Tousif Thesis 2010

DEVELOPMENT AND EVALUATION OF
KETOCONAZOLE SOLID DISPERSION

INCORPORATED GELS
By
TOUSIF KHAN
Reg. No. 08PU260
Dissertation Submitted to the
Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore
In partial fulfillment
of the requirements for the degree of
MASTER OF PHARMACY
In
PHARMACEUTICS
Under the Guidance of
MOHAMMED NAJMUDDIN
M.Pharm, (Ph.D.)
Asst. Professor
DEPARTMENT OF PHARMACEUTICS
LUQMAN COLLEGE OF PHARMACY
GULBARGA - 585 102
2010
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA, BANGALORE
DECLARATION BY THE CANDIDATE
I hereby declare that this dissertation / thesis entitled

DEVELOPMENT AND EVALUATION OF KETOCONAZOLE
SOLID DISPERSION INCORPORATED GELS is a bonafide and
genuine research work carried out by me under the guidance of Mr.
MOHAMMED NAJMUDDIN, Asst. professor.
Date:
Place: GULBARGA
TOUSIF KHAN
II

CERTIFICATE BY THE GUIDE
This is to certify that the dissertation entitled DEVELOPMENT

AND EVALUATION OF KETOCONAZOLE SOLID DISPERSION
INCORPORATED GELS is a bonafide research work done by Mr.
TOUSIF KHAN in the partial fulfillment of the requirement for the
degree of MASTER OF PHARMACY in PHARMACEUTICS.
Date:
Place: Gulbarga
Mohammed Najmuddin
M.Pharm. (Ph.D.)
Asst. Professor
Dept. of Pharmaceutics,
Luqman College of Pharmacy,
Gulbarga - 585 102
III

CERTIFICATE BY THE CO-GUIDE

TOUSIF KHAN in partial fulfillment of the requirement for the degree of
MASTER OF PHARMACY in PHARMACEUTICS under the direct
guidance and supervision of Mr. MOHAMMED NAJMUDDIN.
Date:
Place: Gulbarga
ASHFAQ AHMED MOHSIN

M.Pharm.
Lecture
Dept. of Pharmaceutics,
Gulbarga
IV

ENDORSEMENT BY THE HOD, PRINCIPAL/

HEAD OF THE INSTITUTION

TOUSIF
KHAN
under
the
guidance
of
Mr.
MOHAMMED
NAJMUDDIN, Asst. Professor.
Date:
Place: Gulbarga
Prof. Syed Sanaullah

Principal,
Gulbarga-585102
COPYRIGHT
DECLARATION BY THE CANDIDATE
I here by declare that the Rajiv Gandhi University of Health

Sciences, Karnataka, shall have the rights to preserve, use and
disseminate this dissertation / thesis in print or electronic format for
academic / research purpose.
Date:
Place: Gulbarga
TOUSIF KHAN
Rajiv Gandhi University of Health Sciences, Karnataka
VI
ACKNOWLEDGEMENT
No work big or small can fructify without the grace and mercy of Almighty Allah,
The Honoror. The most essentially humble solicitation and a lot of thanks to the
Supreme Power for manifesting himself through the various helpful people I came
across in my life. I bow my head to Him and ask for His blessings to be with me
forever.
On the occasion of presenting this thesis, words seem insufficient to express my deep
sense of gratitude to my beloved Parents Mr.Tahseen Khan and Mrs.Hanifa Bano
for all the pains and efforts taken to make me up to this masters level. They not only
initiated my interest in studies but has also led me through the dark alley and abysses
to the brighten path. and my family members especially Ms.Benazeer and Tanveer
khan for their constant love, moral support and encouragement throughout my life
without which it would not have been possible for me to achieve even the wee bits,
what I have achieved today.
I express my highest thanks and gratitude, sincere and heartfelt thanks to beloved and
respected research guide Mr.M.Najmuddin, Assistant Professor for his excellent
guidance, critical supervision, keen observation, continuous encouragement and
support, which I have received from him wholeheartedly. I substituted for the feeling
of indebtedness and appreciation for him who helped me to develop skills and gave
me opportunity to explore my scientific curiosity which brought me to this stage in my
life, which I would never forget.
Its my privilege to express my obligation to our Principal, Prof.Syed Sanaullah,
Dr.Mujeeb, Treasurer, Luqman College of Pharmacy, Gulbarga for providing me all
facilities, support and encouragement throughout the research work.
I gratefully acknowledge the facilities and cooperation extended to me in enriching
my knowledge by Dr.Raghvendra Rao, Head of Department, and Mr.M.A.Saleem,
Department of Pharmaceutics, Luqman College of Pharmacy, Gulbarga for their
timely guidance in enriching my knowledge and encouragement during the course of
my work.
I honest I am delighted to place on record a special thanks to Dr.M.G.Purohit,
Professor Emeritus and Mrs.Syeda Humera, Asst. Professor, Luqman College of
Pharmacy for the valuable help in my analytical work.
I honestly acknowledge my co-guide Mr.Ashfaq Ahmed Mohsin, Lecturer for his
timely encouragement during my entire post-graduation course.
I sincerely thank to all the teaching staff especially Mr.Liyakhat Ali, Mr.Aejaz,
Mr.Khaja Pasha, Mr.Shantosh and Mr.Durga Rao for their constant support,
encouragement, inspiration and cooperation during the course of my study.
VII
I expend my sincere thanks to Dr.Firoz Anwar and Mr.Khurshid Anwar for their
constant source of inspiration and encouragement throughout this course.
I could never forget my brother Mr.Shoaib Dastgir, and Mr.Najam for the
inspiration, encouragement and moral support during the course of my study.
Friendship is a treasured gift and true friends are few. I was lucky enough to get
friends like Asgar, Farukh, Shahid, Aslam, Javed, Juned, Adil, Mohsin, Aizaz,
Dr.Kayum, Firoz, Pushpendra, Pavan, Dilip, Abhishek, Harshdeep, Shashi, Vikash,
Rakesh, Vivek, Sourabh, Bhanu, Aapurve, Vrashabh, and Dr.Deepmala
Nandanwar. Their friendship brought me the inspiration, encouragement and moral
support in my every needful moment during the course of my studies.
My sincere thanks to my seniors Mr.Patil noornadim, Mr.Fayyaz, Mr.Moiz,
Mr.Azmail, Mr.Rahul, Mr.Sarang, Mr.Hitesh, and Mrs.Sumanji for their guidance
and timely assistance.
I am especially thankful to my room-mates Azhar, and Ansari Mohd. Shahid for
their direct and indirect help during the research work.
It gives me immense pleasure to record my thanks to my colleagues Sachin Shelar,
Vishal Patel, Vijay, Ram Pentewar, Aniket, Ganesh, and Ketan, for their support,
who by their honest opinions and diligence kept me lively.
I am especially thankful to Wasim, Kamal, Datta, Devendra, Aasim, and Rana for
helping me to carry out skin irritation test using rabbit model.
I also express my heartily thanks to my juniors Wahid, Izhar, Subhan, Vishal, Vikas
Kakde, Denesh, Hadi, Sudhir, Shrishal, Niraj and Mangesh, for their cooperation
and specially I will mention Mr.Ahnaf UMAir for his assistance during my whole
work.
I am thankful to non-teaching staff Mr.Peer Pasha, Mr.Narendra, Mr.Suresh,
Mr.Hassan, Mr.Anwar and Librarian Mrs.Pratibha.
I am highly grateful to Mr.Mahendra Shingh Gour, Branch Manager, S.B.I., Bhopal
for their cooperation.
Finally, I thank all who have directly or indirectly helped in the successful completion
of my dissertation.
Date:
Place: Gulbarga
TOUSIF KHAN
VIII
LIST OF ABBREVIATIONS USED

DMSO............Dimethyl sulfoxide
DSC................Differential Scanning Calorimeter
FT-IR............... Fourier transform infrared
gm ..................gram
GIT.................. Gastrointestinal tract
HPMC............Hydroxy propyl methyl cellulose.
Hrs..................hours.
mcg.................microgram
mg ..................milligram(s)
ml ...................Milliliter
min .................minutes
MC .................. Methyl cellulose
NaCMC ........... Sodium carboxymethyl cellulose
PEG................Polyethylene glycol
PVP ................Polyvinyl pyrrolidone
PG ................... Propylene glycol
qs....................Quantity sufficient.
rpm .................rotation per minute
SLS.................Sodium lauryl sulphate
Std ..................Standard
TEA................Triethanolamine
ix
FORMULATION CODE:
F1Ketoconazole + Mannitol
F2Ketoconazole + PEG 4000
F4Ketoconazole + PVP K30
F5Ketoconazole + -cyclodextrin
F6Ketoconazole + Mannitol
F8....Ketoconazole + PEG 6000
F9Ketoconazole + PVP K30
F10..Ketoconazole + -cyclodextrin
F11......Ketoconazole + PEG 4000
F12. ....Ketoconazole + PEG 6000
F13..... Ketoconazole + PEG 4000
F14..Ketoconazole + PEG 6000
F15..... Ketoconazole + -cyclodextrin
KCS.Ketoconazole + Carbopol 940 + Sodium lauryl sulfate
KCD.Ketoconazole + Carbopol 940 + Dimethyl Sulfoxide
PD.Pure Drug
MPMarketed Preparation
ABSTRACT
The Goal of the present investigation was to design and evaluate gels for
topical delivery of water insoluble antifungal agent Ketoconazole with an aim to
increase its penetration through skin and thereby its flux. This is a broad spectrum
imidazole derivative useful in the treatment of superficial and systemic fungal
infections. The solubility of Ketoconazole is increased by preparing solid dispersions
with using mannitol, polyethylene glycol (PEG) 4000 and polyethylene glycol 6000,
polyvinylpyrrolidone K30, -cyclodextrin as carrier. Solid dispersion of Ketoconazole
was prepared by fusion, solvent evaporation, melt solvent and kneading method. In
vitro release profiles of all solid dispersions were comparatively evaluated and also
studied against pure drug Ketoconazole. Faster dissolution was exhibited by solid
dispersion containing 1:1 ratio of drug: -cyclodextrin by solvent evaporation method.
The prepared solid dispersions were subjected for percent practical yield, drug
content, infra red (I.R.) spectroscopic studies and differential scanning calorimetry
(DSC). FT-IR spectra revealed no chemical incompatibility between drug and cyclodextrin. Drug - polymer interaction were investigated using differential scanning
calorimetry (DSC). Gels have gained more and more importance because the gelbases formulations are better percutaneously absorbed than creams and ointment
bases. Therefore, Ketoconazole gel formulations were made with different polymers
like carbopol 940, hydroxyl propyl methyl cellulose, methyl cellulose, and sodium
carboxymethylcellulose. Containing various permeation enhancers namely sodium
lauryl sulphate (0.5-1.0%) and dimethyl sulfoxide (5-20%) at different proportions.
xi
The formulated gels were evaluated for various physicochemical parameters like,
drug content, pH, viscosity, spreadability, extrudability, stability, skin irritation, in
vitro drug release and antifungal activity. The in vitro drug release study were carried
out using pH 7.4 phosphate buffer, and antifungal activity was carried out using cup
plate method with Candida albicans as test organism. All the formulated topical
preparation showed pH in the range of 6.5 to 7.4, and also showed good spreadability,
extrudability. The carbopol 940 with 15% of dimethyl sulfoxide (KCD3) showed best
in vitro release 98.07% at the end of 6 hrs.
Keywords: Ketoconazole, Solid dispersion incorporated gels, -cyclodextrin,

Carbopol 940, In-vitro drug release.
xii
TABLE OF CONTENTS
CHAPTER-1
INTRODUCTION..................................................................01
CHAPTER-2
OBJECTIVES ........................................................................29
CHAPTER-3
REVIEW OF LITERATURE...............................................32
CHAPTER-4
METHODOLOGY ................................................................56
CHAPTER-5
RESULTS ..............................................................................73
CHAPTER-6
DISCUSSION .......................................................................113
CHAPTER-7
CONCLUSIONS ..................................................................120
CHAPTER-8
SUMMARY ..........................................................................122
CHAPTER-9
BIBLIOGRAPHY ................................................................124
ANNEXURES.......................................................................139
xiii
LIST OF TABLES
Sl.
No.
Title
Page
No.
1.
Materials / Chemicals used
55
2.
Equipments used and sources
56
3.
Formulation ingredients, preparation, method of Ketoconazole solid

dispersions
59
4.
Formulation of various Ketoconazole gels
63
5.
Formulation of Ketoconazole gels with permeation enhancers
64
6.
Standardization of Ketoconazole
72
7.
Standard calibration data of Ketoconazole in pH 7.4 phosphate

Buffer
73
8.
Standard Calibration data of Ketoconazole in methanol
74
9.
Physical parameters of Ketoconazole solid dispersion
75
10.
Drug content uniformity studies and percentage practical yield of

Ketoconazole solid dispersion
76
11.
Dissolution profile of Ketoconazole pure drug
77
12.
In-vitro drug release profile of Ketoconazole solid dispersion F1
78
13.
78
14.
79
15.
80
16.
80
17.
81
18.
82
19.
82
20.
83
21.
84
22.
84
23.
85
24.
86
xiv
Sl.
No.
Title
Page
No.
25.
86
26.
87
27.
Physical parameters of drug content of formulations
90
28.
Rheological propertied of formulations
91
29.
In-vitro % drug release study of Ketoconazole from Carbopol 940 gel
92
30.
In-vitro % drug release study of Ketoconazole from HPMC gel
92
31.
In-vitro % drug release study of Ketoconazole from Methyl cellulose gel
93
32.
In-vitro % drug release study of Ketoconazole from NaCMC gel
93
33.
In-vitro % drug release study of Ketoconazole from KCS1 gel
96
34.
96
35.
97
36.
97
37.
In-vitro % drug release study of Ketoconazole from KCD1 gel
100
38.
100
39.
101
40.
101
41.
In-vitro % drug release study of Ketoconazole from PD gel
104
42.
In-vitro % drug release study of Ketoconazole from MP gel
104
43.
Statistical analysis data of prepared different Ketoconazole gel

formulations
107
44.
Stability studies of selected formulation at temperature 302C and

Relative humidity (RH) 655 %
108
45.
Stability studies of selected formulation at temperature 53C
108
46.
Dermal response of skin irritation studies conducted on rabbit skin with

prepared Ketoconazole gel (KCD3)
109
xv
LIST OF FIGURES
Sl. No.
Title
Page No.
1.
Structure of skin
23
2.
Layer of stratum corneum
23
3.
73
4.
Standard calibration curve of Ketoconazole in pH 7.4

phosphate Buffer
Standard calibration curve of Ketoconazole in methanol
5.
Release profile of Ketoconazole pure drug
77
6.
Release profile of Ketoconazole from (F1, F2, F3) Solid

dispersion
79
7.

dispersion
81
8.

dispersion
83
9.

dispersion
85
10.

dispersion
87
11.
IR Spectra of A = Ketoconazole, B = -cyclodextrin,

C = Formulation F10 and D = Formulation KCD3
88
12.
Differential scanning calorimetric thermogram of

A=Ketoconazole, B = -cyclodextrin and C= Formulation
F10
89
13.
Cumulative % drug release of Ketoconazole from Carbopol

940, HPMC, MC, and NaCMC gel
94
14.
First order plot of Ketoconazole from Carbopol 940, HPMC,

MC, and NaCMC gel
94
15.
Higuchi diffusion plot of Ketoconazole from Carbopol 940,

HPMC, MC, and NaCMC gel
95
16.
Peppas exponential plots of Ketoconazole from Carbopol

940, HPMC, MC, and NaCMC gel
95
74
xvi
Sl. No.
Title
Page No.
17.
Cumulative % drug release of Ketoconazole from KCS1,

KCS2, KCS3 and KCS4 gel
98
18.
First order plot of Ketoconazole from KCS1, KCS2, KCS3

and KCS4 gel
98
19.
Higuchi diffusion plot of Ketoconazole from KCS1, KCS2,

KCS3 and KCS4 gel
99
20.
Peppas exponential plots of Ketoconazole from KCS1,

KCS2, KCS3 and KCS4 gel
99
21.
Cumulative % drug release of Ketoconazole from KCD1,

KCD2, KCD3 and KCD4 gel
102
22.
First order plot of Ketoconazole from KCD1, KCD2, KCD3

and KCD4 gel
102
23.
Higuchi diffusion plot of Ketoconazole from KCD1, KCD2,

KCD3 and KCD4 gel
103
24.
Peppas exponential plots of Ketoconazole from KCD1,

KCD2, KCD3 and KCD4 gel
103
25.
Cumulative % drug release of Ketoconazole from

formulation KCD3, Pure drug and Marketed preparation
(MP)
105
26.
First order plot of Ketoconazole from formulation KCD3,

Pure drug and Marketed preparation (MP)
105
27.
Higuchi diffusion plot of Ketoconazole from formulation

KCD3, Pure drug and Marketed preparation (MP)
106
28.
Peppas exponential plots of Ketoconazole from formulation

KCD3, Pure drug and Marketed preparation (MP)
106
29.
Rabbit when applied with Ketoconazole gel (KCD3)
110
30.
Rabbit skin on application on prepared gel (KCD3)
110
31.
Comparative antifungal activity of Ketoconazole (KCD3)

with reference and marketed formulations
111
xvii
xviii
INTRODUCTION
CHAPTER-1
INTRODUCTION
Solubility is an important physicochemical factor affecting absorption of drug
and its therapeutic effectiveness. Consequences of poor aqueous solubility would lead
to failure in formulation development. The poor solubility of drug substances in water
and their low dissolution rate in aqueous G.I.T fluid often leads to insufficient
bioavailability1.
Poorly water-soluble drugs present many difficulties in the development of
pharmaceutical dosage forms due to their limited water solubility, slow dissolution
rate and low bioavailability. Solid dispersions have been widely reported as an
effective method for enhancing the dissolution rate and bioavailability of poorly water
soluble drugs2.
Nearly one-third of drugs in development are water insoluble and one-half fail
in trials because of underprivileged pharmacokinetics3. These poorly water soluble
drugs are allied with slow drug absorption leading to inadequate and variable
bioavailability and G.I. mucosal toxicity of drugs 4.
Poorly water soluble drugs belong to BCS class II and Class IV group of
compounds5. In the process of absorption of drug from oral route dissolution is the
rate limiting step for lipophilic drugs. Therefore it is necessary to enhance dissolution
of these drugs to ensure maximum therapeutic utility of these drugs. Before studying
the various approaches to enhance dissolution it is necessary to understand the basic
process of dissolution. Dissolution is a process by which a solid substance goes into
Luqman College of Pharmacy, Gulbarga
INTRODUCTION
solution. The extents to which the dissolution proceeds, under a given set of
conditions are referred to as the solubility of the substance in the solvent i.e. rate of
solution (dissolution) and amount that can be dissolved (solubility) are not same. The
dissolution rate of a drug is directly proportional to its solubility as per NoyesWhitney equation and therefore solubility of a drug substance is a major factor that
determines its dissolution rate and hence its absorption and bioavailability
eventually6.
The various properties of drug that affect drug dissolution and its rate includes
solubility, particle size, polymorphism, salt form, complexation, wettability, etc7.
For complete absorption and good bioavailability of orally administered drug,
the drug must be dissolved in gastric fluids. Dissolution of drug is the rate-controlling
step which determines the rate and degree of absorption. Drugs with slow dissolution
rates generally show erratic and incomplete absorption leading to low bioavailability
when administered orally. Since aqueous solubility and slow dissolution rate of BCS
class II and class IV drugs is a major challenge in the drug development and delivery
processes, improving aqueous solubility and slow dissolution of BCS Class II and
Class IV drugs have been investigated extensively. Various techniques have been
used in attempt to improve solubility and dissolution rates of poorly water soluble
drugs which include solid dispersion, micronization, lipid based formulations, melt
granulation, direct compaction, solvent evaporation, coprecipitation, adsorption,
ordered mixing, solvent deposition inclusion complexation and steam aided
granulation. In these techniques carrier plays an important role in improving solubility
and dissolution rate8.
INTRODUCTION
The goal of any drug delivery system is to provide a therapeutic amount of
drug to the proper site in the body to promptly achieve and then maintain the desired
drug concentration9,10. The route of administration has a significant impact on the
therapeutic outcome of a drug11. Most of these drug delivery systems are composed of
polymer, which contain the drug in the form of a dispersion of the solid drug particles
either in a solid or in liquid medium12.
1.1
Introduction:
Solid dispersion is a unique approach which was introduced by Sekiguchi and
Obi. In solid dispersion method, the drug is dispersed in extremely fine state in an
inert water-soluble carrier in solid state. In order to achieve increased dissolution rate,
sustained release of drugs and thus improve solubility and stability13. Solid
dispersions have attracted considerable interest as an efficient means of improving the
dissolution rate and hence the bioavailability of a range of hydrophobic drugs14. A
number of freely water soluble materials such as citric acid, succinic acid, bile acids,
sterols and related compounds and polymers like mannitol, polyvinyl pyrrolidone
(PVP), polyethylene glycols (PEG), and -Cyclodextrin used as carriers for solid
dispersions. By this approach the dissolution rate and bioavailability of poorly soluble
drug can be increased.
1.1.1
Definition and Classification of Solid Dispersions15:
Definition: Solid dispersion technology is the science of dispersing one or more

