahalli.

Date: Dr. R. Nagendra Rao, M.Pharm., Ph.D.


Place: Harapanahalli
.

COPYRIGHT

DECLARATION BY THE CANDIDATE

I hereby declare that the Rajiv Gandhi University of Health Sciences,


Karnataka shall have the rights to preserve, use and disseminate this dissertation
in print or electronic format for academic/ research purpose.

Date:
Place: Harapanahalli Hajaratumar Doddamani

© Rajiv Gandhi University of Health Sciences, Karnataka


ACKNOWLEDGEMENT

My sincere pranamas to his holiness


Sha. Bra. Sri. Chandramouleeshwara Swamiji
President, T.M.A.E. Society, Harapanahalli, for his blessings.

Every completed task has got many hands to accomplish it. Mere mention
of them will not justify their true contribution. My knowledgements are, therefore
many more than what I have expressed here.
I consider myself most lucky to work under the guidance of
Prof. G M Sreenivasa, M.Pharm., Ph.D Department of Quality Assurance,
SCS College of Pharmacy, Harapanahalli. I take this opportunity to express my
heartfelt gratitude to my reverend guide. His discipline, principles, simplicity,
caring attitude and provision of fearless work environment will be cherished in all
walks of my life. I am very much grateful to him for his invaluable guidance and
ever-lasting encouragement throughout my course.
I express my sincere gratitude to my co-guide Dr. E Jayachandran Prof
and Head, Department of Pharmaceutical Chemistry for his continuous support
and for his worthy suggestions and encouragement during the course of work.
It is indeed a great pleasure to express my deep sense of gratitude
and whole hearted thanks to Mr. M Shankraiah Asst. Prof. Dept of
Pharmaceutics for his invaluable guidance and constant encouragement that
framed the foundation of this project. It has been a most fruitful and enjoyable
experience to work under his untiring guidance. Without his encouragement and
constant guidance I could not have finished this dissertation. He taught me how
to express my ideas. He showed me different ways to approach a research problem
and the need to be persistent to accomplish any goal.
Words cannot express my feelings towards our beloved
Dr. R Nagendra Rao Principal and Head, department of Quality Assurance
SCS College of Pharmacy, Harapanahalli. I render my grateful respect and
sincere thanks for his valuable help and providing necessary facilities to carry out
this work with great ease and precision.
I am thankful to Prof. K Prabhu, vice principal for his worthy
suggestions & encouragement during my study.
I express my sincere gratitude to visiting professor Dr. Y S Agasimudin,
for his worthy suggestions & encouragement during my study.
I wish to convey my sincere thanks to Prof. J S Venkatesh,
Dr. C Nagesh and Mr. Ravindra Adhikar Department of pharmaceutics, for
their help and moral support during this dissertation work.
I am also thankful for the kind co-operation of Prof. Veerana Gouda,
Dr. S V Rajendra, and Prof. I Shanmukha, Department of Pharmacology for
extending their help in carrying out the research project and for their wise
suggestions.
I express my sincere thanks to Dr. B H M Jayakumar Swamy,
Department of Pharmaceutical chemistry for their worthy suggestions.

I am also thankful to Prof. S V Gopalkrishna, Department of


Pharmacognosy for his worthy suggestions & encouragement during my study.

Special and heartful thanks to Mrs. Shailaja, Mr. Shambhulingaiah,


Mr. Eeranna Jajjuri, Mr. Basavana Gouda, Mr. Biswajit Naha and
Mr. Sriranga, lecturer, S.C.S. College of pharmacy, Harapanahalli, for their help
and moral support during dissertation work.

I extend my thanks to Mr. S L Gurunath, Mr. Neelapa, Mr. Srinivas,


and Mr. Vijay Kumar, Lab Technician and especially Mr. Nagaraj, Lab
Attender, all other non-teaching staff of for their kind co-operation and help
extended during my research work.

I am thankful to my friends who have always cared for me specially


Gireesh, Manju, Basu (mama), Pradi (macha) and Ravi with whom I have
everlasting beautiful memories which will remain with me until my last breath.
This page is incomplete without thanking my adorable friends wishing
them success in life Sindhu Patil, Vani, Jagadish Pasargi (Dumma), Ganesh
and Gajendra I thank for their kind support during the work.

Words sail me to express my profound gratitude to my dearest Shilpa,


Samina, Mangala and Jyoti.

Preserved unforgettable moments of joy shared with my classmates


Chintan, Jasmin, Satyan, Nirav for their kind support and team work that will
never be forgotten.

A special thanks to Madhusudan, Jagadish Rabadiya, Chetan, Nandini,


Shruthi, Priyanka, Hiren, Ramkrishna, Subodh, Bhuvnesh, Ajay, Pavan, Mahesh,
Shrikant, Dayanand, Naveen, Ranga, Ambarish, Santosh raj, Sreenivasa,
Surendra, Raju, Shambu, Nazeer will remain fresh in my memory.

A very special thanks to my B pharm friends Manoj, Arun,


Madhusudhan, Nadeem, Rajesh, Harish, Praveen, Pavan, Satish, Madan,
Iliyaz for their kind support and wise suggestions that will never be forgotten

I am also thankful to my seniors Hashmukh, Pradip, Keyur and also


thankful to my juniors Nagarjun, Chand basha, Zaman, Ashwini H M, Manoj,
Medhini, Priyal, Karthik, Mukesh, Sagar, Rajan, Jani Jaimin, Priyank and
Vinuth for their assistance during course of work.

I ALWAYS CHERISH THE MOMENTS THAT I SPENT WITH MY

FRNDZ SHARING TEA IN THE CANTEEN WHICH WAS OUT OF THE

WORLD. CHEERS GUYZ…..!! MISS U ALL……!

I owe my special thanks to my grandfather and my grandmother for their


continuous blessings.
I feel great to express my deep sense of gratitude to my beloved father
Sri. Dadapeer, one whose constant encouragement, support and indefinable love
has been the foundation of this research work, my mother Smt. Haseenabanu ,
who taught me to face life and sacrificed a lot for my career which I cannot express
in mere words. I am immensely pleased in expressing my deepest sense of
gratitude and regards to them and to my whole family to be the real sources of
inspiration at each and every front of my life to transform my dreams into reality.
Their confidence in me inspired to work hard and hard.
I owe a very special thanks to my dearest brother Nijaamuddin, bhabi
Seema Kousar, my lovely sister Noorjahan Begum & my cute little niece
Samyan for their love, support and boosting encouragement throughout my
career.
I extend my profound respect and heartful gratitude to my beloved aunties
Smt. Jaibun, Sm.t Khuresha, Smt. Akhtarbi, my cousin sister Smt. Bibijaan and
uncle Sri. Rasool sab. I am immensely pleased in expressing my deepest sense of
gratitude and regards to my whole family to be the real sources of inspirations at
each and every front of my life to transform my dreams into reality.
Wholeheartedly I express my special thanks to my lovely cousin sister
Reshma Banu for constant love, support, and encouragement throughout my
studies.
I express my sincere thanks to all those who were instrumental both
directly and indirectly in completing my studies.
lastly i thank ‘god’ the almighty, to show
the path to the ladder of success.

Thanks to one and all…!!!!!!

HAJARATUMAR DODDAMANI
Dedicated To

My Parents, Family Members


&
Friends
List of Abbreviations 2012
% Percentage

˚C Degree Celsius

λ max Maximum wavelength

µg Microgram

cm Centimeter

CDR Cumulative drug release

FTIR Fourier Transform Infrared Spectroscopy

g Grams

GI Gastro Intestinal

GIT Gastro Intestinal Tract

Hrs Hours

IP Indian pharmacopoeia

KE first order elimination rate constant

kg Kilogram

min minutes

ml Milliliter

mm millimeter

nm Nanometer

pH Hydronium ion Concentration

R2 Regression

RH Relative humidity

Rpm Rotation per minute

SD Standard deviation

Sec Second

SI.No Serial number

PG Dept. of Quality Assurance, SCSCOP, Harapanahalli


List of Abbreviations 2012
SO Sunflower oil

UV Ultraviolet

Wt Weight

PG Dept. of Quality Assurance, SCSCOP, Harapanahalli


Table of Contents 2012

TABLE OF CONTENT

SL. No. TITLE PAGE No.

01 Introduction 1-11

02 Objectives 12

03 Review of literature 13-29

04 Materials and methods 30-39

05 Results and discussion 40-50

06 Conclusion 51

07 Summary 52

08 Bibliography 53-64

PG Dept. of Quality Assurance, SCSCOP, Harapanahalli


List of Tables 2012
LIST OF TABLES

Table Page
Particulars of the tables
No. No.

Organogels used in controlled or sustained delivery of


01 11
drugs

02 Formulation of Terbinafine Hydrochloride Gel 33

42
03 Standard plot of Terbinafine Hydrochloride

Observations of pH, Spreadability, Viscosity, Gel-Sol


04 46
Transition temperature

05 Drug content of Terbinafine HCL 46

In-vitro drug release through Cellophane Membrane


06 47
(Release Kinetics)

07 49
Observations of the Antifungal activity

08 50
Observations of the Stability study

PG Dept. of Quality Assurance, SCSCOP, Harapanahalli


List of figures 2012
LIST OF FIGURES

Sl. No. Particulars of the figures Page No.

