Anagrelide Dispersion Solida

STUDY OF SOLUBILITY ENHANCEMENT
OF ANAGRELIDE HCl BY
SOLID DISPERSION
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
BY
MORGE GANESH VASANTRAO B. Pharm.

Reg. No.09PU032
Under the guidance of
Mrs.BRAHMANI PRIYADARSHINI SR.
Department of Pharmaceutics
Dayananda Sagar College of pharmacy
Bangalore-78.
March - 2011
© Rajiv Gandhi University of Health Sciences, Karnataka.

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
JAYANAGAR 4th T- Block, BANGALORE,
KARNATAKA
DECLARATION BY THE CANDIDATE
I hereby declare that this dissertation entitled “Study of solubility enhancement of
Anagrelide hydrochloride by solid dispersion” is a bonafide and genuine research
work carried out by me under the guidance Mrs. BRAHMANI PRIYADARSHINI SR.
Associate Professor, Department of Pharmaceutics, Dayananda Sagar College of
Pharmacy, Bangalore -78.
Date: Signature of the Candidate
Place: Bangalore Mr. Morge Ganesh Vasantrao

DAYANANDA SAGAR COLLEGE OF PHARMACY
KUMARASWAMY LAYOUT, BANGALORE-560078,
KARNATAKA
CERTIFICATE BY THE GUIDE
I hereby declare that this dissertation entitled “Study of solubility enhancement of
Anagrelide hydrochloride by solid dispersion” is a bonafide research work done
by Mr. Morge Ganesh Vasantrao in partial fulfillment of the requirement for the
degree of “Master of Pharmacy in Pharmaceutics”
Date: Signature of the Guide
Place: Bangalore Mrs. BRAHMANI PRIYADARSHINI SR.

Associate Professor,
Department of Pharmaceutics,
Dayananda Sagar College of Pharmacy,
Kumaraswamy Layout,
Bangalore-78.
KARNATAKA
ENDORSEMENT BY THE HOD, PRINCIPAL/HEAD
OF THE INSTITUTION
This is to certify that the dissertation entitled “Study of solubility enhancement of
Anagrelide hydrochloride by solid dispersion” is a bonafide research work done
by Mr. Morge Ganesh Vasantrao under the guidance of Mrs. BRAHMANI
PRIYADARSHINI SR. Associate Professor, Department of Pharmaceutics.
Dayananda Sagar College of Pharmacy, Bangalore-78.
Seal and signature of the HOD Seal and signature of the Principal
Dr. B. Wilson, M. Pharm., Ph. D., Dr. V. Murgan, M. Pharm., Ph. D., A.I.C.,
Professor & Head, Professor & Principal,
Dept of Pharmaceutics, Dayananda Sagar College of Pharmacy,
Dayananda Sagar College of Pharmacy, Kumaraswamy Layout,
Kumaraswamy Layout, Bangalore-560078.
Bangalore-560078.
Date: Date:
Place: Bangalore Place: Bangalore

KARNATAKA
COPYRIGHT
Declaration by the Candidate
I hereby declare that the Rajiv Gandhi University of Health Sciences,
Karnataka shall have the rights to preserve, use and disseminate this
dissertation in print or electronic format for academic/research purpose.
Date: Signature of the candidate
Place: Bangalore Mr. Morge Ganesh Vasantrao
© Rajiv Gandhi University of Health Sciences, Karnataka.

Dedicated To
My Beloved
Brother,
Teachers,
Friends
And
Special
Thanks, To
My Parents
ACKNOWLEDGMENT
I take this privilege and pleasure to acknowledge the contributions of

many individuals who have been inspirational and supportive throughout
my work undertaken and endowed with the most precious knowledge to see
success in my endeavor.
It is with pleasure of immense gratitude that I express my most

cordial and humble thanks to my esteemed teacher and guide of Mrs.
Brahmani Priyadarshini SR. Associate Professor, Department of
Pharmaceutics, Dayananda Sagar College of College of Pharmacy, for her
valuable guidance, keen interest, perennial inspiration and everlasting
encouragement. I shall for ever remain indebted to her for having inculcated
in me a quest for excellence, a spirit of diligence and perseverance, a sense of
humility, honesty and respect for the moral and ethics which govern our
sciences and without whom this work would not have seen the light of the
day.
I am gratefully indebted to Dr. V. Murugan, M. Pharm., Ph.D.

principal of, Dayananda Sagar College of College of Pharmacy, Bangalore
for providing necessary facilities to carry out my work and for his constant
support and encouragement.
I consider it as a great privilege to express my heartfelt gratitude and

sincere thanks to Dr. B.WILSON, M. Pharm. PhD, Head of the
department of pharmaceutics, Dayananda Sagar College of Pharmacy,
Bangalore for inspiration and cooperative nature, with due respect in my
heart.
I take this opportunity to express my sincere thanks to teaching and
nonteaching staff members, Dayananda Sagar College of Pharmacy,
Bangalore.
I will not forget the help and company given by my classmates

Madhusudhan, Ashwini, Mehul, Dharmesh, Hiren, Ankit,
Nagabhushan, Manisha, Aadarsh and Ambika and dearest friends
Durga N. for their moral support good company and encouragement.
My special thanks and appreciation goes to all my seniors, especially,