active ingredients in an inert matrix in the solid stage in order to achieve increased
dissolution rate, sustained release of drugs, altered solid state properties, and
INTRODUCTION
enhanced release of drugs from ointment and suppository bases, and improved
solubility and stability.
Types of solid dispersions:
Simple eutectic mixture: A eutectic mixture of a sparingly water soluble drug and a
highly water soluble carrier may be regarded thermodynamically as an intimately
blended physical mixture of its two crystalline component. The increase in surface
area is mainly responsible for increased rate of dissolution. This led to a conclusion
that the increase in dissolution was mainly due to decreased particle size.
Solid solutions: Solid solutions consist of a solid solute dissolved in a solid solvent.
A mixed crystal is formed because the two components crystallize together in a
homogenous one-phase system. Hence, this system would be expected to yield much
higher rates of dissolution than simple eutectic systems.
Glass solution of suspension: A glass solution is a homogenous system in which a
glassy or a vitreous of the carrier solubilizer drug molecules in its matrix. PVP
dissolved in organic solvents undergoes a transition to a glassy state upon evaporation
of the solvent.
Compound or complex formation: This system is characterized by complexation of
two components in a binary system during solid dispersion preparation. The
availability of the drug from the complex is dependent on the solubility dissociation
constant and the intrinsic absorption rate of the complex.
Amorphous precipitation: Amorphous precipitation occurs when drug precipitates
as an amorphous form in the inert carrier. The higher energy state of the drug in this
system generally produces much greater dissolution rates than the corresponding
crystalline forms of the drug.
INTRODUCTION
Ideal Characteristics16:
Based upon the above mention requirement following polymers are being used
extensively for the preparation of solid dispersion system:
It should be chemically inert and free from leachable impurities.
It should have good mechanical strength.
It should have non-toxic and compatible with environment.
It should be easily sterilized.
It should be inexpensive and easy to fabricate.
It should be demonstrated acceptable shelf-life.
1.1.2 Polymers used in solid dispersions:
The properties of the carrier have a major influence on the dissolution
characteristics of the dispersed drug. A carrier should meet the following criteria to be
suitable for increasing the dissolution rate of a drug:
a) It should be freely water-soluble with intrinsic rapid dissolution properties.
b)
It should be non-toxic and pharmacologically inert.
c) It should be heat stable with a low melting point for the melt method.
d) It should be soluble in variety of solvents and pass through a vitreous state upon
solvent evaporation for the solvent method.
e) It should be able to preferably, increase the aqueous solubility of the drug.
f)
It should be chemically compatible with the drug and should not form a strongly
bonded complex with the drug17.
INTRODUCTION
1.1.3 Methods of Preparing Solid Dispersions:
Physical Mixture: This method involves mixing, an accurately weighted quantity of
drug and carrier in suitable/ required proportion in a glass mortar and sieved through
mesh No. 100. Physical mixture method was used by K.Himasanker who studied solid
dispersion of Glipizide with PVP (K-90) and PEG 6000 as carriers.
Fusion Method18: The fusion process is technically the less difficult method of
preparing dispersions provided the drug and carrier are miscible in the molten state. A
sulphathiazole-urea mixture of eutectic composition at above its eutectic temperature,
solidified the dispersion on an ice bath and pulverized it, to a powder, since a super
saturation of the drug can be obtained by quenching the melt rapidly (when the solute
molecules are arrested in a solvent matrix by instantaneous solidification), rapid
congealing is favoured.
Fusion method was used by Shoba Rani who melted clofazimine with
mannitol and PEG 600019.
Solvent evaporation method: A Solid dispersion prepared by solvent removal
process was termed as co-precipitates. They should more correctly be designated as
co-evaporates, a term that has been recently adopted. The solvent process uses
organic solvents, the agent to intimately mix the drug and carrier molecules. The
choice of solvent and its removal rate are critical to quality of dispersion.
A solvent process was used by Kuchekar BS who dissolved paracetamol
and -cyclodextrin in 25% ammonia20.
INTRODUCTION
Melting-solvent Method21: About 5-10% (w/w) of liquid compounds could be
incorporated into PEG 6000 without significant loss of its solid property. Hence, it is
possible to prepare solid dispersion by first dissolving a drug in a suitable liquid
solvent and then incorporating the solution directly into the melt of PEG, obtainable
below 70C, without removing the liquid solvent.
Melting solvent method was used by K.Venkatesh Kumar who formulated and
evaluated Nalidixic acid-PEG 6000 surfactant system22.
Kneading Method23: Here the required quantity of polymer was weighted as per ratio
required and water was added to get dough like consistency. To the mass, weighted
quantity of drug was added. The mixture was kneaded in glass mortar for 1 hour and
then completely dried in hot air oven at 60 for 2 hours then dried mass was sieved
through 120 meshes. Kneading method was used by M.M.Soniwala who studied on
various approaches in dissolution enhancement of Rofecoxib by -cyclodextrin as
carrier.
1.1.4
Methods of Determination of Types of Solid Dispersion15:

Various methods, which can contribute information regarding the physical
nature of the solid dispersions, are thermo analytical methods (Thermal Analysis,
DSC, X-ray Diffraction Methods, Spectroscopic Methods and Microscopic Methods).
1.1.5
Advantages of Solid Dispersions17:

Solid dispersions have rapid dissolution rates that result in an increase in the
rate and extent of the absorption of the drug and a reduction in presystemic
metabolism.
Increase in solubility of many numbers of water insoluble drugs.
INTRODUCTION
Transformation of the liquid form of the drug into a solid form (e.g., clofibrate
and benzyl benzoate can be incorporated into PEG 6000 to give a solid,
avoidance of polymorphic changes and thereby bio-availability problems).
1.1.6
Disadvantages of Solid Dispersions:

Major disadvantages of solid dispersion are related to their instability. Several
systems have shown changes in crystallinity and a decrease in dissolution rate
with aging. The crystallization of ritonavir from the supersaturated solution in
a solid dispersion system was responsible for the withdrawal of the ritonavir
capsule (Norvir, Abboft) from the market.
Some solid dispersion may not lend them selves to easy handling because of
tackiness.
1.2
Moisture and temperature have more deteriorating effect on solid dispersion.

INTRODUCTION TO GELS:
Topical dosage forms have been used since ancient times. The application of
medicinal substances to the skin or to various body orifices is a concept as old as

humanity. Various ointments, creams, gels, lotions, pastes, powders and plasters have
been used for many years.
Topical dosage forms are those which are applied to skin. These preparations
are applied to skin either for physical effects that is for their ability to serve as skin
protectants, lubricants, emollients, drying agents etc. or for the specific effect due to
medicinal or chemical agent present. Those agents showing physical effect have
limited chemical and pharmacological activity. Topical agents that have chemical
reactivity include astringents, rubefacient, vesicants, sclerozing agents, caustics,
INTRODUCTION
antipruritic agents, keratolytic agents, etc. Topical administration is employed to
deliver a drug at or immediately beneath the point of application. Although
occasionally enough drug is absorbed into systemic circulation to cause systemic
effects. Topical administration of drugs rapidly is becoming an important route of
drug administration of systemic drugs. Previously used only for the application of
drugs to local effects in disease of skin, it is now being explored as a means of
administering drugs for their systemic effects24. These topical agents deliver the drug
topically by various routes like skin, cornea, nasal mucosa, vagina, buccal tissues,
urethral membrane and external ear lining25. Topical dermatological products are
intended for localized action on one or more layers of skin. Although some
medication from this topical product may unintentionally reach systemic circulation,
it is usually in sub-therapeutic concentrations, and does not produce effects of any
major concern except in special situations such as pregnant or nursing patients26.
1.2.1
Topical Semi-solid Preparations27:

Topical semi-solid preparations are intended to be applied to the skin or to
certain mucous surfaces for local action or percutaneous penetration of medicaments

or for their emollient or protective action.
Topical semi-solid preparations consists of a simple or compound basis in
which, usually, one or more active substances are dissolved or dispersed. According
to its composition, the basis may influence the action of the preparation and the
release of the active substance.
The bases may consist of natural or synthetic substances and may be singlephase or multiphase systems. According to the nature of the basis, the preparation
INTRODUCTION
may have hydrophilic or hydrophobic properties. Several categories of topical semisolid preparation can be distinguished - ointments, creams, gels and pastes.
1.
Ointments28:
Ointments are greasy, semi-solid preparation for application to the skin. They
are often anhydrous and contain the medicament. Substances, which are dispersed,
should be in the form of a fine powder. Undedicated ointments are used for the
physical effects they provide as protectants, emollients or lubricants. The bases that
are used mainly in the preparation of ointments may be classified into hydrocarbon
bases, absorption bases, emulsifying bases and water soluble bases.
2.
Creams:
The term cream in pharmacy and medicine is applied to viscous emulsions
of semi-solid consistency intended for application to the skin or mucous membrane.

They may be of the water-in-oil (oily creams) or oil in water (aqueous cream) type.
The vanishing creams are oil-in-water emulsions containing large percentages of
water and stearic acid or other oleaginous components. After application of the cream,
the water evaporates, leaving behind a thin residual film of the stearic acid or other
oleaginous component.
3. Pastes:
Pastes are semisolid preparation intended for application to the skin. Pastes are
stiffer preparation than ointments and contain a high proportion of powder dispersed
in fatty basis. They are originally formulated on the principle that the high content of
powder would absorb exudates but it is unlikely that a powder which has been
preferentially wetted with oil will be capable of absorbing an aqueous fluid. Because
of their very stiff consistency, pastes are useful for applying active medicaments (e.g.
10
INTRODUCTION
dithranol and coal tar) to circumscribed areas of the skin since they tend to localize
the effect of the active ingredients.
1.2.2
Gels:
The word gel is derived from gelatin and both gel and jelly can be
traced back to the Latin gelu for frost and gelare, meaning freeze or congeal.
This origin indicates the essential idea of a liquid setting to a solid like material that
does not flow, but is elastic and retains some liquid characteristics29.
Definition:
The term gels is broad, encompassing semisolids of a wide range of
characteristics from fairly rigid gelatin slabs, to suspensions of colloidal clays, to
certain greases. Gels can be looked on as being composed of two interpenetrating
phases30. The United States Pharmacopoeia defines gels as semisolids, being either
suspensions of small inorganic particles or large organic molecules interpenetrated
with liquid.
Classification of gels:
Gels are classified in the BP according to hydrophobic or hydrophilic
characteristics of the gelled liquid:
A) Hydrophobic gels:
The bases of hydrophobic gels usually consists of liquid paraffin with
polyethene or fatty oils gelled with or aluminum or zinc soaps.
11
INTRODUCTION
B) Hydrophilic gels:
The bases of hydrophilic gels (hydrogel) usually consists of water, glycerol or
propylene glycol gelled with suitable gelling agents such as tragacanth, starch,
cellulose derivatives, carboxyvinyl polymers and magnesium aluminum silicates.
Characteristics of gels30:
Ideally, gelling agents for pharmaceutical and cosmetic use should be inert,
safe and non-reactive with other formulation components. The inclusion of a gelling
agent in a liquid formulation should provide a reasonable solid like matrix during
storage that can be broken easily when subjected to the shear forces generated in
shaking a bottle or squeezing a tube, or during topical application. The gel should
exhibit little viscosity, changes under the temperature variation of normal use and
storage. A topical gel should not be tacky. Too high a concentration of gel former or
the use of an excessive molecular weight may produce a gel difficult to dispense or
apply. The gel characteristics should match the intended use. The aim is to produce a
stable, elegant, economical gel product adequately suited for its intended use.
Use of gels30:
The uses of gels and gelling agents are quite widespread. Gels find use as
delivery systems for oral administration as gels proper or as capsule shells made from
gelatin. Gelling agents are useful as binders in tablet granulation, protective colloids
in suspensions, thickeners in oral liquids and suppository bases.
Cosmetically, gels have been employed in a wide variety of products including
shampoos, fragrance products, denitrifies skin and hair care preparation. Medicated
12
INTRODUCTION
gels may be prepared for administration by various routes including the skin, the eye,
the nose, the vagina and the rectum.
1.2.3
Applications31:
Avoids risk and inconveniences of intravenous therapy.
No drug decomposition by gastrointestinal influences.
Permits lower daily dose of drug, because of no loss of drug by hepatic first
pass effect.
Improved patient compliance.
Allows rapid termination of drug input by removal of gel by washing it from

surface of skin with exception of drug depot in stratum corneum.
1.2.4
Disadvantages:
Limited drug permeability of skin.
Usable for low drug doses only.
High cost of treatment.
Possibility of irritation and hypersensitivity reaction.
The USP defines gels as semisolid systems consisting of either suspension made
up of small inorganic particles or large organic molecules interpenetrated by a liquid.
The favorable properties of dermatological gels are thixotropic, good spreadability,
greaseless, easily removed, emollient, demulcent, non-staining, and comparable with
number of excipients32.
13
INTRODUCTION
1.2.5
Gel Forming Substances32:

Gels forming hydrophilic polymers are typically used to prepare lipid-free
semisolid dosage forms. Gel vehicles containing therapeutic agents are especially
useful for application to mucous membranes and ulcerated/ burned tissues.
Examples of various gel forming substances are as follows:
Proteins:
Collagen, gelatin.
Polysaccharides:
Alginates, carrageenan, hyaluronic acid, starch.
Semi synthetic polymers:
Carboxymethyl cellulose sodium, hydroxypropyl

cellulose, methyl cellulose, hydroxypropyl methyl
cellulose.
Synthetic polymer:
Carbomer, poloxamer, polyacrylamide, polyvinyl

alcohol..
Inorganic substances:
1.2.6
Aluminum hydroxide, smectite clays.
Application of Polymer/ Surfactant Gels:

Numbers of applications are seen with polymer/ surfactant gels:
1. Solubilization of drugs.
2. Modulation of rheological behaviour.
3. Improvement of drug-control release.
4. Promotion of cutaneous and mucosal drug penetration.
When a surfactant is added to a polymer gel, aggregation phenomena usually
occurs as a result of hydrophobic interactions or hydrogen bonds between non-polar
surfactant tail and polymer backbone, and/ or electrostatic interactions between polar
heads of surfactant and changed groups of polymer.
14
INTRODUCTION
1.2.7
Methods of preparation of gel33:
Chemical reaction: In the preparation of sols by precipitation from solution e.g.

Aluminium hydroxide sol. prepared by interaction in aqueous solution of an
aluminium salt and sodium carbonate, an increased concentration of reactants will
produce a gel structure. Silica gel is another example and is produced by the
interaction of sodium silicate and acids in aqueous solution.
Temperature effect: The solubility of most Lipophilic colloids e.g. Gelatin, Agar is
reduced on lowering temperature, so that, cooling a concentrated hot solution will
produce a gel. In contrast to this some materials such as the cellulose owe their water
solubility to hydrogen bonding with water. Raising the temperature, of these solutions
will disrupt the hydrogen bonding and the reduced solubility will cause gelation.
Flocculation with salts and non-solvents: Gelation is produced by adding just
sufficient precipitants to produce the gel state, but insufficient to bring about complete
precipitation. It is necessary to ensure rapid mixing to avoid local high concentrations
of precipitant. Solution of ethyl cellulose, polysterene etc, in benzene can be gelled by
rapid mixing with suitable amounts of a non-solvent such as petroleum ether. The
addition of salts to hydrophobic solution to bring about coagulation and gelation is
rarely observed. However, the addition of suitable proportion of salts to moderately
hydrophilic solutions, such as aluminium hydroxide and bentonite produces gels. As a
general rule, the addition of about half of the amount of electrolyte needed for
complete precipitation is adequate. The gels formed have frequently thixotropic
behaviour.
15
INTRODUCTION
1.2.8
Structure of Gels:
Elastic Gels: Gels of agar, pectin and gelatin are elastic, the fibrous molecules being
linked at points of junction by relative weak bonds such as hydrogen bonds and dipole
attraction.
Rigid Gels: Rigid gels can be formed from macromolecules in which framework is
linked by primary valency bond e.g., silica gel.
Thixotropic Gels: The term thixotropy describes the property of fluid passing from
gel to sol state through agitation. Physical factors to be considered for a gel modifying
effects are agitation time, storing time. The bonds between particles in these gels are
very weak and can be broken by agitation or shaking. The resulting sol will revert
back to gel. This is termed as thixotropy.
1.2.9 Types of gels34:
Gelation of lyophobic sols: Gels may be flocculated lyophobic solution where the gel
can be looked upon as a continuous floccules e.g., aluminum hydroxide gel,
magnesium hydroxide gel.
Gelation of lyophilic sols: Gels formed by lyophilic solutions can be divided into
two groups depending upon nature of bonds between the chains of network.
Type - I gels: are irreversible systems with a three-dimensional network formed by
covalent bonds between macromolecules e.g., poly (2-hydroxy ethyl methacrylate)
[Poly (HEMA)]. Cross linked with ethylene glycol dimethacrylate
(EGDMA] forms a 3-dimensional structure.
Type - II gels: are held together by much weaker inter-molecular bonds such as
hydrogen bonds. These gels are heat reversible, a transition from sol to gel occurring
an either heating or cooling e.g., polyvinyl alcohol.
16
INTRODUCTION
1.3
Fungi35:
Fungi are eukaryotic protista that differ from bacteria and other prokaryotes.
They possess rigid cell walls containing chitin, mannan and other polysaccharides.
The cytoplasmic membrane contains sterols. They possess true nuclei with nuclear
membrane and paired chromosomes. They divide asexually, sexually or by both
processes. They may be unicellular or multicellular.
Fungi had been recognized as causative agents of human disease earlier than
bacteria. Fungi causing farms (Trichophyton schonleinni) and thrush (Candida
albicans) had been described as early as in 1839.
Fungus infections are extremely common and some of them are serious and
even fatal. With the control of most bacterial infections in the developed countries,
fungus infections have assumed greater importance.
1.3.1 Classification36:
Depending on cell morphology, fungi can be divided into four classes:
1. Yeasts
2. Yeast like fungi
3. Moulds
4. Dimorphic fungi.
1.
Yeasts: The yeasts are unicellular fungi which occur mainly as single
spherical or ellipsoidal cells and reproduce by budding on artificial media,
they form compact colonies with a creamy, mucoid or pasty consistence (e.g.,
like those of Staphylococcus). Cryptococcus neoformens is the only important
pathogen.
17
INTRODUCTION
2.
Yeast like fungi: The yeast like fungi grow partly as yeast and partly as long
filamentous cells joined end to end, forming a pseudo-mycelium e.g.,
Candida Albicans.
3.
Moulds: The moulds (filamentous, mycelial fungi) grow as long filaments or

hyphae which branch and interlace to form a meshwork or mycelium, and
reproduce by the formation of various kinds of spores. When grown to a large
size on artificial medium, the mycelium is seen as a filamentous mould
colony, this may become powdery on its surface due to the abundant
formation of spores (e.g., ring worm fungi).
4.
Dimorphic fungi: Dimorphic fungi can occur as filaments or as yeasts,

depending on the conditions of growth. In host tissues or cultures at 37C they
occur as yeasts, while in the soil and in cultures at 22C, they appear as
moulds. Most fungi causing systemic infections are dimorphic fungi.
1.3.2
Fungal infections37:
Fungal infections are termed mycoses and in general can be divided into
superficial infections (affecting skin, nails, hairs or mucous membranes) and systemic
infections (affecting deeper tissues and organs).
In the last 20-30 years, there has been a steady increase in systemic fungal
infections, not only by known pathogenic fungi but also by fungi previously thought
to be innocuous. These last are termed opportunistic infections. In the UK, the
commonest systemic fungal infection is systemic candidiasis. In the rest of the world
the commonest systemic fungal infections are blastomycosis, histoplasmosis,
coccidiomycosis and paracoccidiomycosis.
18
INTRODUCTION
1.3.3
Superficial Fungal Infections:

Superficial fungal infections can be classified into the dermatomycoses and
candidiasis.
Dermatomycoses:
Dermatomycoses are infections of the skin, hair and nails, caused by
dermatophytes. The commonest are due to Tinea organisms, which cause various
types of ringworm. Tinea capitis affects the scalp, tinea cruris, the groin, Tinea pedis,
the feet and Tinea Corporis, the body. In superficial candidiasis, yeast like organism
infects the mucous membrane of the mouth (thrush) or vagina, or skin.
Some of the surface fungal infections and cutaneous fungal infections which
fall into superficial mycoses groups are:
1. Pityriasis versicolor: Pityriasis versicolor (Tinea versicolor) is a chronic usually
asymptomatic, involvement of the stratum corneum, characterized by discrete or
confluent macular areas of discoloration or depigmentation of the skin. The areas
involved are mainly the chest, abdomen, upper limbs and back. The causative agent is
lipophilic, yeast like fungus, Pityrosporum arbiculare (Malassezia furfur).
2. Tinea Nigra: Tinea nigra is a localized infection of the stratum corneum,
particularly of the palms, producing black or brownish macular lesions. It is found
mainly in the tropics and is caused by cladosporium Wernickii (now designated as
Hortaea Wernickii). Skin scrapings show brownish, branched, septate hyphae and
budding cells.
3. Piedra: Piedra is a fungus infection of the hair, characterized by the appearance of
firm, irregular nodules along the hair shaft. The nodules are composed of fungus
19
INTRODUCTION
elements cemented together or the hair. Two varieties of Piedra are recognized black
piedra caused by Piedraia hortae and white piedra caused by Trichosporon beigelli.
4. Chromoblastomycosis: The most common form of chromomycosis is known as
chromoblastomycosis or verrucous dermatitis. The lesion consists of warty cutaneous
nodules which resemble the florest of cauliflower. The disease is usually confined to
the subcutaneous tissue of the feet and lower legs.
5. Sporotrichosis: Sporotrichosis is caused by the fungus sporothrix (sporotrichum)
schenckii and is characterized by the development on the skin, in subcutaneous tissues
and in lymph nodes, of nodules which soften and break down to form indolent ulcers.
6. Rhinosporidosis: Rhinosporidiosis is a chronic granulomatous disease
characterized by the development of friable polyps, usually confined to the nose,
mouth or eye but rarely seen on the genitalia or other mucous membrane.
Histologically the lesion is composed of large numbers of fungal spherules embedded
in a stroma of connective tissue and capillaries. The causative fungus is
Rhinosporidium seeberi.
7. Blastomycosis: This is a chronic infection caused by the dimorphic fungus
blastomyces dermatitis, characterized by the formation of suppurative and
granulomatous lesions in any part of the body. The cutaneous disease is usually on the
skin of the face or other exposed parts of the body.
8. Candidasis: Candidosis (Candidiasis, moniliasis) is an infection of the skin,
mucosa and rarely of the internal organs, caused by yeast like fungus Candida
albicans, normally present in the mouth, intestine and vagina.
20
INTRODUCTION
Candida albicans is an ovoid or spherical budding cell, which produces
pseudo-mycelia both in culture and in tissues. Candida species are normal inhabitants
of the skin and mucosa.
Over the last two decades, there has been a dramatic increase in the rate of
superficial and invasive fungal infections. Approximately threequarters of all women
experience at least one episode of vulvovaginal candidiasis during their life time and
nearly half of them suffer from multiple episode.
The manifestations of vulvo-vaginal candidiasis are often painful and
uncomfortable and can include intense itching, irritation, vaginal discharge and
dysuria37.
The antifungal agents such as Ketoconazole have improved the prevention of
fungal infections. Ketoconazole, a triazole antifungal drug is used in the treatment of
superficial and systemic fungal infection.
1.3.4
Fungal Disease in Man:
Cutaneous (superficial) Infection38, 39:
Dermatophytes e.g. Trichophyton rubrum and pityrosporum.
Tinea vesicular affecting upper trunk.
Candidiasis
Tinea pedis affecting web spaces between toes.
Tinea barbae affecting beard of adult.
Tinea cruris affecting groin in obese men.
Tinea capitis affecting scalp in children.
Subcutaneous Infections38:
21
INTRODUCTION
Mycetoma.
Sporotrichosis.
Chromoblastomysis.
Systemic Infection38:
Histoplasmosis.
Cryptococcosis.
Aspergillosis.
Candidosis.
Blastomycosis.
Coccidiomycosis.
Paracoccidiomycosis.
1.3.5
TOPICAL ANTIFUNGALS40,41:
These agents are meant for topical use for fungal infection. Topical application
of drug at the affected site offers potential advantage of delivering drug directly to site
of action. Local infection can be treated by application of products which forms
transparent water vapours and air permeable film over the skin surfaces, from which
drug releases continuously to the skin site and skin structure infection and the disease
of the patient would be treated. Antifungal therapy is clearly beneficial for both
recoveries from infections as well as preventing disease progression, Topical
application of antifungal agent is useful tool for skin therapy and soft tissue
infections. It has several potential merits compared with systemic therapy. The
various advantages of topical antifungal agents are as firstly degradation of the drug
in gut flora is avoided, secondly it is seen that high local drug concentration in topical
22
INTRODUCTION
application avoid many nutritional resistance. Thirdly, topical applications are less
than systemic therapy to cause side effects.
At present, there are number of antifungal agents used in topical applications
like clotrimazole, griseofulvin, itraconazole, fluconazole, etc. Topical therapy with
azoles (e.g. miconazole, econazole) and the allylamines (e.g., naftifine, terbinafine) is
effective for treatment of localized tinea corporis and uncomplicated tinea pedis.
1.4
The Skin42:
The skin is one of the most extensive and readily accessible organs of the
human body. The skin of an average adult body covers a surface area of
approximately 2 m ( or 3000 inch ) and receives about one - third of the blood
circulating through the body. It is elastic, rugged and under normal physiological
conditions, self-regenerating, with a thickness of only a few mm (2.970.28 mm).
1.4.1
Anatomy of Skin43, 44:

The skin is one of the largest organs of the body in surface area and weight. In
adults, the skin covers an area of about 2 square meters and weight 4.5 to 5 Kg.
structurally, the skin consists of two principle parts. The outer, thinner portion, which
is composed of epithelium is called epidermis. The epidermis is attached to the inner,
thicker, connective tissue part called dermis.
a)
Epidermis:
The epidermis is composed of stratified squamous epithelium and contains
four principal types of cells. Epidermal cells are keratinocytes cell, malenocytes cell,
langerhans cells, Merkel cell. The names of the five layers (strata) from the deepest to
the most superficial are:
23
INTRODUCTION
Stratum basale: This single layer of cuboidal to columnar cells contains stem cells
which are capable of continued cell division and melanocytes. The stem cells
producing keratinocytes, which push up toward the surface and become part of the
more superficial layer.
Stratum spinosum: This layer of the epidermis contains 8 to 10 rows (sheets) of
polyhedral cells that fit closely together. Many cells have delicate spines protruding
from their surface, hence also called as prickle cells. Some new cells are formed
and are pushed to surface to replace cornified cells of stratum corneum.
Figure-1: Structure of Skin
Figure-2: Layers of stratum corneum
24
INTRODUCTION
Stratum granulosum: The third layer of the epidermis consists of three to five rows
of flattened cells that develop darkly staining granule of a substance called
keratohyaline. This layer initiates the process of keratinization, associated with dying
process of cells.
Stratum Lucidum: Normally only the thick skin of the palms and soles has this
layer. It consists of three to five rows of clean, flat, dead cells that contain droplets of
an intermediate substance that is formed from keratohyalin and is eventually
transformed to keratin.
Stratum Corneum: This layer consists of 25 to 30 rows of flat, dead cells completely
filled with keratin. These cells are continuously shed and replaced by cells from
deeper strata.
b)
Dermis:
The second principal of the skin, the dermis is composed of connective tissue
containing collagen and elastic fibers. The outer portion of dermis, about one-fifth of
the thickness of the total layer is named the papillary region. It consists of aveolar
connective tissue containing fine elastic fibers. The deeper portion of the dermis is
called the reticular region. It consists of dense, irregular connective tissue containing
interlacing bundles of collagen and coarse elastic fibers. The combination of collagen
and elastic fibers in the reticular region provides the skin with strength extensibility
and elasticity.
c)
Epidermal Derivatives:
Hair: Hairs or pilli are growths of the epidermis variously distributed over the body.
Their primary function is protection. Although the protection is limited, hair on the
head guards the scalp from injury and the sun rays. It also decreases heat loss.
25
INTRODUCTION
Glands: Several kinds of glands are associated with the skin viz., sebaceous glands,
sudoriferous glands, cerecminous glands.
Sebaceous glands: Sebaceous glands or oil glands with few exceptions are connected
to hair follicle. Sebaceous glands secrete an oily substance called sebum.
Sudoriferous (Sweat) glands: Three to four million sudoriferous or sweat glands
empty their secretions onto the skin surface. They are divided into principal types,
eccrine and apocrine, based on their structure, location and type of secretion.
Sweat: is the fluid produced by fluid glands, mainly eccrine sweat glands because
they are so much numerous.
Nails: are plates of tightly packed, hard, keratinized cells of epidermis. The cells form
a clear, solid covering over the dorsal surfaces of the terminal positions of the fingers
and toes. Each nail consists of a nail body, a free edge and a nail root.
1.4.2 Functions of skin 43,44,45:
1. Regulation of temperature: It involves heat loss and heat production.
2. Protection: Skin acts as a physical barrier and protects underlying tissues.
3. Sensation: Skin contains many nerve endings and receptors that detect
stimuli related to temperature, touch, pain and pressure.
4. Excretion: Heat, water, sweat along with some salts and organic
compounds are excreted.
5. Immunity: some cells of epidermis are important component of immune
system.
6. Blood reservoir: skin blood vessels provide more blood for circulation
during contraction of muscles in exercise.
26
INTRODUCTION
7. Synthesis of vitamin D: skin forms calcitriol which is active form of
vitamin D, which helps in homeostatis of body fluids.
1.5
Rheological Properties:
The rheological properties (study of deformation and flow of matter) are
required in various pharmaceutical areas. Some of the reasons for determining

rheological properties are:
1. It helps in understanding the physicochemical nature of the vehicle and the
quality control of ingredients, test formulation and final products, together
with manufacturing process such as mixing, milling, pumping, stirring, filling
and sterilization.
2. It reflects the effects such as temperature and storage time.
3. It helps to assess a topical formulation with respect to patient usage e.g., ease
of removal of preparation from the jar or tube without spillage or spreadability
and adherence to the skin.
4. Finally it helps to monitor the effects of the vehicle consistency on the release
of a drug from the preparation and its subsequent percutaneously penetration.
Spreadability:
One of the criteria for gels to meet the ideal qualities is that it should possess
good spreadability. Spreadability is a term express to denote the extent of area to
which the gel readily spreads on application to skin or the affected parts. The
therapeutic efficiency of a formulation also depends upon its spreading value. Hence,
determination of spreadability is very important in evaluating gel characteristics.
27
INTRODUCTION
Spreadability is expressed in terms of time in seconds taken by two slides to
slip-off the gel, placed in between the slides under the direction of certain load. Lesser
the time taken for separation of the two slides, better the spreadability.
Extrudability:
It is a useful empirical test to measure the force required to extrude the
material from a deformable bottle or tube. Since the packing of gels have gained a
considerable importance in delivery of desired quantity of gel from jar or extrusion of
gel from collapsible tube, therefore, measurement of extrudability becomes an
important criteria for gels. While no strictly a test of the product characteristics due to
inclusion of the force necessary to deform the container, the method applies shear in
the region of the flow curve corresponding to a shear rate exceeding the yield value
and exhibiting consequent plug flow.
28
OBJECTIVES
CHAPTER-2
OBJECTIVES
2.1
NEED FOR STUDY:

The skin often has been referred to as the largest of the body organs. An
average adults skin has surface area of about 2m2. Its accessibility and the opportunity
it affords to maintain applied preparation intact for a prolonged time have resulted in
its increasing use as a route of administration whether for local, regional or systemic
effects.
The extensive studies on release properties have revealed that the active
ingredients in gel based formulations are better percutaneously absorbed than cream
or ointment bases.
Ketoconazole is a broad spectrum imidazole antifungal agent marketed as
creams and tablets. It interacts with 14-demethylase, a cytochrome P-450 enzyme and
inhibits ergosterol synthesis and increased fungal cellular permeability. It is effective
topically for the management of cutaneous candidiasis and tinea infection.
The major drawback of this drug is its low aqueous solubility. Increasing the
water solubility of insoluble or slightly soluble compounds is a major concern for
pharmaceutical researchers.
The techniques generally employed to enhance the solubility of poorly water
soluble drugs are use of surface active agent, hydrates and solvates, polymorphism,
complexation, solid dispersion. Among this Solid dispersion is a unique technique
used to increase solubility, dissolution and bioavailability of poorly water-soluble
29
OBJECTIVES
drugs. Conventional methods for preparing solid dispersion include physical mixture,
complex formations, and solvent evaporation techniques.
Hence, in the present investigation an attempt will be made to develop solid
dispersion incorporated gels of Ketoconazole to overcome solubility problems of drug
and to treat fungal infections of skin more effectively.
2.2
OBJECTIVES OF THE STUDY:

The objective of the present study includes:
1. To prepare solid dispersions of Ketoconazole using mannitol, polyethylene
glycol 4000, polyethylene glycol 6000, polyvinylpyrrolidone K30, cyclodextrin as carrier.
2. To evaluate Ketoconazole solid dispersions for various parameters viz., %
practical yield, drug content, in vitro release study, drug-excipients interaction
study, etc.
3. To incorporate selected dispersions of Ketoconazole into various gel bases to
develop solid dispersion incorporated gels of Ketoconazole.
4. To evaluate solid dispersion incorporated Ketoconazole gels for drug content,
in vitro diffusion study, rheology, spreadability, extrudability, gel strength,
antifungal activity, skin irritation test, stability study, etc.
2.3
SCHEME OF WORK:
PART-I:
1. Extensive literature survey.
2. Procurement of raw materials and drug
3. Standardization of raw materials and drug.
30
OBJECTIVES
PART-II:
Preparation of solid dispersions using different carrier systems by physical
mixture, fusion method, solvent evaporation method, melts solvent and kneading
method.
Carrier Systems Used:
1. Mannitol,
2. Polyethylene glycol 4000,
3. Polyethylene glycol 6000,
4. Polyvinyl pyrrolidone K30,
5. -cyclodextrin.
PART-III: Evaluation of Ketoconazole Solid Dispersions System:
1. Physical appearance,
2. Construction of standard calibration curve of Ketoconazole in methanol and
pH 7.4 phosphate buffer.
3. Drug-content uniformity.
4. In vitro drug release studies.
PART-IV: Statistical Analysis, Data Interpretation and Conclusions.
1. DSC
2. IR
PART-V: Incorporation of best solid dispersions into gel.
PART-VI: Evaluation of gels.
31
REVIEW OF LITERATURE
CHAPTER-3
3.1
Literature Survey:
Mudhusudan B et al developed and evaluated the antifungal activity of o/w
type creams containing solid dispersion of clotrimazole. Improved antifungal activity