01 FT-IR Spectra of Terbinafine Hydrochloride 41

02 FT-IR Spectra of F1 41

03 λ -max of Terbinafine Hydrochloride in Methanol 42

04 Standard plot of Terbinafine Hydrochloride in Methanol 43

05 Gelation process of organogel 44

06 In-vitro drug release profile (Zero Order) 48

07 In-vitro drug release profile (First Order) 48

08 In-vitro drug release profile (Higuchi) 48

09 In-vitro drug release profile (Korsmeyer Peppas) 49

PG Dept. of Quality Assurance, SCSCOP, Harapanahalli


Abstract 2012
ABSTRACT

Organogel, a viscoelastic system, can be regarded as a semi-solid preparation

which has an immobilized external non-polar phase. The non-polar phase gets

immobilized within spaces of the three-dimensional networked structure formed due

to the physical interactions amongst the self assembled structures of compounds

regarded as gelators. The current study describes the development of span-60 based

organogels using sunflower oil (SO) as the non-polar solvent and Span60 as gelator.

Terbinafine HCL is the most potent and it is an alkylamine synthetic

antifungal drug. It is highly lipophilic and only slightly soluble in water. Terbinafine

HCL was incorporated within gels and the organogels were subjected for pH

measurement, spreadability, viscosity, gel-sol transition studies, FTIR spectroscopy,

in vitro release behavior and antifungal efficiency against Candida albicans and

stability studies were studied. The gel-sol transition study indicated that as the

concentration of the gelator was increased, there was a subsequent increase in the

transition temperature. The pH of the organogels was found to be within the normal

human skin pH range. The Invitro release studies indicated that the release of

terbinafine HCL from the organogels occurred by Higuchian kinetics and were able to

restrict the growth of Candida albicans. The stability tests indicated that the gels were

inherently stable when stored below 25°C. Based on the results, the developed

organogels may be tried as a drug carrier for transdermal and/or topical formulations.

Keywords: Terbinafine HCL, Sunflower oil, Span-60, Antifungal

PG Dept. of Quality Assurance, SCSCOP, Harapanahalli


Introduction 2012
INTRODUCTION

In the recent years, semisolid products have gained much importance in the

areas of food, nutraceutical, cosmetics, and pharmaceutical industries. They have been

used either as gels, lotions, creams, ointments and jellies. The method of preparation

of these products is very tedious and complicated. Apart from this, there is a great

concern associated with the long-term stability of most of these products due to which

there is a reduced shelf-life of these products. The semisolid preparations having both

solid and liquid components in its structures have been regarded as gels 1. Gel-based

semisolid products have been found to be more stable than other types 2. In general,

gel-based products may be categorized either as hydrogels or organogels, depending

on the polarity of the liquid component. Hydrogels have water as the liquid

component while organogels have a polar solvent (e.g. hexane, isopropyl myristate,

sunflower oil and corn oil) as the liquid component. Amongst the gel-based, the use of

organogel based products is increasing, which may be attributed to the easy method of

preparation and inherent long-term stability of these products 3. Depending on the

mechanism of the formation of the three dimensional skeleton, which help in

immobilizing a polar phase, the organogels are further categorized as fluid-filled

structure and solid-fiber based organogels4. Till most of the organogels based

products were developed using non-biocompatible components. But with the

advancement in the pharmaceutical, food, nutraceutical and cosmetics industries,

various organogel based products were being developed using biocompatible

components and have in use for human consumption5, 6.

Sunflower oil (SO) obtained from healthy dried kernels of Helianthus annuus

and is widely available commonly used edible oil. SO is rich in vitamin E. Presence

of many anti-oxidant and anti-carcinogenic species in SO has been reported7-10.

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Introduction 2012
In the present study, an attempt was made to develop and characterize SO

based organogels, using span-60 as the organogelator for probable application in

controlled drug delivery.

Terbinafine hydrochloride is a synthetic alkylamine drug with broad spectrum

antifungal activity. It is used for immediate relief in Jock itch (burning sensation in

groin area, thigh folds or anus, genital areas etc.) or Tinea cruris (fungal infection in

groin area) and in various types of onchomycosis or Tinea unguium (fungal infection

of nail bed, matrix or plate, toenails are mostly affected). It occurs mainly due to

Trichophyton rubrum, Candida albicans, Trichophyton mentageophytis and

Epidermophytion floccosum. Terbinafine hydrochloride is highly lipophilic and

slightly soluble in water11.

INTRODUCTION OF ORGANOGEL

A gel may be defined as a semi-solid formulation having an external solvent

phase, apolar (organogels) or polar (hydrogel), immobilized within the spaces


12-18.
available of a three dimensional networked structure In the current review,

attempts will be made to have an insight on the mechanism of formation and

applications of the organogels as a delivery system.

The organogels may be regarded as bi-continuous systems consisting of

gelators and apolar solvent, which may or may not contain water-molecules entrapped

within the self-assembled structures of the gelator. The gelators, when used in

concentration < 15 % (approx.), may undergo physical or chemical interactions so as

to form self-assembled fibrous structures which get entangled with each other

resulting in the formation of a three-dimensional networked structure. Thus formed,


12, 19
prevents the flow of external non-polar phase . Some common examples of

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Introduction 2012
gelators include sterol, sorbitan monostearate, lecithin and cholesteryl anthraquinone

derivatives. The thermo-reversible property of the organogels has generated much

interest for the potential use of the organogels as drug delivery system. The

thermodynamic stable nature of the organogels has been attributed to the spontaneous

formation of fibrous structure by virtue of which the organogels reside in a low

energy state. The occurrence of the gel-to-sol transition above room-temperature

indicates that external energy has to be supplied to the organogels so as to disrupt the

three-dimensional structure and subsequent transformation of the gelled state to the

sol state. Apart from the temperature sensitivity, organogels are also sensitive to the

presence of moisture which has also been explored to develop controlled delivery
20
systems . Various organogel-based formulations have been designed to administer

of the bioactive agents by different routes administration.12

Properties of organogels:

In the present section, attempts will be made to discuss about the various

physicochemical properties of the organogels.

1. Viscoelasticity:

The organogels behaves like a solid at lower shear rates and hence show an
21
elastic property . As the shear stress is increased, the physical interacting points

amongst the fiber structures start getting weakened until the shear stress is high

enough to disrupt the interactions amongst the fiber structures, then the organogels

starts flowing.22, 23. 24

2. Non-birefringence:

Organogel which is not allowing the polarized light to pass through its matrix

is regarded as non- birefringent.25, 26, 27

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Introduction 2012
3. Thermo reversibility:

As the organogels are heated up above a critical temperature, they organogels

loses its solid matrix like structure and starts flowing. 28-31

4. Thermo stability:

The organogels are inherently thermostable in nature. 32

5. Optical clarity:

Organogels may be transparent or opaque in nature. 33

6. Biocompatibility:

Initially, organogels were developed using various non- biocompatible agents

which renders the organogels non-biocompatible. Later, research on organogels

revealed that using various biocompatible constituents have opened up a new

dimensions for the use of the same in various biomedical applications.12, 34

7. Chirality effects:

The presence of chirality in the low molecular weight gelators has been found

to affect the growth and the stability of the solid-fiber networks. Thermoreversibilty

of the gels formed due to the formation of the self-assembled solid-fiber network has

also been associated with the chirality. 12, 35, 36, 37

Advantages:

1. Template vehicle:

Lecithin organogels provide opportunities for incorporation of wide range of

substances with diverse physicochemical characters viz, chemical nature, solubility,

molecular weight and size etc.

2. Process benefits:

Self-assembled supra molecular arrangement of surfactant molecules makes

the process very simple and easy to handle.

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Introduction 2012
3. Structural/Physical stability:

Structural integrity of organogels is maintained for longer time periods.

4. Chemical stability:

Organogels are not susceptible to moisture and due to organic character also

resists microbial contamination.

5. Topical delivery potential:

They enhance the skin penetration and transport of the molecules.

6. Safety:

Use of biocompatible, biodegradable and non-immunogenic materials makes them

safe for long-term applications. 38, 39, 40

Limitations:

1. In the lecithin organogels, the lecithin should be pure otherwise no gelling will

occur.

2. The organogel has greasy property.

3. The organogel is less stable to temperature 41.

Types of Gels:

1. Fatty acid derived Sorbitan Organogels:

The gelators categorized under this category include sorbitan monostearate and

orbitan monopalmitate. These gelators are hydrophobic non-ionic molecules having

surface active properties and have the ability to immobilize various solvents viz.

isopropyl myristate, and vegetable oils. These gelators form solid-fiber matrix when

the heated solution of gelator in non polar solvent is cooled down. The formation of

the gel has been attributed to the formation of toroidal reverse micelles as the

temperature is lowered. The toroidal reverse micelles reorganize themselves to form

rod-shaped tubules which subsequently undergo physical interaction amongst each

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Introduction 2012
other thereby forming a three-dimensional networked structure. The gels developed

by using these gelators are opaque, thermoreversible and thermostable at room-

temperature for weeks 26, 42.

Organogels using fatty acid gelators may also be prepared by dissolving the

gelators in a water-in-oil emulsion at a higher temperature followed by the decrease

of the emulsion temperature. The decrease in the temperature results in the decrease

in the solubility of the gelator with the subsequent precipitation and self-assembly of

the gelators into network of tubules, which gets entangled so as to form a gelled

structure 43.

2. Lecithin organogels:

Lecithin is a phospholipid, extracted from various plants and animal tissues apart

from the egg yolk. The use of lecithin for designing the organogels was first described

by Scartazzini and Luisi during the year 1988 33. Since then, a lot of research has been

done on lecithin-based organogels. The lecithin procured from natural sources is able

to form the gelled structures and has been attributed to the presence of unsaturated

chemistry within its structure. The synthetic lecithin and hydrogenated soy lecithin

failed to develop organogels. Apart from the chemical structure, the purity of the

extracted lecithin also plays an important role in the formation of organogels.

Experimental results indicate that the lecithin fails to initiate the process of

gellification of the apolar solvent if the lecithin contains < 95% phosphatidyl content.

The lecithin-based organogels have been found to be thermodynamically stable,

thermoreversible (sol-to-gel transition at temperature 40oC), transparent, viscoelastic,


23, 44
biocompatible and nonirritant . The organogels prepared using lecithin has been

found to have an isotropic structure. The lecithin organogels help either in the

solubilization or accommodation of various guest molecules within its structure.

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Introduction 2012
These properties of the lecithin organogels have generated great potential for the use

of the same as a controlled delivery vehicle. Typically, in a lecithin organogels the


33
molar ratio of water to lecithin may vary from 1 to 12 . The formation of the

organogel in the presence of lecithin may be attributed to the entanglement of fluid-

fiber reverse micellar tubular structures 23. From the above discussion, it is clear that

the lecithin-based organogels have three distinct components viz. an apolar phase, a

polar phase and a surfactant (lecithin).

3. Pluronic Lecithin Organogel (PLO):

PLO is a soy lecithin-based organogels which consists of isopropyl palmitate or

isopropyl myristate, water and Pluronic F127 (also known as Poloxamer 407). PLO

may or may not contain sorbic acid in both the phases, which acts as a preservative. It

occurs as yellow a colored, odorless and opaque gel which is quickly absorbed from

the skin. Like lecithin organogels, PLO also consists of entangled tubular reverse-

micelle structures which form temporal three-dimensional structures.45 The non-polar

phase in the PLO constitutes 22 % (v/v) and hence is often regarded as

micro-emulsion-based gel 46. PLO is thermostable, viscoelastic and biocompatible in

nature. PLO has also been found to produce minimal skin irritation. It has been used

as a delivery vehicle for both hydrophobic and hydrophilic molecules for topical and

transdermal applications. 45

4. Limonene GP1/PG organogel:

Limonene, a terpene, has been found to be an excellent penetration enhancer

and hence has been incorporated within various transdermal formulations for the

improving the penetration of the bioactive agent across the transdermal layer, thereby

improving the bioavailability of the bioactive agent within the dermal tissue47.

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Introduction 2012
Limonene incorporated within dibutyllauroylglutamide (GP1) in propylene glycol

(PG) biocompatible organogels has been studied extensively. 13, 47

GP1 is an organogelator, which can be categorized as amino acid-type

gelators. It has been proposed that the GP1 organogelators undergoes extensive

intermolecular hydrogen bonding amongst the amide groups present within its

structure apart from the hydrophobic interactions amongst the long alkyl chains. Like

any other amino acid-type organogelators, GP1 also forms a solid-fiber based matrix.

The GP1/PG organogels can be prepared by mixing the appropriate amounts of GP1,

limonene and PG with the subsequent incubation of the same at 120oC. When the

mixture is cooled down, it forms a white gel 13, 48, 49. It was found that the presence of

limonene within the GP1/PG organogels resulted in the alteration of the rheological

properties of the organogels though there was no significant change in the chemical

stability of the organogels. Apart from limonene, various other terpene-based

penetration enhancers (e.g. linalool, farnesol and cineole) have also been incorporated

successfully in GP1/PG organogels. The presence of penetration enhancers within the

organogels results in the improvement of the rate permeation of the bioactive

agents. 13, 47, 50

5. Gelatin stabilized microemulsion based organogel (MBG):

Gelatin is a protein which has been used as a structuring agent in various food

preparations having excess of aqueous phase. It forms a gelled structure when a

concentrated heated solution of gelatin having temperature in excess of 40oC is cooled

down to a temperature below 35oC. Based on the above, it is expected that gelatin will

only gel the aqueous phase (shielded within the reverse micelles) of the water-in-oil

microemulsion, which may be responsible for the phase separation of the aqueous gel

and would make the system cloudy in nature. But this does not happen. The addition

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Introduction 2012
of gelatin to the water-in-oil microemulsion results in the gelation of the whole

micellar solution and the gel formed is transparent in nature 51, 52. Microemulsions are

preferred for the development of gelatin stabilized organogels because of the


53
thermostable nature and the ease of preparation of the same . A typical

pharmaceutical grade water-in-oil microemulsion used for the preparation of MBG


24, 52
contains isopropyl myristate, AOT, tween 85 and water . The MBGs have been

used to device topical and/or transdermal controlled delivery vehicle for hydrophobic

bioactive agents 54.

6. Poly (ethylene) organogels:

The polyethylene organogels are colorless in nature, which are formed when

the low molecular weight polyethylene is dissolved in mineral oil at a temperature

>130oC and subsequently shocked cooled. These organogels have been extensively

used as ointment bases. The formation of gelled structure may be attributed to the

physical interactions of the solid-fibers formed due to the precipitation of the

polyethylene molecules 12.

Applications of organogels:

Skin acts as an effective barrier for most of the drugs except nitroglycerine

scopolamine, nicotine, clonidine, fentanyl, estradiol, testosterone, lidocaine, and

oxybutinin. Hence topical formulation which will enhance permeability of drug and
55
reduce the side effects is always a need of formulation . Many organic substances

like lipids act as a penetration enhancer and hence give an additional edge to the

organogel formulations prepared from them. Organogels have been investigated

successfully as dermal pharmaceuticals 56.

Severe gastric irritation caused due to oral administration of aceclofenac can


57
be avoided by topical transdermal drug delivery . It’s a choice of drug for

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Introduction 2012
osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Ethyl oleate based

lecithin organogels (EO/Lecithin) were used for topical delivery of aceclofenac. They

have found to be more effective than conventional hydrogels. The histopathological

studies also proved the safety of the system 58. Aceclofenac was also formulated in

the form of microemulsion for topical application59. Microemulsions have

disadvantages that it needs a large amount of surfactant and co surfactants for

stabilization of nanodroplets, poor viscosity and spreadability. On the other hand

Lecithin organogels doesn’t require addition of any extra surfactant or penetration

enhancer, as lecithin serves both the purposes. Organogels were having better

viscosity and spreadability than microemulsion. Soyabean lecithin organogels

showed a faster rate of transdermal drug delivery of scopolamine and broxaterol as

compared to conventional patches60. It has found to improve skin penetration of


61
Diclofenac and Indomethacin when used with isopropyl palmitate . Piroxicam an
62
effective NSAID has been successfully incorporated into lecithin gels . Ketorolac

Tromethamine could also be incorporated into lecithin organogels in high amounts 63.

Organogels have been extensively used as controlled drug delivery systems as

summarized in table no.01

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Introduction 2012
Table No. 01: Organogels used in controlled or sustained delivery of drugs

Organic Solvent
Organogelator Pharmacological activity
gelled Model drug used
used or category of the drug
12-HAS Soybean oil Ibuprofen NSAID 64
(Hydroxystearic
acid)

Stearyl acrylate Oley alcohol Indomethacin. NSAID 65

Pluronic lecithin Topical analgesic for cancer


Water Morphine
organogels pains 66

Gelatin
containing
Topical Drug delivery
microemulsion Isopropyl myristate, Sodium Salicylate through iontophoresis 24
based gel Tween 85

Sweet almond oil,


Sorbitan Alkanes like Antihypertensive and
hexane, decane, Propranolol,
monostearate Immunosuppressant 67
Vegetable oils, etc Cyclosporin

Lecithin Various organic Diclofenac Analgesic 68


solvents

Ketorolac
Tromethamine,
Isopropyl Cyclobenzaprine+ NSAID 63
Soya Lecithin
Mysristate Ketoprofen+ Anti-Psychotic 69
Diazepam

Soybean Lecithin Isopropyl palmitate


Diclofenac, Analgesic 61
Indomethacin.

i-propyl myristate,
N-stearine-N0-
Tween 80,
stearyl-L-
propylene glycol Sodium Salicylate Anti-bacterial 70
phenylalanine
and water

Bis-(4-
stearoylaminoph Propylene Ferrocene,
Anti-cancer 71
enyl) methane carbonate Ferricenium
(BSAPM).

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Objectives 2012
OBJECTIVES

In the present work, organogels of Terbinafine hydrochloride will be prepared

by employing suitable literature methods. Thus prepared organogels of Terbinafine

hydrochloride will be evaluated by various analytical techniques. The process

employed for preparation of organogels of Terbinafine hydrochloride will be

validated (if required) by modification of employed method. Thus prepared

formulations will be validated for selecting an ideal formulation by employing various

parameters. The steps which are intended to be carried out are as follows.

1. Formulation of organogels of Terbinafine hydrochloride

2. Characterization of Terbinafine hydrochloride organogels

3. To evaluate the influence of formulation variables on the release rate

of Terbinafine hydrochloride.