was found with clotrimazole solid dispersion. The highest activity was observed with
1:6 solid dispersion prepared by melting method 46.
Kales SN, Gudsoorkat et al have prepared solid dispersion of piroxicam using
PEG-6000. Solid dispersion prepared by fusion method found to be more superior
than prepared by solvent method with increased dissolution rate as compared to
dissolution rate of pure drug (piroxicam) 47.
Chowdary KPR and Kamalakara Reddy prepared sustained release
mucoadhesive tablets of nifedipine containing solid dispersions. Solid dispersion of
nifedipine in HPMC and HPC has markedly enhanced the dissolution rate of
nifedipine. Increase in the dissolution efficiency of nifedipine was observed with NHPMC (1:3) and N-HPC (1:3) solid dispersions respectively 48.
Trivedi BM et al studied on dissolution behaviour of sulphadimidine PVP
solid dispersion and concluded that solid dispersion containing 7:3 PVP drug released
all the drug at the faster rate when compared to other ratios and pure drug49.
Kai T et al studied a new triazole antifungal agent (+)-2-(2,4-difluoro-phenyl)3-methyl-i-(iH-1,
2,4-triazol-i-yl)-3-(6-(iH-1,24-triazol-I-ly)
pyridazin-3
ylthio)
butan-2-ol (MFB-i04i), shows poor oral absorption and is practically insoluble in
32
water. Solid dispersion systems with an enteric polymer such as hydroxy propyl
methylcellulose phthalate (HP-55) and carboxymethyl cellulose (CMEC) and a
nonenteric polymer, hydroxy propyl methyl cellulose (metolose) were evaluated to
improve drug absorption and solubility. The oral bioavailability of these solid
dispersions in beagle dogs were over 6-times higher than that of a suspension system
with increasing drug solubility in an alkaline medium50.
Gowthamarajan K et al formulated and studied the dissolution properties of
meloxicam solid dispersion incorporated suppositories. The in vitro release of
meloxicam from its solid dispersion incorporated suppositories was significantly
improved when compared to the intact bulk drug incorporated suppositories51.
Torrado S et al prepared and evaluated solid dispersion systems of the
sparingly water soluble drug, albendazole (ABZ), were mixed with varying
concentrations of polyvinylpyrolidone (PVP K 12) in an attempt to improve the
solubility and dissolution rate of ABZ. As expected, the albendazole dissolution rate,
expressed as the dissolution efficiency, and also the solubility coefficient were
increased when albendazole was mixed with PVP. Solid dispersion were prepared
using a solvent evaporation method52.
Betageri GV et al evaluated the preparation of a solid dispersion of tolazamide
in polyethylene glycol 8000 by solvent and melt methods are reported, and the
dissolution of tolazamide from these dispersions is reported. The rate of dissolution of
tolazamide was faster in the solid dispersions than in physical mixtures and pure
tolazamide. Dispersions prepared by the solvent method showed faster dissolution
rates compared to the melt method53.
33
Patel MM and Patel DM prepared fast dissolving valdecoxib tablets containing
solid dispersion of valdecoxib with the view to increase its water solubility. Solid
dispersion containing PVP-K showed maximum drug release54.
Craig DQM et al investigated the dissolution characteristics of nortriptyline
hydrochloride dispersions in a range of different molecular weight polyethylene
glycol carriers have been investigated. The release rate was found to be higher from
dispersions in PEG 3400 than from the drug alone55.
Nageswara Rao L, Kiran Kumar and Buchi Nalluri studied on maltodextrinpiroxicam solid dispersion and concluded that the dissolution and solubility of
piroxicam a poorly soluble drug was increased with maltodextrin carrier56.
Soniwala MM et al had approved to enhance the dissolution rate of rofecoxib
by formulating its solid dispersion with various carriers. PVPK-30 was found to be
more effective in increasing dissolution rate of the drug rofecoxib57.
Kerc J et al studied solid dispersions containing different proportions of
felodipine to urea and relodipine to mannitol have been prepared and studied in water
dissolution media. Enhanced dissolution rate as a result of both surface area increase
and solubilization was noticed58.
Saers ES et al investigated the solubility, melting and dissolution behaviour of
methyl, ethyl, propyl and butyl p-aminobenzoates (PABAs) have been studied, both
alone and as, dispersions in polyethylene glycol (PEG) 6000 prepared by the fusion
method59.
34
Ho Ho et al studied the solid dispersion of a poorly water-soluble drug,
nifedipine, were prepared in hydroxypropylmethylcellulose (HPMC) on sugar spheres
using a fluidized-bed coating system and characterized by differential scanning
calorimetry (DSC) and dissolution measurements. The result demonstrated that
dissolution rates were fastest at the lowest nifedipine loading. Furthermore, the
dissolution rate of nifedipine increased as more HPMC was added to the solid
dispersions60.
Arias M.J. et al investigated the effects of spray drying in the preparation of
solid dispersions, dispersions containing 10-40% w/w triamterene and mannitol (Dmannitol) were prepared by spray drying or the melting carrier method. Spray dried
dispersions demonstrated reduced dissolution times as compared to melting carrier
dispersions61.
Prajapati ST, Gohel MC and Patel LD studies to enhance dissolution
properties of carbamazepine, the enhancement of dissolution were achieved by
formulating the solid dispersion of the drug using PEG 600 for preparation of
dispersion62.
Anguiano Igea S et al investigated the effect of clofibrate concentration and
molecular weight of polyethylene glycols on the structure and dissolution rates of
solid dispersions, dispersions containing polyethylene glycols of molecular weights of
10,000 35,000 and 2.5-20% clofibrate were prepared and evaluated for structure and
dissolution. Dissolution rates increased with molecular weight of polyethylene glycol
and drug concentration63.
35
Mahaparale PR, Gudsoorkar VR et al have prepared solid dispersion of
meloxicam by solvent evaporation method by using different carriers such as PVP,
PEG 4000 and PEG 6000. Study showed higher solubility and faster dissolution
compared to pure drug64.
Singh C, Jain KA et al explaining about the development, characterization and
stability studies of solid dispersion of terbinafine HCl. So the main purpose of this
investigation was to increase the solubility and dissolution rate of terbinafine HCl by
preparation of its solid dispersion with PEG 6000 using fusion method65.
Tokiko Oribe et al reported in vivo and in vitro correlation of the dissolution
properties of lemildipine solid dispersion incorporated suppositories66.
Dixit RP and Nagarsenker MS have prepared celecoxib surface solid
dispersion by suing various techniques and different ratio of drug and carrier. The
formulation were prepared by using various hydrophilic carrier such as
croscarmellose sodium, Ac-Di-sol, sodium starch glycolate, crospovidone67.
Derle DV et al formulated microemulsion based gel for topical delivery of
water insoluble antifungal agent Ketoconazole with an aim to increase its penetration
through skin and thereby its flux. The microemulsion based gels were evaluated for
rheological behavior, in vitro permeation studies. The in vitro antifungal activity of
Ketoconazole was found to be significant with microemulsion based gel68.
Lei Wang, Xing Tang prepared a bioadhesive effervescent vaginal tablet
formulation of Ketoconazole against candida albicans. The in vivo studies indicated
that the profile of Ketoconazole retained in vagina followed a one-order pattern69.
36
Sanghavi NM, Mahalaxmi D determined in vitro release of clobetasol
propionate from topical bases like gels, creams and ointment using cellophane
membrane and hairless mouse skin. The drug followed diffusion controlled release
kinetics. By using the cellophane membrane, drug diffusion was fastest from the gel,
slower from the cream and ointment bases. The gel formulation had given maximum
release of drug using hairless mouse skin. It was concluded that the in vitro release of
clobetasol from topical bases was fastest from a gel formulation70.
Magdy C. Mohammed have studied optimization of chlorphenesin emulgel
formulation and evaluated emulgel for various parameters like rheological study, in
vitro release study, antifungal activity and stability studies71.
Chowdary KPR and Appan Kumar studied release and antimicrobial activity
of ciprofloxacin from topical drug delivery systems. Gels were prepared with
anhydrous, cream, water soluble and gel bases with drug and evaluated for drug
release, antimicrobial and antifungal activity72.
Panigrahi L et al studied effect of permeation enhancer on the release of
permeation kinetics of Lincomycin hydrochloride gel formulation through mouse
skin. A formulation containing 1.5% carbopol with 10% isopropyl myristate showed
better in vitro skin permeation through abdominal mouse skin and was found to be the
best. The formulations were evaluated for drug content, viscosity, pH, extrudability,
homogeneity, skin irritation test, spreadability and gel strength73.
37
Erika RM et al presented UV spectrophotometric determination of
Ketoconazole using absorption maxima at 222 nm in 0.01M HCl. Beers law was
obeyed in a range of concentration from 4.0 to 13.0 g/ml74.
Saleem MT, Sanaullah S and Faizan S had formulated and evaluated
gatifloxacin topical gels. The release of gatifloxacin was slow and extended for longer
period of time following first order kinetics. Gatifloxacin in case of 1% w/w prepared
with HPMC as gellant and 5% w/w glycerin as humectant was found to be good as
topical gel among the prepared gels75.
Kamal Dua et al evaluated various bases for topical delivery of aceclofenac.
They have concluded that carbopol base is the most suitable base for topical delivery
of aceclofenac as compared to other bases76.
Sang-Chul Shin et al has developed tretinoin gels for enhanced transdermal
delivery. They studied the release characteristics of drug from carbopol gel according
to temperature, receptor medium and drug concentration. The carbopol gel of tretinoin
containing an enhancer could be developed for the enhanced transdermal delivery of
drug77.
Manvi FV et al investigated the effect of permeation enhancers like dimethyl
study and concluded that there was increase in permeation rate with increase in
permeation enhancer concentration78.
Loganathan V et al studied effects of polymers and permeation enhancers on
released of flurbiprofen from gel formulation. The formulated gels were evaluated for
38
drug content, pH, viscosity and in vitro release through the sigma dialysis
membrane79.
Sang-Chul Shin, Cheong-weon Cho, Kyo-Ho Yang has developed lidocaine
gels for enhanced local anesthetic effects. The HPMC based bioadhesive polymer gel
containing an enhancer was formulated. Among various enhancers studied, diethylene glycol showed the greatest enhancing effects on drug permeation through
skin80.
Sankar SV et al has formulated and evaluated stability of diclofenac sodium
ophthalmic gels. The gels were formulated and assessed for various parameters.
Around 96% of drug was released from the HPMC formulation within 9 hours and
HPMC gels were more stable at the ambient, refrigerator and incubator temperature81.
Uma Devi S et al carried out the work on tetracycline gels and evaluated for
pH, consistency, drug content, drug release, extrudability and skin irritancy82.
Venkatesan S and Ravi V investigated the in vitro antifungal activity of eclipta
alba against Candida albicans by using cup-plate method83.
39
3.2
DRUG PROFILE: 40, 84, 85
Ketoconazole:
Molecular formula: C26H28CI2N4O4
Molecular weight: 531.4
Category: Antifungal
Chemical structure:
Chemical name: 1 acetyl-4-([(2RS-4SR)-2-(2-4-dichloro-phenyl)-2-(1, 4-imidazole 1 yl methyl)-1, 3-dioxolan-4 yl] methoxy] phenyl] piperazine.
Description:
Color: White or almost white powder
Odor: Odorless
Nature: Solid
Solubility: Practically insoluble in water, freely soluble in methylene chloride,
soluble in methanol, sparingly soluble in alcohol.
H2O solubility: 0.0866 mg/L
Melting point: 148C to 152C
Storage: Stored in well closed container, protect from light.
PKa: 6.51
Heavy metals: 20 ppm max
40
Loss on drying: 0.5% max
Sulphated ash: 0.1% max
Mechanism of action:
Ketoconazole interacts with 14--demethylase, a microsomal cytochrome
P450 dependent enzyme system, thus impair the biosynthesis of ergosterol for the
cytoplasmic membrane and leads to the accumulation of 14-methyl sterols. These
methylsterols may disrupt the close packing of acyl chains of phospholipids,
impairing the function of certain membrane bound enzyme systems such as ATPase
and enzymes of the electron transport system and thus inhibiting growth of the fungi.
Pharmacokinetics:
Absorption: The absorption of Ketoconazole from the gastro-intestinal tract is
variable and increase with decreasing stomach pH. It requires gastric acid for
dissolution and is absorbed through the gastric mucosa. Drugs that raise gastric pH
such as antacids, or that interfere with gastric acid secretion such as H2-histamine
receptor blockers and proton pump inhibitors, impair absorption.
Distribution: After oral doses of 200, 400 and 800 mg, peak plasma concentration of
Ketoconazole are approximately 4, 8 and 20 g/ml. In blood 84% of Ketoconazole is
bound to plasma proteins, largely albumin, 15% is bound to erythrocyters and 1% is
free.
Metabolism: Ketoconazole is metabolized in the liver to inactive metabolites.
Excretion: It is excreted about 13 % in urine and 57 % is eliminated in the faeces.
41
Protein binding: 99 %
Half-life: 2 hours
Precautions: Its use during pregnancy is not recommended, and because of secretion
of the drug into breast milk, its use in nursing mothers is unwise. It should not be
administered to patients with pre-existing liver disease.
Drug interaction: By inhibiting cytochrome P450, Ketoconazole can potentiate the
toxicities of drugs such as cyclosporine, phenytoin, tolbutamine and warfarin.
Ketoconazole and amphotericin B should not be used together, because the decrease
in ergosterol in the fungal membrane reduces the fungicidal action of amphotericin B.
Adverse effect:
1. Gastrointestinal disturbances
2. Nausea, anorexia, vomiting
3. Endocrine effect, such as gynecomastia, decreased libido, impotence
and menstrual irregularities.
Uses and Administration:
It is given by mouth in chronic mucocutaneous candidiasis, fungal infection of
gastrointestinal tract and dermatophyte infection of the skin and finger nails. It
is effective in blastomycosis, histoplasmosis, coccidioidomycosis, pseudallescheriasis,
ringworm, tinea versicolor, candida vulvovaginitis and esophageal candidiasis.
Dose: 200 mg once a day
42
Analytical parameters:
UV spectrum: Methanol 244 and 296 nm.
IR principal peak: Wave number 1200, 1221, 1240, 1507 and 1640.
Official preparation:
Ketoconazole tablets USP XXIII
Ketoconazole tablets IP
Ketoconazole tablets BP
Shampoo 2%
Cream 2%
Suspension 2%
43
3.3
EXCIPIENT PROFILE:
3.3.1
Mannitol86:
Synonyms: Cordycepic acid, manita, manna sugar, D-mannite, mannite, Mannogem

pearlitol.
Empirical formula: C6H14O6
Structural formula:
Functional Category: Tablet and capsule diluent, sweetening agent, tonicity agent,
vehicle (bulking agent) for lyophilized preparations.
Applications in Pharmaceutical formulations or Technology: Mannitol is widely
used in pharmaceutical formulations and food products. In pharmaceutical
preparations it is particularly used as diluent (10-90% w/w) in tablet formulations,
mannitol is commonly used as excipient in the manufacture of chewable tablets
formulations because of its negative heat of solution, sweetness and mouth feel.
Mannitol has also been used to prevent thickening in aqueous antacid suspensions of
aluminum hydroxide (<7% w/v).
Description: White, odorless, crystalline powder, or free flowing granules.
Typical properties:
Bulk density: 0.430 g/cm for powder; 0.7 gm/cm for granules.
44
Tapped density: 0.734 g/cm for powder and 0.8 g/cm for granules.
True Density: 1.514 g/cm
Melting point: 166 168C
pKa: 13.5 at 18C
Solubility:
Solvent .......................Solubility at 20C
Ethanol (95%) ............1 in 83
Ether...........................Practically insoluble
Glycerin .....................1 in 18
Propanol .....................1 in 100
Water..........................1 in 5.5
Refractive index: 1.33
Specific surface area: 0.37 to 0.39 m/g
Safety: Mannitol is a naturally occurring sugar alcohol found in animals and plants. It
is present in small quantities in almost all vegetables. Laxative effects may occur if
mannitol is consumed orally in large quantities.
3.3.2
Polyethylene Glycol86:
Synonyms: Carbowax, Carbowax sentry, Lipoxol, Lutrol E, PEG, Pluriol E,

Polyoxyethylene glycol.
Empirical Formula: HOCH2 (CH2OCH2)
CH2OH, where n is represents the
average number of oxyethylene groups.

Functional Category: Ointment base, plasticizer, solvent, suppository base, tablet
and capsule lubricant.
45
Structural formula:
Applications in Pharmaceutical Formulation or Technology: PEGs are widely

used in a variety of pharmaceutical formulations including parenteral, topical,
ophthalmic, oral and rectal preparations. It has been used experimentally in
biodegradable polymeric matrices used in controlled release system. PEGs are stable,
hydrophilic, substances that are essentially non-irritant to the skin.
Description: PEG 6000 and above are available as free-flowing milled powders.
Typical Properties:
Apparent density:
1.11-1.14 g/cm3 at 250C for liquid PEGs
1.15-1.21 g/cm3 at 250C for solid PEGs
pH: 4.5 to 7.5
Melting point:
55-63C for PEG 6000,
50-58C for PEG 4000.
Solubility: All grades of polyethylene glycol are soluble in water. Liquid
polyethylene glycols are soluble in acetone, alcohols, benzene, glycerin, and glycols.
Solid polyethylene glycols are soluble in acetone, dichloromethane, ethanol (95%),
and methanol; they are slightly soluble in aliphatic hydrocarbons and ether, but
insoluble in fats, fixed oils, and mineral oil.
46
Safety: Polyethylene glycols are widely used in a variety of pharmaceutical
formulations. Generally they are regarded as non-toxic and non-irritant materials.
3.3.3
Povidone86:
Synonyms: Kollidon, Plasdone, Polyvidone, Polyvinyl pyrrolidone.

Chemical Name: 1-ethyl-2-pyrollidone homopolymer
Molecular weight: 2500 30,00,000
Structural formula:
Functional Category: Suspending agent, tablet binder.

Description:
PVP is fine, white to creamy white coloured, odourless or almost odourless,
hygroscopic powder. PVP with K value equal to or lower than 30 are manufactured
by spray drying and exist as spheres. Povidone K-90 and higher K values povidone
are manufactured by drum drying and exist as plates.
Typical Properties: Acidity/ Alkalinity.
pH 3.0 7.0 (5% w/v aqueous solution)
Density 1.17 1.18 g/cm3
Solubility: Freely soluble in acids, chloroform, ethanol, ketones, methanol and water,
practically insoluble in ether, hydrocarbons and mineral oil.
47
Application:
Although povidone is used in variety of pharmaceutical formulations, it is
primarily used in solid dosage forms. In tableting, povidone solutions are used as
binder in wet granulation processes. Povidone solutions may also be used as coating
agent. Povidone is additionally used as suspending, stabilizing or viscosity increasing
agent in number of formulations (topical, oral suspension and solutions).
Safety: Povidone may be regarded as essentially non-toxic since it is not absorbed
from GIT or mucous membrane. Povidone additionally has no irritant effect on the
skin and cause no sensitization.
3.3.4
-Cyclodextrin86:
Synonyms:
Beta-cycloamylose,
betadex,
beta-dextrin,
cycloheptaamylose,
cycloheptaglucan, cyclomaltoheptose, kleptose.

Functional Category: Solubilizing agent and stabilizing agent.
Empirical Formula: C42H70O35
Molecular Weight: 1135
Structural formula:
Description: White, practically odorless, amorphous powder, having a slightly sweet

taste.
48
Solubility: Soluble in 1 in 200 parts of propylene glycol, 1 in 50 of water at 20C, 1
in 20 at 50C.
Melting point: 255 to 265C
Stability and Storage Conditions: Are stable in the solid state if protected from high
humidity. Should be stored in a tightly sealed container in cool, dry place.
Safety: Used in oral pharmaceutical formulations.
Handling Precautions: Should be handled in a well-ventilated environment. Efforts
should be made to limit the generation of dust, which can be explosive.
3.3.5
Carbopol 94086:
Synonyms: Acritamar, Acrylic acid polymer, carbopol carboxy vinyl polymer,

carboxy polymethelene.
Empirical Formula: Carbomer are synthetic high molecular weight polymers of
acrylic acid a cross-linked with either allylsucrose or allyl ethers of pentacrylthritol.
Approximate molecular weight: 4 x 106
Structural formula:
Functional Category: Emulsifying agent, suspending agent, tablet binder, viscosity

increasing agent.
Application in pharmaceutical formulation or technology: Carbomer are used
mainly in liquid or semisolid pharmaceutical formulation as suspending or viscosity
49
increasing agents. Formulations include creams, gels and ointments and may be used
in ophthalmic, rectal and topical preparations.
Description: Carbomer are white coloured, fluffy acidic, hygroscopic powders with
as light characteristic odour.
Typical properties:
pH: 2.7 to 3.5 for a 0.5% w/v aqueous dispersion
2.5 to 3.0 for 1% w/v aqueous dispersion.
Bulk density: 1.76 g/cm
Solubility: Soluble in water and after neutralization in ethanol.
Specific gravity: 1.41
Safety: Carbomer are extensively used in non-parenteral medicines particularly
topical liquid and semi-solid preparations.
3.3.6
Hydroxypropyl methyl cellulose86, 87:
Non-proprietary names:
BP
Hypromellose
Ph Eur
Methyl hydroxypropyl cellulose
USP
Hydroxypropyl methyl cellulose
Chemical name: Cellulose 2-hydroxypropyl methyl ether.