4. Evaluation of in-vitro antifungal activity of optimized Terbinafine

hydrochloride organogels.

5. Validation of prepared formulation by using various Physico-chemical

parameters.

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Review of literature 2012
REVIEW OF LITERATURE

Drug Profile: 72

Terbinafine Hydrochloride

Molecular Formula: C21H25N · HCl

Molecular Weight: 327.90

Chemical Name: 1-Naphthalenemethanamine, N-(6,6-dimethyl-2-hepten-4-ynyl) N-

methyl-, (E)-, hydrochloride.

Chemical Structure:

Standard: It contains not less than 99.0 percent and not more than 101.0 percent of

C21H25N HCl, calculated on the dried basis.

Physic-chemical properties:

Melting point: 204˚C - 208˚C

Loss on drying: Dry it at 105˚C to constant weight: it loses not more than 0.5% of its

weight.

Residue on ignition: not more than 0.1%.

Pharmacological profile:

Therapeutic category: Antifungal.

Mechanism of action: Terbinafine inhibits ergosterol synthesis by inhibiting squalene

epoxidase an enzyme that is part of the fungal cell membrane synthesis pathway. Because

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Review of literature 2012
terbinafine prevents conversion of squalene to lanosterol, ergosterol cannot be

synthesized. This is thought to change cell membrane permeability, causing fungal cell

lysis.

Pharmacokinetic profile:

Half life: 36 hrs

Oral dose: 125 and 250 mg

Protein binding: >99%

Side Effects:

Gastrointestinal Problems: Diarrhea, constipation, nausea, indigestion, dyspepsia,

gastritis, cholestasis, flatulence.

Central Nervous System / Neurological Problems: Headaches, dizziness, vertigo,

paraesthesia (pins and needles)

Hepatic Problems: Raised liver enzymes, liver inflammation (hepatitis), liver damage,

liver failure

Immune System Problems: Decreased white blood cell counts including pancytopenia,

leucopenia, lymphopenia, thrombocytopenia.

Psychological Problems: Depression, anxiety, insomnia.

Skin Problems: Rash, hives (Urticaria), skin irritation, itching (pruritis), jaundice ,

Stevens-Johnson syndrome.

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Review of literature 2012

SORBITAN MONOSTEARATE: 73

Synonym: Ablunol S-60; Alkamuls SMS; 1,4-Anhydro-D-glucitol, 6-octadecanoate;

anhydrosorbitol monostearate; Arlacel 60; Armotan MS; Atlas 110K; Capmul S; Crill 3;

Dehymuls SMS; Drewmulse SMS; Drewsorb 60K; Durtan 6O; Durtan 60K; E491;

Famodan MS Kosher; Glycomul S FG;

Molecular Formula: C24H46O6

Molecular Weight: 431

Chemical Name: Sorbitan mono-octadecanoate

Structural Formula:

R1 = R2 = OH, R3 = (C 17H35) COO

Functional Category: Emulsifying agent; nonionic surfactant; solubilizing agent;

wetting and Dispersing/suspending agent.

Description: Sorbitan monostearate occur as cream - to amber-colored liquids or solids

with a distinctive odor and taste.

Typical Properties:

Melting point: 53–57 0C

Acid value: 5–10

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Review of literature 2012
Hydroxyl value: 235–260

Stability and Storage Conditions: It should be stored in a well-closed container in a

cool, dry place.

Applications in Pharmaceutical Formulation or Technology: They are widely used

in cosmetics, food products, and pharmaceutical formulations as lipophilic nonionic

surfactants. They are mainly used in pharmaceutical formulations as emulsifying agents

in the preparation of creams, emulsions, and ointments for topical application. When used

alone, sorbitan esters produce stable water-in-oil emulsions and microemulsion but are

frequently used in combination with varying proportions of a polysorbate to produce water-

in-oil or oil-in-water emulsions or creams of varying consistencies.

SUNFLOWER OIL: 74

Non proprietary Names: BP: Sunflower oil, refined

PhEur: Helianthi annui oleum raffinatum

Synonyms: Huile de tournesol; oleum helianthi; sunflower seed oil.

Chemical Name and CAS Registry Number: Sunflower oil [8001-21-6]

Functional Category: Diluent; emollient; emulsifying agent; solvent; tablet binder.

Description: Sunflower oil occurs as a clear, light yellow-colored liquid with a bland,

agreeable taste.

Typical Properties:
_
Melting point: 18 0C

Boiling point: 40–60 0C

Hydroxyl value: 14–16

Iodine number: 125–140

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Review of literature 2012
n
Refractive index: D25 = 1.472–1.474;
n
D40 = 1.466–1.468.

Density: 0.915–0.919

Saponification number: 188–194

Solubility: miscible with benzene, chloroform, carbon tetrachloride, diethyl ether, and

light petroleum; practically insoluble in ethanol (95%) and water.

Stability and Storage Conditions:

Sunflower oil should be stored in an airtight, well-filled container, protected from light.

Stability may be improved by the addition of an antioxidant such as butylated

hydroxytoluene.

Applications in Pharmaceutical Formulation or Technology:

 Sunflower oil is widely used as edible oil, primarily in oleomargarine. It is also

used extensively in cosmetics and pharmaceutical formulations.

 Therapeutically, sunflower oil is used to provide energy and essential fatty acids

for parenteral nutrition. Studies have shown that sunflower oil may be used in

intramuscular injections without inducing tissue damage.

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Review of literature 2012
REVIEW OF LITERATURE ON DRUG:
75
1. Arun Prasad K et al . Formulated solid dispersion tablet of terbinafine

hydrochloride by using carrier’s polyethylene glycol 6000 (by melting method)

and polyvinyl pyrrolidone K 30 (by solvent method) in the drug carrier ratio of

1:1, 1:2 and 1:3. The prepared solid dispersions were characterized for their drug

content, thermal studies, infrared spectral studies, differential scanning

calorimetric studies, aqueous solubility studies and in-vitro release studies. From

the results, it was clear that solid dispersion formulation showed improved

dissolution rate than pure drug and physical mixture. The solid dispersion

showing better release profile was chosen to formulate into a tablet dosage form

of weight 600 mg. The tablets compressed were evaluated for its physical

parameters like thickness, hardness, weight variation, friability, drug content and

disintegration tests. The dissolution profile of formulated tablet was compared

with the marketed product and the formulated tablet showed better release profile

than the marketed product.


76
2. Sateesh Kumar Vemula et al . Formulated fast disintegrating tablets of

terbinafine hydrochloride by using superdisintegrants. Terbinafine hydrochloride

fast disintegrating tablets were prepared by using direct compression method and

were characterized for both pre-compression parameters and post-compression

parameters to comply with pharmacopoeial limits. From the in-vitro drug release

studies the optimized formulation showed almost complete drug release.


77
3. İpek Özcan et al . In the present topical gel formulations of terbinafine

hydrochloride (T-HCl) were prepared using different types of chitosan at different

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Review of literature 2012
molecular weight, and the antifungal inhibitory activity was evaluated to suggest

an effective formulation for the treatment of fungal infections. The characteristics

of gel formulations were determined with viscosity measurements and texture

profile analysis. Stability studies were performed at different temperatures during

3 months. The ex-vivo permeation properties were studied through rat skin by

using Franz diffusion cells. The antifungal inhibitory activity of formulations on

Candida species and filamentous fungi was also examined with agar-cup method.

The microbiological assay was found suitable for determination of in-vitro

antifungal activity of T-HCl. A marketed product was used to compare the results.

The antifungal activity of T-HCl significantly increased when it was introduced

into the chitosan gels. A higher drug release and the highest zone of inhibition

were obtained from gels prepared with the lowest molecular weight chitosan

(Protasan UP CL 213) compared to that of other chitosan gels and marketed

product. These results indicated the advantages of the suggested formulations for

topical antifungal therapy against Candida species and Filamentous fungi.


78
4. Ning-Lin Zhou et al .The poly (dimethylsiloxane) (PDMS)/montmorillonite–

terbinafine hydrochloride (PDMS/OMMT) nanocomposite films were obtained by

solution intercalation. Organo-montmorillonite (OMMT) with antifungal activity

was prepared from Na+-montmorillonite (Na+-MMT) and terbinafine

hydrochloride (Ter-HCl) by ion exchange. The microstructure of these

nanocomposite films were characterized by TEM and XRD. The effect of OMMT

on the mechanical properties and thermal stability of the nanocomposites was

investigated. When the OMMT content was b1 mass %, the nanocomposites

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Review of literature 2012
showed excellent mechanical properties. The polymers were tested for antifungal

activity against Candida albicans. The PDMS/OMMT nanocomposite films

strongly inhibited the C. albicans.


79
5. Abdul Hasan Sathali A et al . Formulated niosomes of terbinafine

hydrochloride by thin film hydration method using different ratios of non ionic

surfactant (tween 20, 40, 60, and 80) and cholesterol with constant drug

concentration. The prepared formulations were evaluated for its vesicle size (by

AFM), entrapment efficiency (by dialysis method) in-vitro release studies and

antifungal activities. Increase in surfactant concentration, increased the

entrapment efficiency (up to 84.92%) and the formulation with surfactant

cholesterol ratio 2:1 in each group of surfactant showed good entrapment.

Niosomal preparation were tested for in-vitro antifungal activity using the strain

Aspergillus niger and compared with pure drug solution (as standard). All the

niosomal formulations showed gradual increase in zone of inhibition due to the

controlled release of medicament. The best formulation with maximum zone of

inhibition and sustained release of drug (tween 40 nisomes) incorporated into gel

bases and evaluated. The studies revealed that gel containing total niosomes

possess maximum zone of inhibition values (12mm) initially followed by

sustained release (12mm-16mm) comparing to gel containing drug entrapped

niosomes, gel containing pure drug and marketed preparation.


80
6. Murat Sen et al . Adsorption and controlled release of terbinafine

hydrochloride (TER-HCl) to and from pH sensitive poly(acrylamide/maliac acid)

(P(AAm:MA)) hydrogels were investigated. P(AAm:MA) hydrogels were

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Review of literature 2012
prepared by irradiating the ternary mixtures of AAm:MA:and water by g-rays at

ambient temperature. Antifungal drug, TER-HCl containing hydrogels, at

different drug to polymer ratios, was prepared by direct adsorption method. The

influence of MA content in the gel on the adsorption capacities of hydrogel and

the effect of pH on the releasing behavior of TER-HCl from gel matrix were

investigated. Terbinafine adsorption capacity of hydrogels are found to increase

from 2 to 38 mg TER-HCl per g dry gel with increasing amount of MA in the gel

system. In-vitro drug release studies in different buffer solutions show that the

basic parameters affecting the drug release behavior of hydrogel are the pH of the

solution and MA content of hydrogel.

PAST WORK DONE ON GEL:

1. Gondaliya DP et al 81. Prepared nimesulide clear aqueous gels and emulgel using

acrypol 940p. A 3² factorial design was adopted for the optimization of aqeous gel

formulation. Propylene glycol and polyethylene glycol 400 were chosen as

independent variable to study their effects as cosolvents. The clear aqueous gel

formulation containing 15% w/w ethanol, 20% w/w propylene glycol and 30%

w/w PEG-400 showed maximum drug penetration (18.68%) in 5 hours in in- vitro

diffusion study. Drug diffusion was increased by addition of chromophore EL, a

lipophilic penetration enhancer. (Above 99%) within the 20 minutes.

2. Ilango R et al 82 .Developed transdermal preparation of nimesulide gel. The effect

of polymer-concentration on in-vitro nimesulide release from carbpol 940 HPMC

gel and effect of permeation enhancer like Tween-80 and SLS at different

concentration on drug release were studied.

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Review of literature 2012
3. Willimann H et al 83. Organogels obtained by adding small amounts of water to a

solution of lecithin in organic solvents were studied as matrices for the

transdermal transport of drugs. Gels obtained from isopropyl palmitate and

cyclooctane were used (molar ratios of water to lecithin of 3 and 12, respectively).

Preliminarily histological studies showed that the gels have no harmful effect

when applied to the skin for prolonged periods. Data relative to the stability of the

organogels with time are also presented. Scopolamine and broxaterol were used as

model drugs, and the transdermal experiments were done with a Franz diffusion

cell and human skin obtained from plastic surgery. The transport rate of

scopolamine obtained with the lecithin gels was about one order of magnitude

higher than that obtained with an aqueous solution of the drug at the same

concentration. In contrast, the transport rates of scopolamine obtained with the

microemulsion solution prior to gelation (molar ratio of water to lecithin, 0) were

not different from those obtained with the gel. The same variations in transport

rates were observed for broxaterol, in which case the flux through the skin was

directly proportional to the concentration of drug in the gel. At a concentration of

broxaterol of 75 mg/mL in the donor gel, the flux was 47 pg * h-’ cm-*. Because

preliminary results showed that transdermal transport is successful with amino

acids and peptides also, it is concluded that lecithin gels may be efficient vehicles

for the transdermal transport of various drugs.

4. Sudheep Kumar T et al 84. Tween 80-span 80 based organogels were prepared

by fluid-filled structure mechanism by varying the composition of the organogels.

The microstructures of the organogels were studied by light microscopy. The

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Review of literature 2012
organogels were subjected to the accelerated stability test and time dependent

stability test. The stable organogels were characterized by XRD, FTIR, and

simultaneous DTA-TGA, pH and dc impedance measuring devices. Salicylic acid

(model drug) was incorporated within the organogels and its release properties

from the organogel matrices were studied. The antimicrobial efficiency of the

salicylic loaded product was tested against Bacillus subtilis. The organogels were

analyzed for biocompatibility using hemolysis studies. The microscopic studies

indicated fluid-filled globular structures forming the gelled structures. The

stability and the properties were found to be dependent on the proportion of the

surfactant mixture (SM) and water. In general, when the ratio of SM: water was in

the range of 1.3-1.6, the samples showed higher stability and improved properties.

The release of SA from the organogels was found be combination of Fickian and

non-Fickian kinetics. The samples showed good antimicrobial study and were

found to be biocompatible in nature.

5. Nandini D et al 85. Oxytetracycline hydrochloride is an antibacterial drug used in

the treatment of acne vulgaris and dermatitis. Its oral bioavailability is

intermediate ie.60% and it is rapidly excreted through renal route. This drug has

many side effects such as epigastric pain, nausea, vomiting, diarrhea,

hypersensitivity, and tooth discoloration when taken orally. To overcome the side

effects and to increase the bioavailability of Oxytetracycline hydrochloride,

topical formulations were prepared. Organogels were prepared using sorbitan

monostearate as gelling agent and isopropyl myristate as vehicle with different

permeation enhancers. The prepared formulations were evaluated for drug

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Review of literature 2012
content, viscosity, extrudability, homogeneity, skin limitation test, in-vitro drug

release and anti microbial activity. A formulation containing eucalyptus oil with

isopropyl myristate, showed better in-vitro permeation and higher anti microbial

activity as compared to other formulations with different penetration enhancers.

6. Eros I et al 86. In view of good skin tolerability, glyceryl fatty acid esters were

used as organogelators, and their effects in the topical penetration of piroxicam

(Px) were investigated. The in-vivo skin penetration was evaluated by measuring

the anti-inflammatory effect in rats, where we found that Px incorporated into

glyceryl fatty acid ester organogels exhibited a significantly greater inhibition of

oedema than that of the placebo control either when applied locally (p < 0.001), or

via transdermal absorption (p < 0.01 and <0.05, respectively). As the Px

concentration was increased, the extent of oedema inhibition rose in accordance

with a power law. Comparisons with traditional galenic organogels and a

marketed product revealed that the relative biological availability of Px was better

from glyceryl fatty acid ester organogels, except when calculated for D1 versus

T2 and T3. In order to predict the extent of in-vivo skin absorption, we measured

the penetration coefficient and the in-vitro penetration. In accordance with theory,

the extent of in-vivo oedema inhibition increased as Poct/w increased, and

maximum inhibition was observed at log P = 2.0211. However, the in-vitro

penetration through a synthetic membrane did not correlate with the in-vivo

results, the reason for which might be the different natures of the model barriers.
87
7. Hossein Zia et al . Ketorolac tromethamine (KT) containing microemulsion-

based gels (MBGs) have been formulated, based on the previous phase diagram

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Review of literature 2012
studies, using a pharmaceutically acceptable surfactant (soybean lecithin;

Epikuron 200) and oil (isopropyl myristate; IPM) and the effect of formulation

variables on the release profile of the drug from MBGs through intact guinea pig

skin and various artificial membranes was then determined experimentally. It was

observed that as the lecithin concentration increased from 40 to 50 and then 60%

w/w in formulations, a significant decrease in KT release was obtained. A

remarkable increase in the drug release was also observed in formulations

containing 6.5% w/w of KT compared to those containing 1% w/w of the drug.

Increasing the water content of the organogels also resulted in an increase in KT

release. The optimized formulation of the organogel composed of 40% lecithin

and 60% IPM (containing 0.6% w/w of water and 6.5% w/w of KT) showed the

highest drug release rate. Moreover, the viscosity of different formulations and

their rheological behavior were also determined. All formulations showed a

slightly rheopexic behavior. It was found that an increase in lecithin concentration

resulted in an increase in the viscosity of the organogel. Results have shown that

KT could be incorporated at high concentrations into lecithin organogels and

these systems could be considered as desirable drug delivery vehicles for water

soluble drugs and are capable of providing an appropriate drug release rate and

pattern.

PAST WORK DONE ON POLYMER:

1. Kamble SR et al 88. The studies were conducted with an object to develop stable

safe and efficient delivery system for aceclofenac. During the course of studies

different organogel formulations of aceclofenac for topical application were

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Review of literature 2012
prepared by using sorbitan monostearate (span 60), isopropyl myristate, purified

water, sorbic acid, potassium sorbate, tween 20, vitamin E, methyl salicylate and

menthol. The formulated organogels were evaluated for psycho rheological

characteristic, drug content, pH and spreadability. The viscosities of different

formulations were determined by using Brookfield Viscometer at 25°C, the

viscosity of formulations increases as the surfactant concentration increases. The

developed formulation then subjected to in-vitro diffusion study. The two

formulations showed best release having flux > 0.2 mg/cm /hr were selected and

modified with incorporation of 10% methyl salicylate and 5% menthol. Further

efficacy of these formulations was evaluated and compared with standard

marketed formulation by anti-inflammatory activity on albino rats using

carageenan-induced rat paw edema model, promissing edema inhibition withen

three hr was observed. Safety was determined through skin irritancy testing on

Guinea pigs for seven days showing no signs of skin irritation. Finally stability

studies were carried out for three months showed no separation of gel indicating

overall stability. The result indicates that Sorbitan Monostearate organogels

serves as a better vehicle for topical delivery of aceclofenac.