Molecular weight: 10,000 15, 00, 000.
Functional category: Coating agent, film former, stabilizing agent, suspending agent,
tablet binder, viscosity, increasing agent.
Description: HPMC is an odourless and tasteless white or creamy white coloured
fibrous or granular powder.
50
Structural Formula:
OR
CH2OR
o
O
OR
OR
OR
CH2OR
n
Where R is H, CH3 or [CH3CH (OH) CH2]

Typical properties:
Acidity/ Alkalinity.
pH 5.5 8.0 for 1% w/w aqueous solution.
Ash: 1.5 3% depending upon grade and viscosity.
Bulk density: 0.34 gm/cm

Tapped density: 0.557 gm/cm
True density: 1.326 gm/cm
Melting point: Browns at 190-200C, chars at 225-230C. Glass transition
temperature is 170-180C.
Moisture content: HPMC absorbs moisture from atmosphere, the amount of water
absorbed depending upon initial moisture content and temperature and relative
humidity of surrounding air.
Solubility:
1. Soluble in cold water,
2. Practically insoluble in chloroform, ethanol (95%) and ether
3. Soluble in mixtures of ethanol and dichloromethane and mixtures of methanol
and dichloromethane.
51
Stability and storage conditions:
Stable at pH 3-11
Increasing temperatures reduces viscosity of solution.
It should be stored in well closed container, in a cool and dry place.
Application in pharmaceutical technology: In oral products HPMC is primarily

used as tablet binder, in film coating and as an extended release tablet matrix. HPMC
is also used as suspending and thickening agent in topical formulations. Compared to
methyl cellulose, HPMC produces aqueous solutions of greater clarity. HPMC is also
used in topical gels and ointments. HPMC is used in the manufacture of capsules as
an adhesive in plastic bandages, and as a wetting agent for hard contact lenses. It is
also widely used in cosmetics and food products.
Safety: Hypromellose is widely used as excipients in oral and topical pharmaceutical
formulations. It is also used extensively in cosmetics and food products.
It is
generally regarded as nontoxic and nonirritant material, although excessive oral

consumption may have a laxative effect.
3.3.7
Carboxymethylcellulose Sodium86:
Synonyms: Akucell, Aquasorb, Blanose, Cellulose gum, CMC sodium, sodium

cellulose glycolate, sodium CMC.
Chemical Name: Cellulose, Carboxymethyl ether, sodium salt.
Empirical Formula: The USP describes carboxymethylcellulose sodium as the
sodium salt of polycarboxymethyl ether of cellulose.
Molecular weight: 90,000-7,00,000.
Melting point: Browns at approximately 227C, and chars at approximately 252C.
52
Solubility: Practically insoluble in acetone, ethanol (95%), ether, and toluene. Easily
dispersed in water at all temperatures, forming clear, colloidal solutions.
Functional Category: Coating agent, stabilizing agent, suspending agent, tablet and
capsule disintegrant, tablet binder, viscosity-increasing agent, water-absorbing agent.
Applications in Pharmaceutical technology: Carboxymethylcellulose sodium is
widely used in oral and topical pharmaceutical formulations, primarily for its
viscosity increasing properties. Viscous aqueous solutions are used to suspend
powders intended for either topical application or oral and parenteral administration.
Description: Carboxymethylcellulose sodium occurs as a white to almost white,
odorless, granular powder.
Safety: Carboxymethylcellulose sodium is used in oral, topical, and some parenteral
formulations. It is also widely used in cosmetics, toiletries, and food products, and is
generally regarded as a nontoxic and nonirritant material.
3.3.8
Sodium Lauryl Sulfate (SLS) 86:
Nonproprietary Names:
BP:
Sodium lauryl sulfate
Ph Eur:
Natrii laurilsulfas
USPNF:
Sodium lauryl sulfate
Synonyms: Dodecyl sodium sulfate, sodium dodecyl sulfate, Sodium monolauryl

sulfate.
Chemical Name: Sulfuric acid monododecyl ester sodium salt.
Empirical Formula:
C12H25NaO4S
Molecular Weight:
288.38
Melting point: 204 - 207C
53
Density: 1.07 g/cm3 at 20C.
Solubility: Freely soluble in water, giving an opalescent solution, practically
insoluble in chloroform and ether.
Functional Category: Anionic surfactant, detergent, emulsifying agent, skin
penetrant, tablet and capsule lubricant, wetting agent.
Applications in pharmaceutical technology: Sodium lauryl sulfate is an anionic
surfactant employed in a wide range of non-parenteral pharmaceutical formulations
and cosmetics. It is a detergent and wetting agent effective in both alkaline and acidic
conditions. It is also used as emulsifying agent and skin penetrant.
Description: It consists of white or cream to pale yellow crystals, flakes or powder
having a smooth feel, a soapy, bitter taste and a faint odor of fatty substance.
Safety: It is used in cosmetics and oral and topical pharmaceutical formulations.
3.3.9
Dimethyl sulfoxide (DMSO) 86:
Non-proprietary name:
BP Dimethyl sulfoxide
USP Dimethyl sulfoxide
Synonyms: DMSO, dimexide, deltan, dimethyl sulphoxide
Chemical name: Sulfinyl bismethane
Empirical formula: C2H6OS
Structural formula:
54
Functional category: Penetration enhancer, solvent.
Description: Dimethyl sulfoxide occurs as a colorless, viscous liquid or as colourless
crystals that are miscible with water, alcohol and ether. The material has a slightly
bitter taste with a sweet after taste and is odorless. Dimethyl sulfoxide is extremely
hygroscopic.
Pharmaceutical specification:
Specific gravity ............................................ 1.095 to 1.101
Freezing point ........................................................ 16.3C
Refractive index ........................................1.4755 to 1.4775
Typical properties:
Boiling point ............................................................. 189C
Dissociation constant pKa ............................................ 31.3
Solubility: Miscible with water with evolution of heat, also miscible with ethanol
(95%). Practically insoluble in acetone, chloroform, ethanol.
Viscosity: 1.1 mpas
Application in Pharmaceutical Formulation:
Dimethyl sulfoxide enhances the topical penetration of drugs owing to its ability to
displaced bound water from the stratum corneum.
Safety: It has low systemic toxicity but causes local toxic effects. It is readily
absorbed after injection or after oral or percutaneous administration and is widely
distributed throughout the body.
55
METHODOLOGY
CHAPTER-4
METHODOLOGY
4.1
MATERIALS:
Table-1: Materials/chemicals used
SL.
MATERIALS/ CHEMICALS
SOURCE
1.
Ketoconazole
FDC Limited, Raigad.
2.
Mannitol
sd fine-chem. Limited, Mumbai
3.
Polyethylene glycol 4000 LR
4.
Methanol
5.
Polyvinyl pyrrolidone K-30
Hi-Media Laboratories Pvt. Ltd.
6.
-cyclodextrin
Hi-Media Laboratories Pvt. Ltd.
7.
Polyethylene glycol 6000
Loba Chemie Pvt. Ltd., Mumbai
8.
Carbopol 940
Hi-Media Laboratories Pvt. Ltd
9.
Methyl cellulose
Hi-Media Laboratories Pvt. Ltd
10.
Hydroxypropylmethyl cellulose
11.
12.
Carboxymethyl cellulose sodium

salt 1100-1900 cps LR
Sodium lauryl sulphate EP
13.
Dimethyl sulphoxide LR,
14.
Triethanolamine LR
15.
Propylene glycol
Loba chemie Pvt. Ltd., Mumbai
16.
Cellophane membrane
Himedia Laboratories Pvt. Ltd.
17.
Aluminum Collapsible tube
Digvijay Containers & Closures.
18.
19.
Potassium dihydrogen
orthophosphate
Sodium hydroxide
20.
Concentrated HCl
NO.

56
METHODOLOGY
4.2
EQUIPMENT USED:
The equipment used in the present work is as follows:
Table-2: Equipments used and source
Sl. No.
Equipment Name
Source
1.
UV/Visible spectrophotometer
Shimadzu 1700, Shimadzu

Corporation, Japan.
2.
Electronics balance
Shimadzu Corporation- BL-220H
3.
pH meter
Elico LI-122
4.
Tablet dissolution apparatus
Electrolab USP (XXIII) TDT-06T

9911090
5.
Digital Controlled Speed Stirrer
Remi Motors RQ 121/D
6.
Brookfield DV-II +
Programmable Viscometer
M/97-164-E0102
7.
Magnetic Stirrer
Remi Equipments
8.
Sonicator
Flexit Jour Laboratories Pvt. Ltd.
9.
IR-Spectrophotometer
Perkin Elmer 1600-Series FTIR
10.
Differential Scanning Colorimeter
Pyris-6 DSC
11.
Spreadability apparatus
Fabricated
11.
Extrudability apparatus
Fabricated
13.
Dessicator
Digvijay Containers & Closures,

Mumbai
14.
Hot air oven
Shital Scientific Industry, Mumbai
15.
Humidity-cum-photo stability
chamber
Thermo lab, Mumbai
57
METHODOLOGY
4.3
SPECTROPHOTOMETRIC
METHOD
FOR
ESTIMATION
OF
KETOCONAZOLE:
4.3.1
Determination of Ketoconazole max in 7.4 pH phosphate buffer:
Stock solution:
Accurately weighed quantity of 100 mg Ketoconazole was taken in 100 ml
volumetric flask and was dissolved by using 5 ml of methanol, finally the volume was
made up with 7.4 pH phosphate buffers up to 100 ml to produce 1 mg/ml of solution.
Scanning:
A series of concentrations i.e. 4, 8, 12, 16, 20 g/ml were prepared by using
above stock solution and scanned between 200-400 nm. The absorption maxima of
223 nm was selected and used for further studies.
4.3.2
Determination of Ketoconazole max in methanol:
Stock solution:
Accurately weighed quantity of 100 mg Ketoconazole was taken in 100 ml
volumetric flask and was dissolved by using 5 ml of methanol, finally the volume was
made up with methanol up to 100 ml to produce 1 mg/ml of solution.
Scanning:
A series of concentrations i.e. 4, 8, 12, 16, 20 g/ml were prepared by using
above stock solution and scanned between 200-400 nm. The absorption maxima of
244 nm was selected and used for further studies.
58
METHODOLOGY
4.3.3
Preparation of Calibration Curve in 7.4 pH phosphate buffer:

Accurately weighed amount of Ketoconazole equivalent to 100 mg was
dissolved in small volume of 0.01M HCl, in 100 ml volumetric flask and the volume
was adjusted to 100 ml with 7.4 pH phosphate buffer and further dilutions were made
with 7.4 pH phosphate buffer. A series of standard solution containing Beers
Lamberts range of concentration from 4 to 15.0 g/ml of Ketoconazole were
prepared and absorbances were measured at 223 nm against reagent blank. All
spectral absorbance measurement was made on Shimadzu 1700 UV-visible
spectrophotometer.
4.3.4
Preparation of Calibration Curve Ketoconazole in methanol88:

A standard solution containing 1 mg/ ml of Ketoconazole was prepared in
methanol by dissolving 50 mg of pure Ketoconazole in 50 ml of methanol. From this

solution, working standard solutions of concentrations 2 to 12 g/ml of Ketoconazole
was prepared by dilution with methanol. The absorbance of the solutions was
measured at 244 nm against reagent blank. All spectral absorbance measurement was
made on Shimadzu 1700 UV-visible spectrophotometer.
59
METHODOLOGY
4.4
METHODS OF PREPARATION OF KETOCONAZOLE SOLID

DISPERSION SYSTEMS:
4.4.1
Preparation of Solid dispersions: Solid dispersions were prepared by various
polymer and different method as shown in Table 3.

Table 3: Formulation ingredients, Preparation method of Ketoconazole Solid
Dispersions:
Batch
Code
Composition
Method
Ratio
F1
Ketoconazole + Mannitol
Physical mixture
1:1
F2
Ketoconazole + PEG 4000
Physical mixture
1:1
F3
Physical mixture
1:1
F4
Ketoconazole + PVP K30
Physical mixture
1:1
F5
Ketoconazole + -cyclodextrin
Physical mixture
1:1
F6
Ketoconazole + Mannitol
Solvent evaporation method
1:1
F7
1:1
F8
1:1
F9
Ketoconazole + PVP K30
1:0.1
F10
1:1
F11
Fusion method
1:1
F12
Fusion method
1:1
F13
Melt solvent
1:1
F14
Melt solvent
1:1
F15
Kneading method
1:1
60
METHODOLOGY
Physical mixture89: Physical mixtures were prepared by mixing the appropriate
amount of Ketoconazole and polymer in pestle and mortar and pass through sieve #
60.
Fusion method: Accurately weighed amount of PEG-4000, and PEG-6000, were
melted in a porcelain dish at 80 - 85 and to this, calculated amount of Ketoconazole
were added with through mixing for 1-2 min followed by quick cooling.90 It were kept
in a dessicator under vacuum for 24 hrs. Then, solid dispersion formulations were
pulverized using a porcelain mortar and pestle. The pulverized powder were classified
using the sieve # 60.91
Solvent evaporation method: The drug and the excipients were dissolved in
sufficient volume of methanol with continuous stirring. The solvent was then
completely evaporated at 40 - 45 with continuous stirring to obtain dry granules90.
The resulting solid dispersion were stored in airtight container till further use.92
Melt-Solvent method: Accurately weighed amount of Ketoconazole were dissolved
in chloroform (10 ml) and the solution was incorporated into the melt of different
polymer by pouring slowly into hot melt with vigorous stirring. The melt was cooled
immediately and the mass was kept under vaccum in a dessicator for 24 hrs. The
solidified mass scrapped, crushed, pulverized and passed through 60/80 mesh.93
Kneading method: -cyclodextrin was added to the mortar, and small quantities of
50% V/V ethanol were added while triturating to get slurry like consistency. Then
slowly the drug was incorporated into the slurry, and trituration was continued further
61
METHODOLOGY
for 1 hrs. The slurry was then air dried at 25C for 24 hrs. Pulverized, and passed
through sieve no. 100 and stored in a dessicator over fused calcium chloride.94
4.5
EVALUATION OF KETOCONAZOLE SOLID DISPERSIONS:
4.5.1
Physical Appearance:
All the batches of Ketoconazole solid dispersions were evaluated for colour
and appearance.
4.5.2
Percent Practical Yield (PY) 95

Percentage practical yield were calculated to know about percent yield or
efficiency of any method, thus its help in selection of appropriate method of

production. Solid dispersions were collected and weighed to determine practical yield
(PY) from the following equation.
PY (%) = Practical Mass (SD) / Theoretical Mass (Drug + Carrier)] 100
4.5.3 Drug Content 96
The Physical mixture and solid dispersion equivalent to 25 mg of model drug
were taken and dissolved separately in 25 ml of methanol. The solutions were filtered
and were further diluted such that the absorbance falls within the range of standard
curve. The absorbances of solutions were determined at 223 nm by UV
spectrophotometer. The actual drug content was calculated using the following
equation as follows:
% Drug content = [Mact / Melt solvents] 100
= Actual Ketoconazole content in weight quantity of solid dispersion x 100

Theoretical amount of Ketoconazole solid dispersion
62
METHODOLOGY
4.5.4
In-Vitro Dissolution Study: 97

Dissolution studies were performed assuring sink condition according to the
paddle method (USP) using USP XXIII apparatus type-II (electrolab TDT-O9T). The
dissolution medium was 900 ml 7.4 pH phosphate buffer kept at 37C 0.5C. The
solid dispersions containing 100 mg of Ketoconazole was taken in a muslin cloth and
tied to the rotating paddle kept in the basket of dissolution apparatus, the basket was
rotated at 100 rpm. Samples of 5 ml were withdrawn at specified time intervals and
analyzed spectrophotometrically at 223 nm using Shimadzu-1700 UV-visible
spectrophotometer, the samples withdrawn were replaced by fresh buffer solutions.
Each preparation was tested in triplicate and then means values were calculated.
4.5.5 Infrared spectroscopy (IR):98
FT-IR spectra of pure Ketoconazole, -cyclodextrin, with its Solid dispersions
were obtained by Perkin-Elmer FT-IR spectrophotometer using potassium bromide
(KBr) pellets. KBr pellets were prepared by gently mixing the sample with KBr
(1:100). The sample was scanned from 4,000 to 400 cm-1.
4.5.6
Differential scanning calorimetry (DSC):99

Thermal analysis of Ketoconazole, -cyclodextrin, and the solid dispersion
were carried out using differential scanning calorimetry method. Samples were
examined using a Shimadzu TGA-50 DSC instrument (Shimadzu Corporation,
Japan). Samples equivalent to approximately 8 mg Ketoconazole were placed in
aluminum pans and heated from 25 to 200C with a heating rate of 10C/min.
63
METHODOLOGY
4.6
PREPARATION OF SOLID DISPERSION INCORPORATED GELS:
Preparation of gels:
Gels were prepared by various polymers as shown in table 4, 5. The polymer
and purified water I.P. were taken in a mortar and allow soaking for 24 hrs. And solid
dispersion containing required amount of drug was dissolved in ethanol and other
additives were added. The trituration was continued to get homogenous dispersion of
drug in the gel100.
Permeation Enhancers:
The permeation enhancers like sodium lauryl sulphate and dimethyl
sulfoxide were incorporated in different concentration (0.25-1.0%) and (5-20%)
respectively (Table -5) was added by dissolving in little quantity of distilled water
with the selected carbopol 940 formulations.
TABLE 4: FORMULATION OF VARIOUS KETOCONAZOLE GELS:
2%
Methyl
cellulose gel
2%
Sodium
CMC gel
2%
1.0%
--
--
--
HPMC
--
10%
--
--
Methyl cellulose
--
--
5%
--
Sodium CMC
--
--
--
3%
Triethanol amine
0.50%
0.50%
0.50%
0.50%
Propylene glycole
10%
10%
10%
10%
Ethanol
2.5%
2.5%
2.5%
2.5%
Water
100ml
100ml
100ml
100ml
Ingredients
Carbopol gel
HPMC gel
Ketoconazole
2%
Carbopol 940
64
METHODOLOGY
TABLE 5: FORMULATION OF KETOCONAZOLE GELS WITH
PERMEATION ENHANCERS
Ingredients
KCS1
KCS2
KCS3
KCS4
Ketoconazole
2%
2%
2%
2%
2%
2%
2%
2%
Carbopol 940
1.0%
1.0%
1.0%
1.0%
1.0%
1.0%
1.0%
1.0%
Triethanol
amine
KCD1 KCD2 KCD3 KCD4
0.50% 0.50% 0.50% 0.50% 0.50% 0.50% 0.50% 0.50%
Sodium lauryl
sulphate(mg)
250
500
750
1000
Dimethyl
sulfoxide (ml)
10
15
20
Propylene
glycole
Ethanol
10%
10%
10%
10%
10%
10%
10%
10%
2.5%
2.5%
2.5%
2.5%
2.5%
2.5%
2.5%
2.5%
Water (ml)
100
100
100
100
100
100
100
100
4.7
EVALUATION OF GELS:
Prepared gels of Ketoconazole were evaluated for the following parameters:
4.7.1
Physical appearance and homogeneity:

Gel formulation containing Ketoconazole were visually inspected for clarity,
color, homogeneity, presence of particles and fibers.

4.7.2 Determination of pH101:
The pH of gels was checked by using a digital Elico pH meter at room
temperature. Initially, the pH meter was calibrated using standard buffers of pH 4 and
9.2. Accurately 2.5 gm of gel was weighed and dispersed in 25 ml of purified water
and then pH meter was dipped in the dispersion and the pH was noted.
65
METHODOLOGY
4.7.3
Drug content analysis102:

The drug content of the prepared gels was carried out by dissolving accurately
weighed quantity (0.5 g) of gel equivalent to 10 mg of drug was dissolved in 10 ml of

methanol, the volume was made up to 100 ml and 5 ml of the above solution was
further diluted to 25 ml with methanol. After suitable dilution absorbance of the
solution was recorded by using Shimadzu UV/ visible spectrophotometer at 244 nm.
4.7.4
Viscosity and Rheological studies103:

The viscosity of gels was determined by using Brookfield (DV-II+)
viscometer. The gel was placed in the sample holder and the suitable spindle selected
was lowered perpendicularly into the sample. The spindle was attached to viscometer
and then it was allowed to rotate at a constant optimum speed at room temperature.
The readings of viscosity of the formulation were measured after 2 minutes.
4.7.5
Gel Strength103:
The gel strength was measured by apparatus described by Chul Soon et al in
which a fixed weight candle (30 g) was placed on the 15 ml gel in a 25 ml measuring
cylinder and the time required to travel the candle down to 5 cm was noted.
4.7.6
Spreadability104:
The spreadability of gel formulations was determined 48h after preparation, by
measuring two 20X20 cm glass plates after 1 min. The mass of the upper plate was
standardized at 125 g. The spreadability was calculated by using the formula S= m.l/t,
where S is spreadability, m is the weight tied to the upper slide, l is the length of the
glass slide, and t is the time taken.
66
METHODOLOGY
4.7.7
Extrudability105:
In the present study, the method adopted for evaluating gel formulation for
extrudability was based upon the quantity in percentage of gel extruded from tube on
application of certain load. More the quantity extruded better was extrudability. The
formulation under study was filled in a clean, lacquered aluminum collapsible oneounce tube with a nasal tip of 5 mm opening. It was then placed in between two glass
slides and was clamped. Extrudability was determined by weighing the amount of gels
extruded through the tip when a constant load of 1 Kg was placed on the slides and
gels extruded was collected and weighed. The percentage of gel extruded was
calculated and grades were allotted (++ good; + fair).
4.4.8
In-Vitro Diffusion Study105:

The apparatus consists of a glass cylinder with both the ends open, 10 cm in
height, 3.7 cm in outer diameter and 3.1 cm in inner diameter was used as a
permeation cell. A cellophane membrane soaked in distilled water (24 hours before
use) was fixed to the one end of the cylinder with aid of an adhesive. Gels equivalent
to 10 mg of Ketoconazole was taken in the cell (donor compartment) and the cell was
immersed in a beaker containing 100 ml of phosphate buffer of pH 7.4 (receptor
compartment). The whole assembly was fixed in such a way that the lower end of the
cell containing gel was just touched (1-2 mm deep) to the diffusion medium, the
medium in the compartment was agitated using a magnetic stirrer at the temperature
371C. Aliquots (5 ml) were withdrawn from the receptor compartment periodically
(0.5, 1.0, 2.0, 3.0, 4.0, 5.0 and 6 hours) and replaced with 5 ml of fresh buffer. After
suitable dilution, the sample was analyzed by using Shimadzu UV visible
spectrophotometer at 223 nm.
67
METHODOLOGY
4.4.9 IR Spectroscopy98:
FT-IR spectra of KCD3, and pure Ketoconazole were obtained by PerkinElmer FT-IR spectrophotometer using potassium bromide (KBr) pellets. KBr pellets
were prepared by gently mixing the sample with KBr (1:100). The sample was
scanned from 4,000 to 400 cm-1.
4.4.10 Skin irritation test106:
Gels should not produce skin irritation when applied topical drug delivery
system. Hence, skin irritation study was performed. The skin irritation test was
performed on healthy white rabbit of average weight 1.75 to 2.25 Kg. About 9 cm
area on the dorsal surface of the rabbits in each group was shaved and cleaned with
spirit.
Rabbits were divided into three groups (n=3) as follows:
Group-I (control): There was no application on the surface of the rabbit skin.
Group-II (negative control): An aqueous solution of 1 ml containing 0.8% formalin
soaked in 9 cm cotton wool (standard irritant) was placed in the back of the rabbit as
negative control. The cotton wool was secured firmly in the place with adhesive
plaster.
Group-III (test): 1 ml of gel containing 20 mg of Ketoconazole was applied to 9 cm
area on the dorsal surface of the rabbit. The visual inspection was observed for 3 days
to check any evidence of skin irritation (sign of edema and erythrema). The scoring
system of Draize et al was followed in grading the severity of the effect.
68
METHODOLOGY
4.4.11
In-Vitro Antifungal Activity107:
Preparation of the Ketoconazole reference substance:

Twenty-five milligrams of Ketoconazole reference substance was transferred
into a 25 ml volumetric flask, 1 ml HCl 1N, 1.25 gm gel base, 0.25 ml polysorbate 80
and 10 ml of methanol were added and shaken for 20 min, followed by sufficient
quantity of methanol. After filtration, the dilutions were made with phosphate buffer
pH 7.4 to achieve final concentration of 100 g/0.1 ml.
Preparation of the sample:
The sample (CS3K) was prepared by weighing 1.25 gm of gel (Ketoconazole
2%) into a 25 ml volumetric flask, 0.25 ml polysorbate 80 and 10 ml of methanol
were added and shaken for 20 minutes followed by sufficient quantity of methanol.
After filtration, the dilutions were made with phosphate buffer 1 N (1%), pH 7.4 to
achieve final concentration of 100 g/0.1 ml.
Sabourauds Dextrose Agar:
Composition:
Dextrose..................................................4%
Peptone ...................................................1%
Agar ........................................................2%
Chloramphenicol.............................50 mg/L
Amoxicillin ...................................500 mg/L
Distilled water.......................... up to 100 ml
This medium has acidic pH 5.6.
69
METHODOLOGY
Organism and inoculum:
The cultures of Candida albicans were cultivated on Sabourauds dextrose
agar maintained on slants in the refrigerator (42C).
Cup-plate method:
The composition of Sabourauds dextrose agar was taken in a 250 ml of
conical flask and was dissolved in 100 ml of distilled water. The pH was adjusted to
5.6. The medium was sterilized in an autoclave at 15 lbs for 20 minutes.
After the completion of sterilization, the medium was kept aside at room
temperature. 0.5 ml diluted suspension culture in NaCl 0.9% were added to 100 ml of
medium at 472C and used as inoculated layer.
The medium (20 ml) was poured into a sterilized petridish to give a depth of
3-4 mm, and was assured that the layer of medium is uniform in thickness by placing
petridish on a leveled surface.
After solidifying the medium at room temperature, with the help of a sterile
cork borer, cups of each 6 mm diameter were punched and scooped out from the
petridish. Using sterile pipettes sample solutions (0.1 ml) of known concentration
were fed into the cup. The petridish was then incubated for 24 hours at 37C. After
incubation the zone of inhibition was measured.
70
METHODOLOGY
4.4.12 Stability studies108:
Formulated gel preparations were kept at different temperature condition like
ambient temperature 53C (refrigerator temperature), 452C at 755C (condition
of accelerated stability testing) for span of three months. The following parameters of
the gel such as color, pH, viscosity, spreadability, extrudability, and drug content and
in-vitro drug release were studied.
4.7.13 Statistical Analysis of Data:
Statistics is rightly defined as logic, which makes use of mathematics in the
science of collecting, analyzing and interpreting data for the purpose of making
decisions.
Now, after many evaluations carried out on the various gel formulations, the
data obtained were further subjected to statistical analysis. A computer aided
calculations were done using a pre-programmed CD.
The statistical calculations apart from average or mean, standard deviation,
standard error from mean, also included coefficient of correlation, t test of
significance.
In case of different drug release profiles obtained, curve fitting and linear
correlations with respect to best curve were also done.
71
METHODOLOGY
Correlation:
Coefficient of correlation (r) was calculated using a pre-programmed
computer. Thet values fort test for significance were also calculated and fromt
tables. The probabilities (p) of significant departure from the expected values were
obtained.
Considering linear correlation y=bx+a, the b value (slope) and a value (yintercept) were obtained.
4.7.14 Model Fitting for Release of Ketoconazole:
The different drug release profile was analyzed using a preprogrammed
computer package. The best fit models for the following release profiles were
analyzed:
1. Zero order
2. First order
3. Higuchi
4. Peppas.
72
RESULTS
CHAPTER-5
RESULTS
5.1 Standardization of Ketoconazole:
Table-6: Standardization of Ketoconazole
Sl. No.
Characteristics
test (performed)
Standard as per the

manufacturer sheet
(Ketoconazole)
Observation
1.
Description
Almost white powder
Complies
2.
Melting range
149.1 150.20C
150C
3.
Loss on drying
0.35% NMT 0.57%
0.37%
4.
Identification
IR spectrum
IR spectrum positive
Identification:
Infrared Spectrum: This compound showed a significant peak at 1650 cm-1 as a C=O
of acetyl moiety present in the drug molecule.
73
RESULTS
5.2
Standard Calibration Curve of Ketoconazole:
a)
Standard Calibration Curve of Ketoconazole in pH 7.4 phosphate buffer

Solvent
pH 7.4 phosphate buffer
Wave length
223nm
Unit for concentration
mcg/ml
Table-7: Standard calibration data of Ketoconazole in pH

7.4 phosphate buffer
Sl No.
Concentration(mcg/ml)
Absorption (nm)
0.00
0.075
0.15
0.204
0.27
10
0.34
12
0.42
*Average of triplicates
Figure-3: Standard calibration curve of Ketoconazole in pH 7.4

phosphate buffer
0.45
R2 = 0.9981
A b s o rb a n c e ( n m )
0.4
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0
0
10
12
14
Concentration (mcg/ml)
74
RESULTS
b) Standard Calibration Curve of Ketoconazole in Methanol
Solvent
Methanol
Wave length
244nm
Unit for concentration
mcg/ml
Table-8: Standard calibration data of Ketoconazole in Methanol

Sl. No.
Concentration(mcg/ml)
Absorption (nm)
0.000
0.081
0.149
12
0.221
16
0.281
20
0.355
*Average of triplicates
Figure-4: Standard calibration curve of Ketoconazole in Methanol
0.4
Absorbance (nm)
0.35
R2 = 0.9986
0.3
0.25
0.2
0.15
0.1
0.05
0
0
10
15
20
25
Concentration (mcg/ml)
75
RESULTS
5.3
Physical Appearance of Ketoconazole solid dispersion:

Table-9: Physical parameters of Ketoconazole solid dispersion
Formulation
Code
Physical Appearance
Colour
Appearance
F1
White
Fine Powder
F2
White
Fine Powder
F3
White
Fine Powder
F4
White
Fine Powder
F5
White
Fine Powder
F6
White
Fine Powder
F7
White
Fine Powder
F8
White
Fine Powder
F9
White
Fine Powder
F10
White
Fine Powder
F11
White Creamy
Powder (Granular )
F12
White Creamy
Powder (Granular )
F13
White Creamy
Powder (Granular )
F14
White Creamy
Powder (Granular )
F15
White
Fine Powder
76
RESULTS
5.4
Drug content uniformity studies and percentage practical yield :
Table-10: Drug content uniformity studies and percentage practical yield of

Ketoconazole solid dispersion
Formulation
Code
Drug Content uniformity (%)
% Practical
Yield
1st
2nd
3rd
Mean SD
F1
93.6
92.89
94.01
93.500
94.75
F2
92.68
92.45
92.18
92.437
93.75
F3
91.76
91.45
91.18
91.463
92.55
F4
95.89
95.99
95.08
95.653
95.10
F5
96.8
97.08
96.58
96.820
95.75
F6
94.06
93.89
94.56
94.170
93.75
F7
93.15
93.87
93.21
93.410
93.10
F8
94.96
94.38
95.07
94.803
91.25
F9
96.34
97.04
96.21
96.530
94.05
F10
100.4
99.85
99.74
99.997
96.05
F11
91.3
91.83
91.27
91.467
89.25
F12
86.64
86.06
87.11
86.603
85.50
F13
92.2
93.01
92.11
92.440
92.10
F14
98.16
98.12
98.76
98.347
95.50
F15
99.54
99.31
99.04
99.297
94.75
77
RESULTS
5.5
Dissolution profile of Ketoconazole pure drug and solid dispersions:

Table-11: Dissolution profile of Ketoconazole pure drug
Time
(min)
Square
root of
time
Log time
Cum. %
drug
release
Cum. %
drug
remain
Log %
drug
release
Log %
drug
remain
0.000
0.000
0.00
100.00
0.000
2.000
20
4.472
1.301
15.28
84.72
1.184
1.928
40
6.325
1.602
28.79
71.21
1.459
1.853
60
7.746
1.778
36.70
63.30
1.565
1.801
80
8.944
1.903
40.61
59.39
1.609
1.774
100
10.000
2.000
45.24
54.76
1.656
1.738
120
10.954
2.079
47.46
52.54
1.676
1.720
*Average of three replicates
Cum ulative % drug released
Figure-5: Release profile of Ketoconazole pure drug
50
45
40
35
30
25
20
15
10
5
0
0
20
40
60
80
100
120
140
Time (min)
Pure drug
78
RESULTS
Table- 12: In-vitro Drug Release Profile of Ketoconazole Solid dispersion F1:
Time
(min)
Square
root of
time
Log
Time
Cum. % drug
release
Cum. %
drug
remain
Log %
drug
release
Log %
drug
remain
0.000
0.000
0.000
100.00
0.000
2.000
20
4.472
1.301
16.39 1.73
83.61
1.214
1.922
40
6.325
1.602
25.77 3.37
74.23
1.411
1.870
60
7.746
1.778
33.68 2.93
66.32
1.527
1.821
80
8.944
1.903
41.50 4.51
58.5
1.618
1.767
100
10.000
2.000
45.42 0.55
54.58
1.657
1.737
120
10.954
2.079
50.48 1.62
49.52
1.703
1.694
Time
(min)
Square
root of
time
Log
time
Cum. % drug
release
Cum. %
drug
remain
Log %
drug
release
Log %
drug
remain
0.000
0.000
0.000
100.00
0.000
2.000
20
4.472
1.301
16.30 2.24
83.7
1.212
1.922
40
6.325
1.602
27.33 5.47
72.67
1.436
1.870
60
7.746
1.778
37.77 1.46
62.23
1.577
1.821
80
8.944
1.903
47.28 6.16
52.72
1.674
1.767
100
10.000
2.000
50.93 7.36
49.07
1.706
1.737
120
10.954
2.079
56.35 3.88
43.65
1.750
1.694
79
RESULTS
Time
(min)
Square
root of
time
Log
time
Cum. % drug
release
Cum. %
drug
remain
Log %
drug
release
Log %
drug
remain
0.000
0.000
0.000
100.00
0.000
2.000
20
4.472
1.301
14.66 2.54
85.34
1.166
1.931
40
6.325
1.602
27.33 1.31
72.67
1.436
1.861
60
7.746
1.778
36.17 3.54
63.83
1.558
1.805
80
8.944
1.903
41.77 1.73
58.23
1.620
1.765
100
10.000
2.000
48.17 1.10
51.83
1.682
1.714
120
10.954
2.079
57.59 1.66
42.41
1.760
1.627
Cu m u lative % Dru g Released
Figure -6: Release profile of Ketoconazole from (F1, F2, and F3) solid dispersion:
70
60
50
40
30
20
10
0
0
20
40
60
80
100
120
140
Time(min)
F1
F2
F3
80
RESULTS
Time
(min)
Square
root of
time
Log
time
Cum. % drug
release
Cum. %
drug
remain
Log %
drug
release
Log %
drug
remain
0.000
0.000
0.000
100.00
0.000
2.000
20
4.472
1.301
17.19 2.79
82.81
1.235
1.918
40
6.325
1.602
29.73 8.86
70.27
1.473
1.846
60
7.746
1.778
39.90 3.17
60.10
1.600
1.778
80
8.944
1.903
48.35 8.41
51.65
1.684
1.713
100
10.000
2.000
52.26 6.01
47.74
1.718
1.678
120
10.954
2.079
56.97 2.56
43.03
1.755
1.633
Time
(min)
Square
root of
time
Log
time
Cum. % drug
release
Cum. %
drug
remain
Log %
drug
release
Log %
drug
remain
0.000
0.000
0.000
100.00
0.000
2.000
20
4.472
1.301
22.75 1.00
77.25
1.356
1.887
40
6.325
1.602
34.57 1.89
65.43
1.538
1.815
60
7.746
1.778
44.62 7.03
55.38
1.649
1.743
80
8.944
1.903
56.44 0.85
43.56
1.751
1.639
100
10.000
2.000
63.02 2.01
36.98
1.799
1.567
120
10.954
2.079
70.84 4.04
29.16
1.850
1.464
81
RESULTS
Time
(min)
Square
root of
time
Log
time
Cum. % drug
release
Cum. %
drug
remain
Log %
drug
release
Log %
drug
remain
0.000
0.000
0.000
100.00
0.000
2.000
20
4.472
1.301
50.57 10.02
49.43
1.703
1.693
40
6.325
1.602
60.35 5.07
39.65
1.780
1.598
60
7.746
1.778
70.66 9.37
29.34
1.849
1.467
80
8.944
1.903
85.50 2.59
14.5
1.931
1.161
100
10.000
2.000
93.06 1.74
6.94
1.968
0.841
120
10.954
2.079
--
--
--
--
Cum ultive % Drug released
100
90
80
70
60
50
40
30
20
10
0
0
20
40
60
80
100
120
140
Time(min)
F4
F5
F6
82
RESULTS
Time
(min)
Square
root of
time
Log
time
Cum. % drug
release
Cum. %
drug
remain
Log %
drug
release
Log %
drug
remain
0.000
0.000
0.000
100.00
0.000
2.000
20
4.472
1.301
48.88 3.02
51.12
1.689
1.708
40
6.325
1.602
58.66 2.11
41.34
1.768
1.616
60
7.746
1.778
68.62 1.46
31.38
1.836
1.496
80
8.944
1.903
91.19 2.70
8.81
1.959
0.944
100
10.000
2.000
95.64 1.60
4.36
1.980
0.639
120
10.954
2.079
--
--
--
--
Time
(min)
Square
root of
time
Log
time
Cum. % drug
release
Cum. %
drug
remain
Log %
drug
release
Log %
drug
remain
0.000
0.000
0.000
100.00
0.000
2.000
20
4.472
1.301
54.48 2.85
45.52
1.736
1.658
40
6.325
1.602
65.24 4.08
34.76
1.814
1.541
60
7.746
1.778
70.57 5.46
29.43
1.848
1.468
80
8.944
1.903
92.86 2.06
7.14
1.967
0.853
100
10.000
2.000
96.35 2.26
3.65
1.983
0.562
120
10.954
2.079
--
--
--
--
83
RESULTS
Time
(min)
Square
root of
time
Log
time
Cum. % drug
release
Cum. %
drug
remain
Log %
drug
release
Log %
drug
remain
0.000
0.000
0.000
100.00
0.000
2.000
20
4.472
1.301
55.10 2.03
44.9
1.741
1.652
40
6.325
1.602
62.30 3.77
37.7
1.794
1.576
60
7.746
1.778
74.13 0.70
25.87
1.869
1.412
80
8.944
1.903
88.17 4.80
11.83
1.945
1.072
100
10.000
2.000
90.04 2.07
9.96
1.954
0.998
120
10.954
2.079
--
--
--
--
Cum ulative % drug released
120
100
80
60
40
20
0
0
20
40
60
80
100
120
140
Time(min)
F7
F8
F9
84
RESULTS
Time
(min)
Square
root of
time
Log
time
Cum. % drug
release
Cum. %
drug
remain
Log %
drug
release
Log %
drug
remain
0.000
0.000
0.000
100.0
0.000
2.000
20
4.472
1.301
57.33 3.27
42.67
1.758
1.630
40
6.325
1.602
68.26 3.98
31.74
1.834
1.501
60
7.746
1.778
77.68 7.80
22.32
1.890
1.348
80
8.944
1.903
98.48 0.15
1.52
1.993
0.181
100
10.000
2.000
--
--
--
--
120
10.954
2.079
--
--
--
--
Time
(min)
Square
root of
time
Log
time
Cum. % drug
release
Cum. %
drug
remain
Log %
drug
release
Log %
drug
remain
0.000
0.000
0.000
100.0
0.000
2.000
20
4.472
1.301
50.13 3.24
49.87
1.700
1.697
40
6.325
1.602
65.68 1.51
34.32
1.817
1.535
60
7.746
1.778
71.28 5.47
28.72
1.852
1.458
80
8.944
1.903
84.97 4.56
15.03
1.929
1.176
100
10.000
2.000
93.33 1.66
6.67
1.970
0.824
120
10.954
2.079
--
--
--
--
85
RESULTS
Time
(min)
Square
root of
time
Log
time
Cum. % drug
release
Cum. %
drug
remain
Log %
drug
release
Log %
drug
remain
0.000
0.000
0.000
100.0
0.000
2.000
20
4.472
1.301
48.79 9.61
51.21
1.688
1.709
40
6.325
1.602
60.52 4.40
39.48
1.781
1.596
60
7.746
1.778
67.55 9.06
32.45
1.829
1.511
80
8.944
1.903
87.64 1.20
12.36
1.942
1.092
100
10.000
2.000
94.84 2.53
5.16
1.976
0.712
120
10.954
2.079
--
--
--
--
Cu m u lative % Dru d released
Figure -9: Release profile of Ketoconazole from (F10, F11, F12) solid dispersion:
120
100
80
60
40
20
0
0
20
40
60
80
100
120
140
Time(min)
F10
F11
F12
86
RESULTS
Time
(min)
Square
root of
time
Log
time
Cum. % drug
release
Cum. %
drug
remain
Log %
drug
release
Log %
drug
remain
0.000
0.000
0.000
100.00
0.000
2.000
20
4.472
1.301
52.53 4.28
47.47
1.720
1.676
40
6.325
1.602
59.81 3.25
40.19
1.776
1.604
60
7.746
1.778
68.17 6.09
31.83
1.833
1.502
80
8.944
1.903
89.86 4.89
10.14
1.953
1.006
100
10.000
2.000
95.99 2.93
4.01
1.982
0.603
120
10.954
2.079
--
--
--
--
Time
(min)
Square
root of
time
Log
time
Cum. % drug
release
Cum. %
drug
remain
Log %
drug
release
Log %
drug
remain
0.000
0.000
0.000
100.00
0.000
2.000
20
4.472
1.301
54.3 8.27
45.70
1.734
1.659
40
6.325
1.602
63.46 4.23
36.54
1.802
1.562
60
7.746
1.778
72.7 3.90
27.30
1.861
1.436
80
8.944
1.903
87.82 6.65
12.18
1.943
1.085
100
10.000
2.000
99.19 0.53
0.81
1.996
0.091
120
10.954
2.079
--
--
--
--
87
RESULTS
Time
(min)
Square
root of
time
Log
time
Cum. % drug
release
Cum. %
drug
remain
Log %
drug
release
Log %
drug
remain
0.000
0.000
0.000
100.00
0.000
2.000
20
4.472
1.301
56.26 2.01
43.74
1.750
1.640
40
6.325
1.602
66.57 0.81
33.43
1.823
1.524
60
7.746
1.778
76.08 5.07
23.92
1.881
1.378
80
8.944
1.903
90.13 6.28
9.87
1.954
0.994
100
10.000
2.000
98.93 0.70
1.07
1.995
0.029
120
10.954
2.079
--
--
--
--
C u m u la ti v e % D ru g re le a s e d
Figure-10: Release profile of Ketoconazole from (F13, F14, F15) solid dispersion:
120
100
80
60
40
20
0
0
20
40
60
80
100
120
140
Time(min)
13
14
15
88
RESULTS
5.6
FTIR Studies:
Figure -11: IR Spectra of A = Ketoconazole, B = -cyclodextrin,
C = Formulation F10 and D = Formulation KCD3
%T
cm-1
89
RESULTS
5.7
DSC Studies:
Figure - 12: Differential Scanning of Calorimetric thermogram of A =
Ketoconazole, B = -cyclodextrin and C = Formulation F10
90
RESULTS
5.8:
EVALUATION OF SOLID DISPERSION INCORPORATED IN