2. Shiv Kumar Lalit et al 89. Studied the different Amphiphilogel formulations of

fluconazole for topical application using sorbitan monostearate (Span 60), Tween

80 and Tween 20, Iso-propyl myristate, purified water. The formulated

fluconazole were evaluated for psychorheological characteristic, drug content,

pH, spreadability. The viscosity of different formulations were determined by

using Brookfield Viscometer at 25°C, the viscosity of formulations increases as

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Review of literature 2012
the surfactant concentration increases. In-vitro release studies were carried out

using Franz diffusion cell at Phosphate buffer pH 7.4 at 50 rpm. The cumulative

% drug releases the formulation was found to be 88.70- 96.48 %. Finally stability

studies were carried out for one month’s showed no separation of gel indicating

overall stability. TLC studies clearly indicated that Y there is no any interaction in

formulation.
90
3. Meenakshi Singh et al . Developed sorbitan monostearate (Span 60) based

organogels with mustard oil as the solvent. Different compositions of organogels

were prepared by varying the concentrations of span 60. During the preparation of

organogels, their microstructures were studied under compound light microscope.

The formulated organogels were characterized by light microscopy, gel-to-sol

transition temperature, long-term stability, pH, opacity measurements and

hemocompatibilty studies. Metronidazole was incorporated within the organogels

and its release behaviour was determined. The anti-microbial action of the drug

loaded organogels on E. coli was studied. The microscopy of the organogels

suggests that a three-dimensional network of rod-like tubular aggregates of

gelator is responsible for immobilising the solvent. Clusters of span 60 are

visualised as dispersed in the liquid phase. The rate of formation of organogels

and the release rate of metronidazole from the organogels was found to depend on

span 60 proportions in the formulated organogels. The pH of the samples was

found to be in the range of 6.4-7.1. The organogels were found to be

hemocompatible in nature indicating their probable use as controlled delivery

vehicles.

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Review of literature 2012
4. Meenakshi Chauhan et al 91. Prepared Niosomes with different molar ratios of

surfactant and cholesterol and their morphological properties have been

determined by scanning electron microscopy. Different batches of Fluconazole

niosomal preparations were prepared by changing the surfactant concentration but

keeping the cholesterol concentration constant. The surfactant used was Span 60

and the five batches of niosomal preparations prepared were in the ratios 1:1:1,

1.5:1:1, 2:1:1, 2.5:1:1 and 3:1:1 (surfactant: cholesterol: drug). Furthermore, the

release profile, entrapment efficiency, size distribution and stability of these

niosomes under various temperatures were studied.


92
5. Abdul Hasan Sathali A et al . Formulated topical gel containing clobetasol

propionate niosomes to prolong the duration of action and prevent its side effects.

The clobetasol propionate niosomes were prepared by altering the ratios between

various non-ionic surfactants (Span 40, 60, 80) and cholesterol by three methods

such as thin film hydration method, ether injection method and hand shaking

method. The prepared niosomes were subjected to drug content analysis,

entrapment efficiency, size analysis and in-vitro drug release studies. The higher

entrapment efficiency (91.37%) was obtained with Span 60 niosomes (ratio of

surfactant, cholesterol- 1: 0.5) prepared by thin film hydration method was

evaluated for its stability and formulated as gel formulation. The prepared

niosomal gel (G2) and marketed gel (G3) were subjected to drug content analysis,

in-vitro drug release studies and in-vivo pharmacodynamic studies. Our results

suggested that the niosomal delivery of clobetasol propionate in carbopol gel base

acts as a suitable topical drug delivery system to prolong the duration of action.

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Review of literature 2012
6. Diana Badiui et al 93. The present paper presents new formulations of three lipid

extracts of Mytilus galloprovincialis Lmk., Rapana venosa molluscs and those

mixed (1:1, v/v) through their incorporation in W/O emulsions. These consisted

of 4% lipid extracts (active ingredients), 60% liquid paraffin as the oil phase, 3%

glycerin, 25.96% water as the water phase, 6% Span 60 as the surfactant and

0.04% nypagin as preservative. The smell was adjusted with 1% Oleum

lavandulae. The scope of this study regards the formulation and pharmaceutical

evaluation of the three W/O emulsions. Their evaluation consisted of color, smell,

type of emulsion by dilution, electric conductibility and total dissolved salts

(TDS) methods, dynamic viscosity, and stability by heating at 700C and

centrifugation at 3000 rpm, pH and tension determinations. The results showed a

good stability over 90 days of observation period of the three emulsions evaluated

through the pharmaceutical parameters.

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Materials and Methodology 2012
Materials and Equipments

Drug:

Sl. No. Drug used Make

Yarrow. Chem. Product. Ltd.


1 Terbinafine hydrochloride
Mumbai

Chemicals:

Sl. No. Chemicals used Make

1 Methanol SD Fine chem. Ltd. Mumbai

2 Sorbitan Monostearate SD Fine chem. Ltd. Mumbai


(Span 60)
3 Sunflower Oil Kaleesuwari. Refinery. Pvt. Ltd

Equipments:

Sl. No. Chemicals used Make

Digital melting point


1 Ana Lab. Scientific Pvt. Ltd.
Apparatus

2 Electronic balance Essaae teraoka, ltd. Bangalore


3 Magnetic stirrer Remi elektrotechnik ltd. Mumbai

4 UV visible
UV-1700 Pharmaspec Shimadzu
Spectrophotometer
Brookfield Engineering
5 Brookfield viscometer Laboratories, Inc. USA

FT-IR
6 Shimadzu
Spectrophotometer
7 Franz diffusion cell Fabricated

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Materials and Methodology 2012
METHODOLOGY:

Preformulation study:

Preformulation study is the process of optimizing the delivery of drug through

determination of physicochemical properties of the new compound that could affect drug

performance and development of an efficacious, stable and safe dosage forms, first

preformulation studies were performed. Various preformulation studies which were

carried out are discussed in following sections.

Identification:

Determination of melting point:

Melting point of Terbinafine Hydrochloride was determined by using open

capillary tube method in digital melting point apparatus.

Method:

In this method the capillary tube was sealed with gentle heating from one end.

Then the small quantity of drug Terbinafine Hydrochloride was filled into the sealed

capillary. Capillary was tied to the tube containing the oil phase in such a way that the

sealed part of the capillary containing Terbinafine Hydrochloride was dipped into the oil.

Gently the oil bath was heated. As soon as the powder starts melting, the heating was

stopped and the temperature was noted down.

Drug-Excipient Compatibility study:

Compatibility is the one of the most important factor which affects the stability of

the product. Compatibility of drug with polymer which was used in the formulation of the

dosage form was determined with FTIR study. For determining the compatibility of drug

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Materials and Methodology 2012
with polymer, IR spectra of pure drug Terbinafine Hydrochloride, pure polymer like

Span60 and physical mixture of drug and polymer were taken.

PREPARATION OF STANDARD CALIBRATION CURVE:

Determination of analytical wave length:

10mg of Terbinafine Hydrochloride was taken in volumetric flask and dissolved

in small volume of methanol and the volume was made up to 100ml with methanol to get

the concentration 100µg /ml and as stock solution. The resulting stock solution

containing 100µg/ml was scanned between 200 to 400nm using methanol as blank.

Calibration curve:

From the stock solution 0.5, 1, 1.5, 2, 2.5, 3 of the solution was pipette out into

the test tubes labeled as 1, 2, 3, 4,5 and 6 respectively and diluted to 10ml with methanol

to make the final concentration 5 10, 15, 20, 25 and 30µg/ml. Absorbance was taken by

UV spectrophotometer using methanol as blank. The standard plot was obtained by

plotting concentration in µg on X-axis Vs absorbance on Y-axis.

Method of Preparation of organogels: 2, 58

Organogels were prepared by dissolving specified amount of Span60 (solid) was

taken in a beaker and melt at 600C. Add Specified amount of Sunflower oil and heating

was continuing until the clear solution obtained. The proportion of span-60 in SO was

varied from 1- 5 % (w/w).

Drug (100mg of Terbinafine Hydrochloride) was loaded to the above hot solution

and stirred at 500rpm and allowed to cool down at room-temperature (RT) so as to allow

gel formation. The sample was regarded as organogel, if upon cooling, the solution

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Materials and Methodology 2012
mixture failed to flow when the beaker was inverted. Then obtained gel was filled in well

closed container and kept at room-temperature for further analysis.

Table No.02: Formulation of Terbinafine Hydrochloride Gel

Formulation Code Drug(mg) Span60 (gm) Sunflower oil (ml)


F1 100 1.5 8.5
F2 100 2.0 8.0
F3 100 2.5 7.5
F4 100 3.0 7.0
F5 100 3.5 6.5

Evaluation of Gels: 2, 58, 94


Thus prepared gels were evaluated for various parameters like

 Organoleptic evaluation

 PH

 Spreadability

 Viscosity

 Gel to Sol Transition Study

 Drug Content

 In-vitro diffusion study

 Antifungal Activity

 Stability Studies

Organoleptic evaluation:

Freshly prepared organogels samples were observed for their color, odour, appearance

and texture.

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Materials and Methodology 2012
pH Measurement:

Digital pH meter was used to measure the pH of the organogel at constant

temperature prior to this pH meter was calibrated using standard buffer solution of pH 7

and 9.2 then electrode was washed with de-mineralized water. The electrode was inserted

into the sample for 10 min then taken the reading.

Spreadability:

One of the criteria for the gels to ideal qualities is that it should posses good

spreadability. Spread is a term express to denote the extent of area to which the gel

readily spreads on application to skin or the affected part. The therapeutic efficacy of

formulation also depends upon its spreading value. Hence determination of spreadability

is very important in evaluating gel characteristics.

Spreadability of the formulation was determined an apparatus suggested by

Mutimer et al, which was suitably modified in the laboratory and used for the study.

It consists of a wooden block, which was provided by a pulley at one end. A rectangular

ground glass plate was fixed on the block. An excess of gel (about 2 gm) under study was

placed on this ground plate. The gel was then sandwiched between these two plates and

another glass plate having the dimension of the fixed ground plate and provided with

hook. A 300gm weight was placed on the tip of 2 plates for 5 mints to expel air and to

provide uniform film of the gel between the plates. Excess of the gel was scraped from

the edges. The top plate was then subjected to pull with specified weight with the help of

a string attached to the hook and the time in second required by the top plate to cover

distance of 10cm was noted. A shorter time intervals indicates better spreadability.

The spreadability was determined by using the following formula.

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Materials and Methodology 2012
S=ml/t.

Where; S= Spreadability.

m= weight tied to the upper slide.

l= length of the glass slide.

Determination of viscosity:

The viscosity of prepared organogels was determined using a Brook field

viscometer. The sample holder taken for the viscosity measurement was filled with the

sample and then inserted into the flow jacket mounted on the viscometer. The sample

adapter (spindle LV 64) rotated at optimum speed to measure the viscosity of the

preparation.

Gel-Sol Transition study:

Organogels were incubated at various temperatures in the range of 30°C and 60°C

in a constant temperature water bath. An increment of 5°C was made after 5 min

incubation at previous temperature. Samples were analyzed by inverted test tube method

after each incubation period. The temperature at which samples started flowing was

recorded as gel-sol transition temperature (Tg).

Drug Content:

Weigh accurately 100mg of gel and dissolved in 100ml of methanol. The solution

was filtered through what man filter paper NO-1.The absorbance of solution (filtrate) was

taken at 282nm and drug content was calculated.

In-vitro diffusion study:

The in‐vitro diffusion study for the gels was carried out by using diffusion cell

which was opened at both the ends. 1gm of gel formulation was spread uniformly on the

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Materials and Methodology 2012
surface of cellophane membrane (previously soaked in 7.4 pH phosphate buffer for

overnight). Whole assembly was fixed in such a way that the lower end of diffusion tube

containing gel was just touching the surface of diffusion medium i.e. 20ml water

contained in receptor compartment which was placed in water bath and maintained at 37

± 2°C. The contents of diffusion cell were stirred using magnetic stirrer at 50 ± 5 rpm.

The sampling was done at different time intervals over a period of 24 hours and

absorbance was measured at 282nm using Shimadzu UV‐visible spectrophotometer.

Antifungal Activity: 95

The gels were screened against selected fungal strain Candida albicans by using

diffusion method. The 48 hours old fungal culture inoculated into nutrient broth by

following aseptic techniques and incubated for 48 hours at 370± 20C in an incubator. This

culture mixed with sterilized and cooled media like, Potato-dextrose agar media and

poured into petriplates. After solidification two bores were made at equal distance by

using sterile steel cork borer (8 mm in diameter). Into these bores in one bore standard

drug and in another bore prepared gel were introduced. After introduction of standard

drug and prepared gel, the plates were placed in a incubator and maintained at 37 0± 20C

for 48 hours. After the incubation period, the plates were observed for zone of inhibition

by using zone reader. Results were evaluated by comparing the zone of inhibition shown

by the prepared gel with standard drug. The results were the mean value of zone of

inhibition measured in millimeter of three sets. The standard drug was dissolved in

minimum quantity of distilled water.

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Materials and Methodology 2012
RELEASE KINETICS:

The results of in-vitro release profiles obtained for all the formulations were fitted

into four models of data treatment as follows:

1. Cumulative percent drug released versus time (zero-order kinetic model).

2. Log cumulative percent drug remaining versus time. (First-order kinetic model).

3. Cumulative percent drug released versus square root of time (Higuchi’s model).

4. Log cumulative percent drug released versus log time (Korsmeyer-Peppas

equation).
96
1) Zero Order Kinetics: A zero-order releases would be predicted by the

following equation.

A = A – K t……………………………………. (6)
t 0 0

Where:

A = Drug release at time ‘t’


t

A = Initial drug concentration


0

-1
K = Zero-order rate constant (hr ).
0

When the data is plotted as cumulative percent drug release versus time, if the plot is

linear then the data obeys zero-order release kinetics, with a slope equal to K .
0

2) First Order Kinetics: 96A first-order release would be predicted by the following

equation

Log C = Log C – 303.2Kt……………………….. (7)


0

Where; C = Amount of drug remained at time t’

C = Initial amount of drug


0

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Materials and Methodology 2012
-1
K = First-order rate constant (hr ).

When the data are plotted as a log of percent cumulative drug release remaining

versus time yields a straight line, indicating that the release follows First-order kinetics.

The constant ‘K’ can be obtained by 6ultiplying 2.303 with slope values.

3) Higuchi’s Model: 97

Drug released from the matrix devices by diffusion has been described by following

Higuchi’s classical diffusion equation.

1/2
……………………. (8)

Where,

Q = Amount of drug released at time ‘t’

D = Diffusion coefficient of the drug in the matrix

A = Total amount of drug in unit volume of matrix

C = The solubility of the drug in the diffusion medium


S

ε = Porosity of the matrix

τ = Tortuosity

t = Time (hrs) at which ‘Q’ amount of drug is released.

Equation-8 may be simplified if one assumes that D, C and A are constant. Then
S

equation-8 becomes:
½
Q = Kt ………………………….. (9)

When the data is plotted according to equation-4 i.e., cumulative drug released versus

square root of time, yields a straight line, indicating that the drug was released by

diffusion mechanism. The slope is equal to ‘K’.

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Materials and Methodology 2012
4) Korsmeyer and Peppas Model: 98, 99

The release rates from controlled release polymeric matrices can be described by the

equation (10) proposed by korsmeyer et al.


n
Q = K t ………………………………. (10)
1

Q is the percentage of drug released at time‘t’, K is a kinetic constant

incorporating structural and geometric characteristics of the tablets and ‘n’ is the

diffusional exponent indicative of the release mechanism.

For Fickian release, n=0.45 while for anomalous (Non-Fickian) transport, n ranges

between 0.45 and 0.89 and for zero order release, n = 0.89.

Stability studies: 100

The duration of the time period for which a gel maintains its integrity, without

any separation of the solid and the liquid phases, when stored in sealed vessels at a given

environmental condition helps in predicting the shelf-life of the product at the given

condition. In order to determine the lifetime of the organogels under different

environmental conditions, the samples were kept at 5°C, 400c and room temperature.

Objective of the study:

The purpose of stability studies is to provide evidence that the quality of drug

substance or drug product varies with time under the influence of a verity of

environmental factors such as temperature, humidity and light enables recommended

storage conditions, re-testing periods and shelf-lives to be established.

Accelerated stability study was carried out as per the ICH guidelines.

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Results & Discussion 2012
RESULTS AND DISCUSSION

Terbinafine hydrochloride is a synthetic alkylamine drug with molecular

formula C21H25N · HCl which is partially soluble in water. The present study was

carried out to develop organogels for the topical delivery of Terbinafine

hydrochloride. The organogel based systems were prepared by 3 different materials

such as drug span 60, sunflower oil. The detailed composition of the organogels was

shown in the table no.02.

Melting point determination:

Melting point of Terbinafine HCL was determined by using digital melting

point apparatus by capillary method (in triplicate). The melting point of the

Terbinafine HCL was found between the 213˚C to 218˚C. Thus obtained melting

point is in agreement with literature melting point, confirming the purity of drug.

Drug-Excipient Compatibility study:

This Preformulation study was carried out to study the compatibility of the

pure drug Terbinafine Hydrochloride with polymer prior to the preparation of the gel.

All these peaks were also found into the drug-polymer mixture, spectra’s indicates no

interaction between the drug and polymers as shown in figure: 01-02

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Results & Discussion 2012

Figure.NO.01: FT -IR Spectra of Terbinafine Hydrochloride

Figure.NO.02: FT-IR Spectra of F1

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Results & Discussion 2012
Determination of λ -max and calibration curve:

Spectrophotometric scanning of Terbinafine HCL in methanol was determined

and λ-max was found to be 282 nm as shown in figure no.03. The calibration curve

was obtained by the procedure described in the methodology. The results are shown in

table no.03 and figure no.04. The linear plot between concentration v/s absorbance

showed that Beer lamberts law in concentration range of 5-40µg/ml. Calculation of

drug content and in-vitro drug release study were based on this standard curve.