KETOCONAZOLE GEL FORMULATIONS:
TABLE- 27: Physical Parameters and Drug Content of Formulations

Sl No.
Formulation
Code
Physical
Appearance
Homogeneity
pH
% Drug content
(mean SD)
Carbopol 940
gel
White
Translucent
++
6.67
98.75 0.15
HPMC gel
White
Translucent
++
6.50
97.25 0.34
MC gel
White
Translucent
++
6.64
96.78 0.49
NaCMC gel
++
7.28
95.36 0.29
KCS1
++
7.63
98.64 0.68
KCS2
White
Translucent
++
7.66
96.43 0.89
KCS3
White
Translucent
++
6.33
97.36 0.72
KCS4
White
Translucent
++
6.54
98.95 0.62
KCD1
White
Translucent
++
6.70
94.32 0.35
10
KCD2
++
7.30
97.35 0.89
11
KCD3
++
6.91
98.89 0.10
12
KCD4
++
7.59
95.33 0.69
13
PD
White
Translucent
++
7.15
94.45 0.72
14
MP
White
Translucent
++
6.71
99.03 0.31
White opaque
White opaque
White opaque
White opaque
White opaque
++ Good
91
RESULTS
5.9
Rheological Properties of the Formulations:

Table-28: Rheological Properties of the Formulations
Sl. No.
Formulation Code
Viscosity (cps)
Spreadability
(gm-cm/sec)
Extrudability
Carbopol 940 gel
2450
13.60
++
HPMC gel
7630
14.75
++
MC gel
5450
15.25
++
NaCMC gel
9010
16.15
++
KCS1
5970
14.85
++
KCS2
7455
15.90
++
KCS3
9750
16.10
++
KCS4
8410
14.90
++
KCD1
3540
15.30
++
10
KCD2
7104
14.40
++
11
KCD3
9775
13.70
++
12
KCD4
8120
11.30
++
92
RESULTS
5.9
In-vitro Release study of Ketoconazole from gel:
Table-29: In-vitro %drug release study of Ketoconazole from Carbopol 940 gel
Time(hrs)
Square
root of
time
Log time
0.0000
0.0000
0.5
0.7071
Cum %
drug
release
Amount of
% Drug
remaining
Log %
drug
release
Log %
drug
remain
0.00
100.00
0.0000
2.0000
0.3010
25.18
74.82
1.4011
1.8740
1.0000
0.0000
33.57
66.43
1.5260
1.8224
1.4142
0.3010
39.79
60.21
1.5998
1.7797
1.7321
0.4771
49.77
50.23
1.6970
1.7010
2.0000
0.6021
54.12
45.88
1.7334
1.6616
2.2361
0.6990
63.50
36.50
1.8028
1.5623
2.4495
0.7782
69.82
30.18
1.8440
1.4797

Table- 30: In-vitro %drug release study of Ketoconazole from HPMC gel
Time(hrs)
Square
root of
time
Log time
0.0000
0.0000
0.5
0.7071
Cum %
drug
release
Amount of
% Drug
remaining
Log %
drug
release
Log %
drug
remain
0.00
100.00
0.0000
2.0000
-0.3010
22.02
77.98
1.3428
1.8920
1.0000
0.0000
28.04
71.96
1.4478
1.8571
1.4142
0.3010
37.62
62.38
1.5754
1.7950
1.7321
0.4771
39.99
60.01
1.6020
1.7782
2.0000
0.6021
46.51
53.49
1.6675
1.7283
2.2361
0.6990
57.15
42.85
1.7570
1.6320
2.4495
0.7782
67.15
32.85
1.8270
1.5165
93
RESULTS
Table-31:In-vitro %drug release study of Ketoconazole from Methyl cellulose gel
Amount
of %
Drug
remaining
Log %
drug
release
Log %
drug
remain
0.00
100.00
0.0000
2.0000
-0.3010
16.49
83.51
1.2172
1.9217
1.0000
0.0000
21.52
78.48
1.3328
1.8948
1.4142
0.3010
30.21
69.79
1.4802
1.8438
1.7321
0.4771
34.15
65.85
1.5334
1.8186
2.0000
0.6021
45.62
54.38
1.6592
1.7354
2.2361
0.6990
52.73
47.27
1.7221
1.6746
2.4495
0.7782
61.32
38.68
1.7876
1.5875
Time(hrs)
Square
root of
time
Log time
0.0000
0.0000
0.5
0.7071
Cum %
drug
release

Table- 32: In-vitro %drug release study of Ketoconazole from NaCMC gel
Cum %
Log time drug
release
Amount
of %
Drug
remaining
Log %
drug
release
Log %
drug
remain
Time(hrs)
Square
root of
time
0.0000
0.0000
0.00
100.00
0.0000
2.0000
0.5
0.7071
-0.3010
19.94
80.06
1.2997
1.9034
1.0000
0.0000
27.55
72.45
1.4401
1.8600
1.4142
0.3010
31.70
68.30
1.5011
1.8344
1.7321
0.4771
39.70
60.30
1.5988
1.7803
2.0000
0.6021
47.00
53.00
1.6721
1.7243
2.2361
0.6990
54.71
45.29
1.7381
1.6560
2.4495
0.7782
62.22
37.78
1.7939
1.5773
94
RESULTS
Figure-13: Cumulative percent drug release of Ketoconazole from Carbopol 940,
HPMC, MC, and NaCMC Gel
Cumulative percent drug released
80
70
60
50
40
30
20
10
0
0
Time (hr)
Carbopol 940
HPMC
MC
NaCMC
Figure-14: First order plot of Ketoconazole from Carbopol 940, HPMC, MC,
and NaCMC Gel
Log percent drug remaining
2.50
2.00
1.50
1.00
0.50
0.00
0
Time (hr)
carbopol 940
HPMC
MC
NaCMC
95
RESULTS
Figure-15: Higuchi diffusion plot of Ketoconazole from Carbopol 940, HPMC,
MC, and NaCMC Gel
80
70
60
50
40
30
20
10
0
0
0.5
1.5
2.5
Square root of time
Carbopol 940
HPMC
MC
NaCMC
Figure-16: Peppas exponential plot of Ketoconazole from Carbopol 940, HPMC,

MC, and NaCMC Gel
Log percent drug released
2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
0
0.2
0.4
0.6
0.8
Log Time
Carbopol 940
HPMC
MC
NaCMC
96
RESULTS
Table- 33: In-vitro %drug release study of Ketoconazole from KCS1 gel
Time(hrs)
Square
root of
time
Log time
0.0000
0.0000
0.5
0.7071
Cum %
drug
release
Amount of
% Drug
remaining
Log %
drug
release
Log %
drug
remain
0.00
100.00
0.0000
2.0000
-0.3010
39.30
60.70
1.5944
1.7832
1.0000
0.0000
45.32
54.68
1.6563
1.7378
1.4142
0.3010
57.18
42.82
1.7572
1.6316
1.7321
0.4771
68.43
31.57
1.8352
1.4993
2.0000
0.6021
74.36
25.64
1.8713
1.4089
2.2361
0.6990
83.64
16.36
1.9224
1.2138
2.4495
0.7782
87.89
12.11
1.9439
1.0831

Time(hrs)
Square
root of
time
Log time
0.0000
0.0000
0.5
0.7071
Cum %
drug
release
Amount of
% Drug
remaining
Log %
drug
release
Log %
drug
remain
0.00
100.00
0.0000
2.0000
0.3010
40.29
59.71
1.6052
1.7760
1.0000
0.0000
48.78
51.22
1.6882
1.7094
1.4142
0.3010
56.48
43.52
1.7519
1.6387
1.7321
0.4771
67.65
32.35
1.8303
1.5099
2.0000
0.6021
76.15
23.85
1.8817
1.3775
2.2361
0.6990
87.69
12.31
1.9430
1.0903
2.4495
0.7782
90.26
9.74
1.9555
0.9886
97
RESULTS
Cum %
Log time drug
release
Amount
of %
Drug
remaining
Log %
drug
release
Log %
drug
remain
Time(hrs)
Square
root of
time
0.0000
0.0000
0.00
100.00
0.0000
2.0000
0.5
0.7071
-0.3010
43.55
56.45
1.6390
1.7517
1.0000
0.0000
49.87
50.13
1.6978
1.7001
1.4142
0.3010
55.70
44.30
1.7459
1.6464
1.7321
0.4771
66.86
33.14
1.8252
1.5204
2.0000
0.6021
76.14
23.86
1.8816
1.3777
2.2361
0.6990
83.75
16.25
1.9230
1.2109
2.4495
0.7782
94.99
5.01
1.9777
0.6998

Cum %
Log time drug
release
Amount
of %
Drug
remaining
Log %
drug
release
Log %
drug
remain
Time(hrs)
Square
root of
time
0.0000
0.0000
0.00
100.00
0.0000
2.0000
0.5
0.7071
-0.3010
44.34
55.66
1.6468
1.7455
1.0000
0.0000
53.03
46.97
1.7245
1.6718
1.4142
0.3010
61.03
38.97
1.7855
1.5907
1.7321
0.4771
70.71
29.29
1.8495
1.4667
2.0000
0.6021
78.81
21.19
1.8965
1.3261
2.2361
0.6990
88.68
11.32
1.9478
1.0538
2.4495
0.7782
92.44
7.56
1.9659
0.8785
98
RESULTS
Figure- 17: Cumulative percent drug release of Ketoconazole from KCS1, KCS2,
KCS3, and KCS4 Gel
100.00
90.00
80.00
70.00
60.00
50.00
40.00
30.00
20.00
10.00
0.00
0
Time (hr)
KCS1
KCS2
KCS3
KCS4
Figure- 18: First order plot of Ketoconazole from KCS1, KCS2, KCS3, and
KCS4 Gel
2.5
2
1.5
1
0.5
0
0
Time (hr)
KCS1
KCS2
KCS3
KCS4
99
RESULTS
Figure- 19: Higuchi diffusion plot of Ketoconazole from KCS1, KCS2, KCS3,
and KCS4 Gel
Cum ulative percent drug released
100
90
80
70
60
50
40
30
20
10
0
0
0.5
1.5
2.5
Square root of time
KCS1
KCS2
KCS3
KCS4
Figure- 20: Peppas exponential plot of Ketoconazole from KCS1, KCS2, KCS3,
and KCS4 Gel
2
1.95
1.9
1.85
1.8
1.75
1.7
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Log time
KCS1
KCS2
KCS3
KCS4
100
RESULTS
Table- 37: In-vitro %drug release study of Ketoconazole from KCD1 gel
Time(hrs)
Square
root of
time
Log time
0.0000
0.0000
0.5
0.7071
Cum %
drug
release
Amount of
% Drug
remaining
Log %
drug
release
Log %
drug
remain
0.00
100.00
0.0000
2.0000
-0.3010
33.08
66.92
1.5196
1.8256
1.0000
0.0000
44.24
55.76
1.6458
1.7463
1.4142
0.3010
52.63
47.37
1.7212
1.6755
1.7321
0.4771
68.54
31.46
1.8359
1.4978
2.0000
0.6021
73.67
26.33
1.8673
1.4205
2.2361
0.6990
83.35
16.65
1.9209
1.2214
2.4495
0.7782
92.63
7.37
1.9668
0.8675

Time(hrs)
Square
root of
time
Log time
0.0000
0.0000
0.5
0.7071
Cum %
drug
release
Amount of
% Drug
remaining
Log %
drug
release
Log %
drug
remain
0.00
100.00
0.0000
2.0000
-0.3010
32.58
67.42
1.5130
1.8288
1.0000
0.0000
38.41
61.59
1.5844
1.7895
1.4142
0.3010
51.65
48.35
1.7131
1.6844
1.7321
0.4771
71.20
28.80
1.8525
1.4594
2.0000
0.6021
80.49
19.51
1.9057
1.2903
2.2361
0.6990
88.88
11.12
1.9488
1.0461
2.4495
0.7782
95.40
4.60
1.9795
0.6628
101
RESULTS
Time(hrs)
Square
root of
time
Log time
0.0000
0.0000
0.5
0.7071
Cum %
drug
release
Amount of
% Drug
remaining
Log %
drug
release
Log %
drug
remain
0.00
100.00
0.0000
2.0000
-0.3010
40.09
59.91
1.6030
1.7775
1.0000
0.0000
47.50
52.50
1.6767
1.7202
1.4142
0.3010
59.74
40.26
1.7763
1.6049
1.7321
0.4771
73.08
26.92
1.8638
1.4301
2.0000
0.6021
80.09
19.91
1.9036
1.2991
2.2361
0.6990
90.76
9.24
1.9579
0.9657
2.4495
0.7782
98.07
1.93
1.9915
0.2856

Table-40: In-vitro %drug release study of Ketoconazole from KCD4 gel
Time(hrs)
Square
root of
time
Log time
0.0000
0.0000
0.5
0.7071
Cum %
drug
release
Amount of
% Drug
remaining
Log %
drug
release
Log %
drug
remain
0.00
100.00
0.0000
2.0000
-0.3010
30.71
69.29
1.4873
1.8407
1.0000
0.0000
44.14
55.86
1.6448
1.7471
1.4142
0.3010
49.77
50.23
1.6970
1.7010
1.7321
0.4771
70.02
29.98
1.8452
1.4768
2.0000
0.6021
82.95
17.05
1.9188
1.2317
2.2361
0.6990
88.29
11.71
1.9459
1.0686
2.4495
0.7782
95.60
4.40
1.9805
0.6435
102
RESULTS
Figure- 21: Cumulative percent drug release of Ketoconazole from KCD1,
KCD2, KCD3, and KCD4 Gel
120
100
80
60
40
20
0
0
Time (hr)
KCD1
KCD2
KCD3
KCD4
Figure- 22: First order plot of Ketoconazole from KCD1, KCD2, KCD3, and
KCD4 Gel
2.5
2
1.5
1
0.5
0
0
Time (hr)
KCD1
KCD2
KCD3
KCD4
103
RESULTS
Figure- 23: Higuchi diffusion plot of Ketoconazole from KCD1, KCD2, KCD3,
cum ulative percent drug

released
and KCD4 Gel

120
100
80
60
40
20
0
0
0.5
1.5
2.5
Square root of time

KCD1
KCD2
KCD3
KCD4
Figure- 24: Peppas exponential plot of Ketoconazole from KCD1, KCD2, KCD3,
L o g p e rc e n t d ru g re le a s e d
and KCD4 Gel
2.05
2
1.95
1.9
1.85
1.8
1.75
1.7
1.65
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Log time
KCD1
KCD2
KCD3
KCD4
104
RESULTS
Table- 41: In-vitro %drug release study of Ketoconazole from PD gel
Time(hrs)
Square
root of
time
Log time
0.0000
0.0000
0.5
0.7071
Cum %
drug
release
Amount
of % Drug
remaining
Log %
drug
release
Log %
drug
remain
0.000
100.00
0.000
2.000
-0.3010
3.20
96.80
0.5051
1.9859
1.0000
0.0000
5.34
94.66
0.7275
1.9762
1.4142
0.3010
8.00
92.00
0.9031
1.9638
1.7321
0.4771
9.54
90.46
0.9795
1.9565
2.0000
0.6021
12.00
88.00
1.0792
1.9445
2.2361
0.6990
14.24
85.76
1.1535
1.9333
2.4495
0.7782
16.49
83.51
1.2172
1.9217
Table- 42: In-vitro %drug release study of Ketoconazole from MP gel
Time(hrs)
Square
root of
time
Log time
0.0000
0.0000
0.5
0.7071
Cum %
drug
release
Amount
of % Drug
remaining
Log %
drug
release
Log %
drug
remain
0.00
100.00
0.000
2.0000
-0.3010
3.97
96.03
0.5988
1.9824
1.0000
0.0000
8.29
91.71
0.9186
1.9624
1.4142
0.3010
11.00
89.00
1.0414
1.9494
1.7321
0.4771
16.40
83.60
1.2148
1.9222
2.0000
0.6021
18.60
81.40
1.2695
1.9106
2.2361
0.6990
22.50
77.50
1.3522
1.8893
2.4495
0.7782
25.30
74.70
1.4031
1.8733
105
RESULTS
Figure- 25: Cumulative percent drug release of Ketoconazole from formulation
KCD3, Pure drug, and Marketed preparation (MP)
120
100
80
60
40
20
0
0
Time (hr)
KCD3
PD
MP
Figure-26: First order plot of Ketoconazole from formulation KCD3, Pure Drug,
and Marketed preparation (MP)
L o g p ercen t d ru g rem ain in g
2.5
2
1.5
1
0.5
0
0
Time (hr)
KCD3
PD
MP
106
RESULTS
Figure- 27: Higuchi diffusion plot of Ketoconazole from formulation KCD3,
Pure Drug, and Marketed preparation (MP)
120
100
80
60
40
20
0
0
0.5
1.5
2.5
Square root of time

KCD3
PD
MP
Figure- 28: Peppas exponential plot of Ketoconazole from formulation KCD3,

Pure Drug, and Marketed preparation (MP)
2.5
1.5
0.5
0
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Log time
KCD3
PD
MP
Table-43: Statistical analysis data of prepared different Ketoconazole gel
107
RESULTS
Formulation:
Zero order
First order
Formulation
Code
Carbopol
0.9423
9.7226
0.9824 0.0760 0.9940 26.9232 0.9921 0.3963
HPMC
0.9544
9.1673
0.9740 0.0675 0.9869 24.8863 0.9803 0.4196
MC
0.9789
9.0369
0.9893 0.0618 0.9893 23.9767 0.9872 0.5205
NaCMC
0.9609
8.8086
0.9846 0.0617 0.9030 23.8962 0.9853 0.4377
KCS 1
0.9123
1.0046
0.9884 0.1380 0.9874 34.1052 0.9935 0.3362
KCS 2
0.9147 12.3571 0.9841 0.1552 0.9857 34.9566 0.9880 0.3309
KCS 3
0.9123 12.2932 0.9513 0.1735 0.9797 34.6565 0.9714 0.3054
KCS 4
0.8945 12.2017 0.9834 0.1662 0.9783 35.0317 0.9905 0.2970
KCD 1
0.9410 12.9821 0.9870 0.1624 0.9950 36.0345 0.9938 0.4049
KCD 2
0.9561 14.2774 0.9843 0.2029 0.9966 39.0668 0.9887 0.4617
KCD 3
0.9301 13.5580 0.9499 0.2372 0.9925 37.9821 0.9931 0.3662
KCD 4
0.9517 14.2138 0.9819 0.2043 0.9946 38.9960 0.9876 0.4593
Higuchi
r
6.6764
Peppas
r
PD
0.9866
2.5329
0.9899 0.0121 0.9906
MP
0.9865
4.0378
0.9917 0.0203 0.9982 10.6175 0.9925 0.7150
0.9976 0.6361
108
RESULTS
5.9
Stability Studies:
Table- 44: Stability studies of Selected Formulation at Temperature
302C and Relative Humidity (RH) 655%
KCD3
Time
(month)
Drug
Content
(%)
In vitro
diffusion
study(%)
6 hrs
Viscosity
(cps)
pH
Spreadability
(gmc/s)
Extrudability
98.89
98.07
9775
6.9
13.70
++
97.50
97.50
9510
6.7
13.90
++
95.89
95.10
8990
6.5
14.10
++
++ Good
Table-45: Stability studies of Selected Formulation at Temperature 53C

KCD3
Time
(month)
Drug
Content
(%)
In vitro
diffusion
study(%)
6 hrs
Viscosity
(cps)
pH
Spreadability
(gmc/s)
Extrudability
98.89
98.07
9775
6.9
13.70
++
97.10
97.35
9510
6.6
13.90
++
95.45
95.62
9135
6.5
14.10
++
++ Good
109
RESULTS
5.10
Skin Irritation:
Best formulation (KCD3) was subjected to skin irritation test and sowed no
edema, erythema and redness after 3 days.