Figure.NO.03: λ -max of Terbinafine Hydrochloride in Methanol

Table NO.03: Standard plot of Terbinafine Hydrochloride

Sl. No. Concentration Absorbance in Methanol


(µg/ml) at 282 nm ± SD
01 5 0.145 ±0.0035

02 10 0.276 ±0.0020

03 15 0.418 ±0.0020

04 20 0.571 ±0.0010

05 25 0.695 ±0.0025

06 30 0.840 ±0.0010

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Results & Discussion 2012

Figure NO.04: Standard plot of Terbinafine Hydrochloride in Methanol

Preparation of Organogels Samples:

The organogels were prepared by dissolving span60 in sunflower oil which was

kept at 600C on stirring at 500rpm, so as obtained a clear homogeneous solution. As

the temperature of the solution lowered, span 60 starts precipitating out of the

sunflower oil due to change in the solubility parameter. The precipitated span 60

crystals starts growing size as fibers. These fibers physically interact with each other

to form a three dimensional networked structure. Clear solution firstly turned into

cloudy solution and finally form cream white color gels as shown in the figures.

After the culture bottles cooled to room temperature the bottles were inverted and

observed for any flow. The samples were regarded as organogels, if they did not flow.

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Results & Discussion 2012

Figure NO.05: Gelation process of organogel. (a) Clear solution after heating;

(b) Uniform, cloudy suspension upon cooling and standing;

(c) Opaque, semi-solid gel upon further standing.

Evaluation of Organogels:

Organoleptic Evaluation:

The samples were found to be a creamy-white in color. Sample lost its

consistency when agitated with hand. As the concentration of the organogelator was

increased, the consistency of the products increased. All the samples were found to be

oily to touch and were having gritty nature.

pH Measurement:

The pH of the formulation was determined by using pH meter and observations

are shown in the table no.04.The pH of the formulations was found to be suitability

for the application on the skin, because skin lies in this range.

Spreadability:

The results of the spreadability are shown in the table no.04. The organogels

showed better spreadability, out of 5 organogels formulations F1 showed the better

spreadability than other 4.

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Results & Discussion 2012
Viscosity:

The viscosity was carried out using the procedure as mentioned in methodology

chapter. The viscosity of the formulations is shown in the table no.04.The viscosity of

formulation (F5) was found to be highest and viscosity of F1 was found to be least.

This may be due to use of more amount of span60.

Gel-Sol Transition:

The organogels were subjected to increasing temperatures starting from 30°C to

60°C. An increment of 5°C was made after 5 min incubation at the previous

temperature. The samples were considered to have undergone gel-sol transition when

they started to flow when the culture bottles were inverted.

Gel-sol transition temperature of organogels was found to be dependent on

gelator concentration. The concentration of span-60 in the lower range in the

organogels affects the gel-sol transition temperature. Gel-sol transition temperature

(Tg) of the organogel containing higher amount of span 60 did not affect the gel-sol

transition temperature. This may be due to the requirement of more heat energy

required for the disruption of the more densely packed network structure as the

gelator proportion was increased. The Gel-sol transition temperature of organogels

shown in the table no.04.

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Results & Discussion 2012
Table NO.04: Observations of pH, Spreadability, Viscosity, Gel-Sol transition
temperature.

Formulation pH Spreadability Viscosity Gel-Sol


Transition
Code gm.cm/second (cps)
temperature
F1 6.93±0.096 12±0.156 5911088±325 ±500C

F2 6.08±0.114 13.33±0.253 15600011±547 ±500C

F3 7.15±0.125 18.15±0.413 25200008±623 ±500C

F4 6.33±0.105 19.23±0.243 37899391±564 ±600C

F5 7.42±0.216 28.71±0.342 48919664±352 ±600C

Drug content:
The drug content was in the range of 67.76% to 88.87%. The values are given

in the table no.05.

Table NO.05: Drug content of Terbinafine HCL

Formulation Code Drug content (%)

F1 84.72±0.324

F2 67.76±0.136

F3 88.87±0.315

F4 69.75±0.368

F5 67.86±0.421

In-vitro Drug release study:

Release of drug from an organogels depends upon its solubility and partition

coefficient. In-vitro drug release study helps predicting the drug release profile and

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Results & Discussion 2012
drug release kinetics. This may help in correlating the drug activity when

administered in the physiological system.

The release profiles of the drug from the organogels have been shown in figure

no. 6,7,8,9 as a function of time. The amount of drug release from the formulation F1

to F5 (88.95% to 70.11 %) respectively at the end of 24 hours. This suggests that as the

amount of gelator increased there is subsequent reduction in the drug release. This

indicates that the drug release is dependent on the solid skeleton network formed by

the gelator molecules. The type of release pattern from all formulations data were

subjected to various drug release kinetic model such as Zero order, First order,

Higuchi and Peppas.

Table no.06 shows the drug release rate constant (k) and regression

determined the different kinetic models of drug release. The release kinetic fit model

indicated that the release of drug from organogels followed Higuchi model kinetic.

Table NO.06: In-vitro drug release through Cellophane Membrane (Release


Kinetics).
Korsmeyer
Formulation Zero order First order Higuchi
% CDR peppas
Code R2 R2 R2 R2 n

F1 88.95 0.754 0.841 0.949 0.981 0.654

F2 84.25 0.715 0.856 0.922 0.888 0.765

F3 77.40 0.863 0.963 0.972 0.900 0.744

F4 72.95 0.742 0.849 0.941 0.957 0.678

F5 70.11 0.749 0.927 0.938 0.933 0.701

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Results & Discussion 2012

Figure NO.06 In-vitro drug release profile (Zero Order)

Figure NO.07: In-vitro drug release profile (First Order)

Figure NO.08: In-vitro drug release profile (Higuchi)

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Results & Discussion 2012

Figure NO.09: In-vitro drug release profile (Korsmeyer Peppas)

Anti fungal activity:


The gels were tested for antifungal activity against Candida albicans. Observations of

the study are shown in the table no.07.

Table NO.07: Observations of the Antifungal activity

Mean zone of inhibition


(in mm)*
Formulation
Sl. No Candida albicans
Code
5mcg/ml 10mcg/ml
Terbinafine
01 24 28
Hydrochloride
02 F1 21(0.87) 25 (0.89)

03 F2 22 (0.91) 24 (0.85)

04 F3 21(0.87) 25 (0.89)

05 F4 21(0.87) 26 (0.92)

06 F5 22 (0.91) 25 (0.89)

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Results & Discussion 2012
Stability study:

Short-term accelerated stability study was performed on the promising

formulation by storing the samples at 40±2ºC /75±2 ºC RH for 90 days. The samples

were tested for any changes in physical appearance and drug content at monthly

intervals. The results of stability studies did not show any significant change in the

physical appearance and drug content of above mentioned formulation as shown in

the table -08

Table NO.08: Stability study of formulation.

Time Drug content


(month) (%)

Zero 92%

First 90.65%

Second 89.74%

Third 89.96%

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Conclusion 2012
CONCLUSION

Organogels have currently generated great interest as topical and transdermal drug

delivery vehicle. In the present investigation, the successful development of Span60 and

sunflower oil based organogels were formulated.

From the study reports the following conclusion can be drawn.

 Organogels can be prepared easily, rapidly and found to be biocompatible in

nature.

 Change in the composition of gelator (Span60) in organogels resulted in change in

the viscosity.

 The pH of the organogels suggested that the organogels might be non-irritant in

nature.

 In-vitro release study indicated prolonged release of Terbinafine HCL from the

organogel matrix and the release of the Terbinafine HCL from the organogel

followed Higuchian kinetics.

 The antifungal studies carried out using Terbinafine HCL loaded samples

suggested that the formulations may be showed a better antifungal organogels.

 Stability studies indicated that the stable nature of the developed organogels.

In short the organogels developed may be tried as a matrix for controlled drug

delivery system.

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Summary 2012

SUMMARY

The ultimate aim of the research work is to formulating the organogels as a model

drug Terbinafine hydrochloride was to prolong the drug release time, reduce the frequency of

administration and to improve patient compliance.

 Five formulations were prepared using span 60 and in different ratios

 The organogels were evaluated for organoleptic properties, pH, spreadability

viscosity, gel sol transition, drug content, in-vitro drug release, antifungal activity and

stability studies.

 The pH was found in the range of 6.08±0.096 to 7.42 ±0.216

 The spreadability was found in the range of 12±0.156 to 28.71± 0.342gm.cm/ sec.

 The viscosity was found in the range of 5911088± 325 to 489196664±352 CPS.

 The gel sol transition was found in the range of ± 500c to ± 600c.

 The drug content was found in the range of 67.76%± 0.136 to 88.87%±.0.315

 The in-vitro diffusion study was carried out in methanol for 24 hours. Cellophane

membrane was used for the diffusion study.

 The formulation F1 showed the best diffusion through the Cellophane membrane.

 It showed the diffusion of 88.95%.

 It shows the better antifungal activity.

 The formulations followed the First order kinetics with diffusion mechanism.

 The stability studies indicated that the all the organogels were stable in nature for

applied conditions.

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