Table- 46: Dermal response of skin irritation studies conducted on rabbit skin
with the prepared Ketoconazole gel (KCD3)
Scores gained by rabbits during 72 hours study
Formulation
number
24 hrs
48 hrs
72 hrs
KCD3
Dermal Response:
0
No evidence of irritation
Minimal erythema, barely perceptible
Definite erythema, readily visible minimum edema or minimal popular

response
Erythema and papules
Definite edema
Erythema, edema and papules
Vesicular eruption
Strong reaction spreading beyond test site
Other Effects
A
Slight glazed appearance
Marked glazing
Glazing with peeling and cracking
Glazing with fissures
Film of dried serous exudates covering all or part of the gels applied
Small petechial erosions and/ or scrabs.
110
RESULTS
Figure- 29: Rabbit when applied with Ketoconazole gel (KCD3)
Figure-30: Rabbit skin - on application of prepared gel (CS3K)
After 24 hrs
after 48 hrs
After 72 hrs
111
RESULTS
5.11
Antifungal Activity:
Comparative antifungal activity of selected KCD3 with reference and
marketed formulation.
Figure- 31: Comparative antifungal activity of Ketoconazole (KCD3) with

reference and marketed formulation.
F
Test formulation (KCD3)
M2
Marketed formulation
Reference
112
DISCUSSION
CHAPTER-6
DISCUSSION
In the present investigation, an attempt were made to improve the solubility

and dissolution rate of a poorly soluble drug, Ketoconazole by solid dispersion
method using mannitol, polyethylene glycol (PEG) 4000 and polyethylene glycol
6000, polyvinylpyrrolidone K30, -cyclodextrin as carrier. Solid dispersion of
Ketoconazole was prepared by fusion, solvent evaporation method, melt solvent and
kneading method. The prepared solid dispersion were evaluated for number of
parameters like DSC, FTIR, percent practical yield, drug content uniformity studies,
and In- vitro drug release studies etc.
With the advent of medicated topical applications for transdermal drug
delivery, the skin is now viewed as a potential portal of entry. Topical application of
the drug at the affected site offers potential advantages of delivering the drug directly
to the site of action. Topical fungal infection can best be treated by application of gels
over the skin surface, from which the drug released continuously to the desired site.
Differential Scanning Calorimetry (DSC) Studies:
The drug Ketoconazole subjected for DSC study, it started melting of 148.4C
and completed at 151.9C, suggesting that these narrow rang of melting is due to the
present of single compound in the pure form.
The carbohydrate polymer -cyclodextrin is taken for DSC measurement this
polymer has given rang to wide rang to melting process started at 111C to 134C.
This is the characteristics behavior of the carbohydrates.
113
DISCUSSION
When the formulation obtained by the drug and -cyclodextrin for DSC study
two melting ranges are obtained in one peak, melting process started at 89.4C and
reach the peak at 116.0C in an another peak process started at 147.75C reach the
peak at 151C, suggesting that, when these two molecules (Drug and -cyclodextrin)
used for the formulation product obtained is nothing but a physical mixture of the
two.
Infrared (IR) Spectral analysis studies:
The drug Ketoconazole was taken for the study which exhibited characteristics
peaks at 3310 and 3410 cm-1 may be due to the molecular water present is determined.
The C O of the amine absorption is notice in 1650 cm-1. In line with the structure of
the molecule taken for the study.
The polymer taken in this study is -cyclodextrin which contains number of
secondary hydroxyl group and primary OH group. These two functionalities present
in the molecules have shown a broad peak around 3400cm-1 corresponding to primary
and secondary OH groups. CH absorption is notice at 2873 and 2895 cm-1. Strong
absorption peak is also notice at 1695 cm-1. These data are in conformity with
structure of the -cyclodextrin.
When these two constituents, Drug and polymer -cyclodextrin used for the
required formulation. The IR spectrum of which has shown the presence of all the
functionalities present in the drug as well as -cyclodextrin suggests these during the
preparation of formulation chemical reaction between two has not taken place. The
formulated product is just take physical mixture none of the functional groups
114
DISCUSSION
absorption is not affected. The formulation done by taking drug and the polymer in
1:1 ratio.
The formulation carried out as reported earlier is taken along with gel carbopol
to get the formulation in the gel form, In the IR spectrum of this gel a very broad band
is obtained 3400 cm-1 corresponding to OH functionalities present in the
constituents a similar band is observed 2950 cm-1 for the C H absorption present in
all the constituents molecule at 1675 cm-1 a broad band is notice corresponding to
CO absorption, these observation suggest that even during gel formulation also the
chemical reaction has not taken place.
Hence this formulated gel is a physical mixture of all the three constituents but
not the reaction product of any constituents.
Percent Practical yield:
Solid dispersions of Ketoconazole were prepared by different method using
carriers like mannitol, PEG-4000, PEG-6000, PVP-K30, and -cyclodextrin. In the
present work, total 15 formulations were prepared and their complete composition is
shown in Table 3. All the Solid dispersions prepared were found to be fine and free
flowing powders. The results of percent practical yield studies are shown in Table-10.
The % Practical yield of the prepared solid dispersions was found to be in the range of
85.50 96.05. The maximum yield was found to be 96.05% in F10.
Drug Content Uniformity Studies:
The actual drug content of all the 15 formulations is shown in Table-10. The
drug content of the prepared Solid dispersions was found to be in the range of 86.60
115
DISCUSSION
99.99% indicating the application of the present methods for the preparation of Solid
dispersions with high content uniformity. The maximum % drug content was found to
be 99.99% in F10.
In Vitro Dissolution study:
Drug release from solid dispersions and physical mixture was faster than pure
drug, Figure 5-10 are shows the plot of cumulative percent released as a function of
time for different formulations. Cumulative percent drug released after 80 minutes
were 41.50, 47.28, 41.77, 48.35, 56.44, 85.50, 91.19, 92.86, 88.17, 98.48, 84.97,
87.64, 89.86, 87.82, and 90.13 for F1 to F15, respectively, while it was 40.61% in 80
minutes for pure drug Ketoconazole.
In vitro release study revealed that there was a marked increase in the
dissolution rate of Ketoconazole from all solid dispersions when compared to pure
Ketoconazole itself. From the in-vitro drug release profile, it can be seen that
formulation F-10 containing -cyclodextrin (1:1 ratio of drug: -cyclodextrin) show
higher dissolution rate compared with other formulations. The increase in dissolution
rate was in the order of -cyclodextrin > PEG 6000 > PEG 4000 > Mannitol >
PVP K30.
Drug applied externally to the affected site provides great advantage of
delivering drug directly to the site of action. Local infection can be treated by
application of products, where there is a continuous of drugs.
Here the preparation and evaluation of Ketoconazole solid dispersion were
done and the best solid dispersion i.e. F10, 1:1 ratio, Ketoconazole: -cyclodextrin, by
116
DISCUSSION
solvent evaporation method were chosen and incorporated into gels by using
Carbopol 940, HPMC, Methyl cellulose and NaCMC as gelling agents.
In-vitro diffusion profile of Ketoconazole from gels containing different
polymer like Carbopol 940, HPMC, Methyl cellulose and NaCMC are 69.82, 67.15,
61.32 And 62.22% respectively drug release in 6 hrs. (Shown in Figure-13) Carbopol
940 shown higher release as compared to HMPC, Methyl cellulose and NaCMC.
Here the preparation and evaluation of Ketoconazole solid dispersion
incorporated gels were done and the best drug release was Carbopol 940. Carbopol
940 was chosen study for effect of different permeation enhancers viz. SLS and
DMSO, are shown in Table 5. From the result, it is clearly evident that all the gel
formulations showed good extrudability, homogeneity, and spreadability. The drug
content was in the range of 94.32% to 99.03%.
The formulations viscosity ranged from 2450 to 9775 cps, and pH of all the
formulations was between pH 6 and pH 7.6. This lies in the normal pH range of the
skin, and does not produce any erythema and edema on application to the skin and did
not produce any skin irritation. Fig. 17 and Fig. 21 depicts the in vitro diffusion
profile of Ketoconazole from gels containing carbopol 940 and different
concentrations of permeation enhancers
sodium lauryl sulphate (0.5-1.0%) and
dimethyl sulfoxide (5-20%) Sodium lauryl sulphate was maximum (94.99%) over a
period of 6 hrs. at 0.75% concentration level. Further in SLS concentration to 1%
level showed decrease in drug release. In fact, the release was found to be slightly
decreased. The incorporation of SLS in higher concentration showed the problem of
frothing. Figure 21 depicts that 15% level of Dimethyl sulfoxide released a maximum
117
DISCUSSION
of 98.07% of Ketoconazole with a period of 6 hrs. Further increase in DMSO
concentration to 20% level showed no further increase in drug release.
Amongst the all formulations the highest release of Ketoconazole was given
by KCD3 i.e. 98.07%.
The pure drug and marketed preparation showed a cumulative percent release
of 16.49 and 25.30% respectively.
The in-vitro drug release data were treated to Zero, First order, Higuchi and
Peppas plot.
Plots were found to be fairly linear indicating the drug release, follows first
order kinetics with diffusion controlled.
IR spectrum of the formulation KCD3 exhibited the identical peaks in
comparison of the IR of the previous compound supporting our conclusion that no
chemical reactions have taken place.
In all above formulations, the drug Ketoconazole is in the free state and
available for absorption.
Spreadability:
Spreadability plays an important role in patient compliance and help in uniform
application of gel to the skin. Gels should spread easily. All the formulations were
found to have better spreadability.
118
DISCUSSION
Skin irritation
The best formulation KCD3 was subjected for skin irritation test. The skin
irritation tests were performed on healthy white rabbit and were observed for a period
of 72 hours. From the results of the study it was clear that there is no (erythema &
edema) found after 72 hours and hence, it was concluded that the gel is free from skin
irritation.
Antifungal Activity
In vitro antifungal activity of prepared gels F, R and M2 were determined by
cup-plate method using Candida albicans as test organisms and zone of inhibition
was measured. Formulation (KCD3) containing carbopol 940 (1%) and dimethyl
sulfoxide (15%) has shown zone of inhibition which was compared to marketed
preparation (M2) and reference.
Stability Studies:
Stability studies were done according to ICH guidelines. The prepared gel
KCD3 were packed in aluminum collapsible tube and kept in different temperature
i.e., 30 2C, RH 655% and 53C for 3 months. The following parameters were
studied viz, spreadability extrudability, pH, drug content, viscosity, in vitro drug
release and results were mentioned in Table-34 & 35.
119
CONCLUSION
CHAPTER-7
CONCLUSION
The data obtain from the study of development and evaluation of

Ketoconazole solid dispersion incorporated gels, Solid dispersions of Ketoconazole
were prepared by different method using carriers like mannitol, PEG-4000, PEG6000, PVP-K30, and -cyclodextrin. And Carbopol 940, HPMC, MC, NaCMC as
gelling agents, the following points can be concluded:
The dissolution rate of Ketoconazole from solid dispersion i.e., F1-F15 was
significantly higher than that of pure drug.
Solid dispersion prepared by Solvent evaporation method showed faster drug

release than the dispersion prepared by Kneading method followed by melt
solvent method then fusion method then physical mixture.
The general trend indicated that there was increase in dissolution rate for solid
dispersion in the following order of -cyclodextrin > PEG - 6000 > PEG 4000 > Mannitol > PVP - K30.
IR studies indicated that no chemical interaction between drug and polymer

took place during preparation of solid dispersion of Ketoconazole.
DSC studies indicated that Ketoconazole was homogeneously distributed

within the carrier in an amorphous state and no drug crystallized out of the
dispersion suggesting that drug and polymer exist in the form of a mixture
rather than the reaction product.
120
CONCLUSION
Ketoconazole solid dispersion incorporated gels were translucent, opaque and

milky white in appearance, the pH, drug content, extrudability, spreadability
and viscosity were found in acceptable range.
In-vitro drug release of Ketoconazole solid dispersion incorporated gels

formulation Carbopol 940 shown higher drug release as compared to HMPC,
Methyl cellulose and NaCMC.
Based on this study the effect of permeation enhancers on Ketoconazole

release, an optimum of 15% DMSO were found to be more suitable to give a
better formulation having good drug release characteristics and consistency.
As in In-vitro study the SLS formulations showed lesser rate of release than
that of the DMSO formulations.
The IR study showed that there was no chemical interaction between

Ketoconazole and polymer for KCD3 formulation.
In vitro antifungal activity of Ketoconazole gel (KCD3) against Candida

albicans were recorded. The formulation KCD3 gives more zone of inhibition
as compared to that of marketed product and reference.
In Skin irritation test of Ketoconazole gel (KCD3) does not produce any
erythema and edema on application to the skin and did not produce any skin
irritation.
Stability studies were performed to assure that the formulation retains its
activity, all selected formulations were found to be stable.
From overall formulation, KCD3, which was formulated using Carbopol 940
polymer with 15% DMSO Permeation enhancer was found to be the best
formulation.
121
SUMMARY
CHAPTER-8
SUMMARY
Solid dispersion technology can be used to improve in vitro dissolution

properties of dissolution dependant poorly water soluble drugs. In the present study,
Ketoconazole, a poorly water soluble anti-fungal agent was selected. The objective
was to investigate the effect of different types of carriers such as mannitol, PEG-4000,
PEG-6000, PVP-K30, and -cyclodextrin as solubilizer on in vitro dissolution rate of
Ketoconazole and to incorporate the best dispersion into the gel.
The need for study and objective is presented in chapter-2. The work was
divided into 6 parts as shown in scheme of work in chapter-2. Initially, theoretical and
technical data was collected by extensive literature survey, the review of literature,
drug profile and polymer profile is presented in chapter-3. Batches of solid dispersion
were prepared by fusion, solvent evaporation, melt solvent and kneading method.
Solid dispersions of Ketoconazole were evaluated for physical appearance,
percent practical yield, drug content uniformity, in vitro dissolution rate, DSC and IR
studies. The methods of evaluation are shown in chapter-4 and corresponding results
are shown in chapter-5.
The discussions based on results obtained are presented in chapter-6. From the
studies carried out on the solid dispersion of Ketoconazole using different carrier
systems, Ketoconazole is homogeneously distributed in an amorphous state within the
carrier and no Ketoconazole crystallized out of the dispersion. The conclusions have
122
SUMMARY
been presented in chapter-7. It was concluded that the dissolution rate of
Ketoconazole from solid dispersions were significantly higher when compared to the
amount dissolved from pure Ketoconazole.
The best solid dispersions were incorporated into gels. The gels were prepared
by using, Carbopol 940, HPMC, Methyl cellulose and NaCMC. Carbopol 940 shown
higher drug release. Some gels were prepared along with SLS (KCS1, KCS2, KCS3
and KCS4) and DMSO (KCD1, KCD2, KCD3 and KCD4) as permeation enhancers
for some preparation.
The prepared Ketoconazole solid dispersion incorporated gels were evaluated
for pH, drug content, spreadability, extrudability, viscosity determination, diffusion
study, IR, skin irritation test and stability studies.
The DMSO permeation enhancer show higher drug release as compare to SLS.
KCD3 was found to be the best formulation.
IR studies showed that no chemical interaction between drug and polymer
took place.
Stability studies for selected Ketoconazole solid dispersion incorporated gel
formulations at temperature 302C and relative humidity (RH) 655% reveals that
formulated gels are stable.
123
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DEVELOPMENT AND EVALUATION OF

KETOCONAZOLE SOLID DISPERSION

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

DECLARATION BY THE CANDIDATE

I hereby declare that this dissertation / thesis entitled

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

CERTIFICATE BY THE GUIDE

This is to certify that the dissertation entitled DEVELOPMENT

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

CERTIFICATE BY THE CO-GUIDE

This is to certify that the dissertation entitled DEVELOPMENT

ASHFAQ AHMED MOHSIN

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

ENDORSEMENT BY THE HOD, PRINCIPAL/

This is to certify that the dissertation entitled DEVELOPMENT

NAJMUDDIN, Asst. Professor.

Prof. Syed Sanaullah

DECLARATION BY THE CANDIDATE

I here by declare that the Rajiv Gandhi University of Health

Rajiv Gandhi University of Health Sciences, Karnataka

LIST OF ABBREVIATIONS USED

Keywords: Ketoconazole, Solid dispersion incorporated gels, -cyclodextrin,

Materials / Chemicals used

Equipments used and sources

Formulation ingredients, preparation, method of Ketoconazole solid

Formulation of various Ketoconazole gels

Formulation of Ketoconazole gels with permeation enhancers

Standard calibration data of Ketoconazole in pH 7.4 phosphate

Standard Calibration data of Ketoconazole in methanol

Physical parameters of Ketoconazole solid dispersion

Drug content uniformity studies and percentage practical yield of

Dissolution profile of Ketoconazole pure drug

In-vitro drug release profile of Ketoconazole solid dispersion F1

In-vitro drug release profile of Ketoconazole solid dispersion F2

In-vitro drug release profile of Ketoconazole solid dispersion F3

In-vitro drug release profile of Ketoconazole solid dispersion F4

In-vitro drug release profile of Ketoconazole solid dispersion F5

In-vitro drug release profile of Ketoconazole solid dispersion F6

In-vitro drug release profile of Ketoconazole solid dispersion F7

In-vitro drug release profile of Ketoconazole solid dispersion F8

In-vitro drug release profile of Ketoconazole solid dispersion F9

In-vitro drug release profile of Ketoconazole solid dispersion F10

In-vitro drug release profile of Ketoconazole solid dispersion F11

In-vitro drug release profile of Ketoconazole solid dispersion F12

In-vitro drug release profile of Ketoconazole solid dispersion F13

In-vitro drug release profile of Ketoconazole solid dispersion F14

In-vitro drug release profile of Ketoconazole solid dispersion F15

Physical parameters of drug content of formulations

Rheological propertied of formulations

In-vitro % drug release study of Ketoconazole from Carbopol 940 gel

In-vitro % drug release study of Ketoconazole from HPMC gel

In-vitro % drug release study of Ketoconazole from Methyl cellulose gel

In-vitro % drug release study of Ketoconazole from NaCMC gel

In-vitro % drug release study of Ketoconazole from KCS1 gel

In-vitro % drug release study of Ketoconazole from KCS2 gel

In-vitro % drug release study of Ketoconazole from KCS3 gel

In-vitro % drug release study of Ketoconazole from KCS4 gel

In-vitro % drug release study of Ketoconazole from KCD1 gel

In-vitro % drug release study of Ketoconazole from KCD2 gel

In-vitro % drug release study of Ketoconazole from KCD3 gel

In-vitro % drug release study of Ketoconazole from KCD4 gel

In-vitro % drug release study of Ketoconazole from PD gel

In-vitro % drug release study of Ketoconazole from MP gel

Statistical analysis data of prepared different Ketoconazole gel