Hardik, Pankaj. Shravani, Nagesh, Avantika and my juniors
Hardik, Richa, Barakha and Priyanka for their good wishes timely
help and unstinted support during the course of study.
Words are not sufficient to express my deepest love and appreciation

to my affectionate, beloved Parents, my Father Morge Vasant
Kashinath my Mother Sarswati V.M. my beloved Brother Yogesh V. M.
and sister in law Komal Y. Morge for their support and boosting
encouragement throughout my career.
I express my deep sense of gratitude to Cipla Pvt. Ltd, Virgonagar,

Bangalore for providing gift samples of Anagrelide HCl
Finally I consider this as an opportunity to express my gratitude to all

the dignitaries who have been involved directly or indirectly with the
successful completion of this dissertation.
Date:
Place: Mr. GANESH V. MORGE
ABSTRACT

The objective of the present study was to enhance the solubility of
Anagrelide hydrochloride by solid dispersion technique. Anagrelide
hydrochloride is a platelet reducing agent having poor water solubility after
oral administration. Solid dispersion is the one of the most commonly used
techniques to improve the aqueous solubility of poorly water soluble drugs.
Solid dispersions of Anagrelide hydrochloride were prepared using

different carriers such as poly ethylene glycol - 4000 (PEG-4000), Polyvinyl
pyrrolidone K30 (PVP K30) and sodium starch glycolate (SSG) by physical
mixture, fusion method and solvent evaporation method in different
drug/carrier ratio.
The prepared solid dispersions of Anagrelide hydrochloride and the

physical mixtures were evaluated for phase and saturation solubility study, FT-
IR studies, differential scanning Calorimetry (DSC), scanning electron
microscopy (SEM), X-ray diffraction (X-RD) and in vitro dissolution studies.
The results revealed that the solid dispersions prepared with carrier PEG-
4000 (F6) significantly increased the dissolution of drug Anagrelide
hydrochloride in comparison with other formulation. In conclusion, solid
dispersion technique can be successfully used to improve the dissolution of
Anagrelide hydrochloride.
KEYWORDS
Anagrelide HCl, Solid dispersion, PEG 4000, SSG, PVP K30. Dissolution
enhancement.
List of Abbreviations…
LIST OF ABBREVIATIONS
PEG Poly ethylene glycol
PVP Polyvinyl pyrrolidone
SSG Sodium starch glycolate
SD Solid dispersion
PM Physical mixture
DMSO Dimethyl sulfoxide
FTIR Fourier Transform Infrared
SEM Scanning Electron Microscopy
DSC Differential Scanning Calorimetry
XRD X-ray diffraction
GIT Gastro Intestinal Tract
USP United States Pharmacopoeia
rpm Revolutions Per Minute
CDR Cumulative drug release
hrs Hours
T Time
gm Gram
mg Milligram
ml Milliliter
µg Microgram
Department of Pharmaceutics, DSCP, Bangalore.

nm Nanometer
M Molar
pH Negative Logarithm of Hydrogen Ion Concentration
min Minutes
Conc. Concentration
Laboratory Reagent
LR
˚C Degree Celsius
Percent weight / volume

%w/v
%v/v Percent volume/ volume
% Percentage
λ Lambda
β beta

FORMULATION CODE
F1 Solid dispersions of Anagrelide HCl containing PEG4000

prepared by physical mixture in 1.1 ratio



prepared by solvent evaporation method in 1.1 ratio



prepared by Fusion Method in 1.1 ratio


F10 Solid dispersions of Anagrelide HCl containing PVP K30






F16 Solid dispersions of Anagrelide HCl containing SSG











TABLE OF CONTENTS
Chapter
Title Page No.
No.
1 Introduction 1
2 Objectives of the study 22
3 Review of literature 24
4 Materials and Methods 38
5 Results 48
6 Discussion 79
7 Conclusion 84
8 Summary 86
9 Bibliography 88
10 Annexure 96
List of Tables…
LIST OF TABLES
Table no. Title Page no.
1.1 Materials used as carrier for solid dispersion 12
4.1 Materials Used for solid dispersion 38
4.2 Instrument and equipments used for solid dispersion 39
5.1 Calibration data of Anagrelide HCl in distilled water 48
5.2 Calibration Curve Data of Anagrelide HCl In Acidic Buffers 50
5.3 Phase solubility studies data 51
5.4 Different formulations of Anagrelide HCl in molar ratio. 53
5.5 Physical Appearance of Anagrelide HCl Solid Dispersions 53
5.6 Determination of Anagrelide HCl Content Uniformity 54
5.7 Phase solubility of study of Anagrelide HCl 56
5.8 Percent Release of Pure Anagrelide HCl 58
In vitro Percent Release of Anagrelide HCl from Solid

5.9 59
Dispersions Containing PEG 4000
5.10 60
Dispersions containing PVP K30

List of Tables…

5.11 61
Dispersions containing SSG
In vitro drug release for pure drug, Physical mixture, Fusion
5.12 62
method and Solvent evaporation method
Short term stability studies of Anagrelide HCl complex at
5.13 78
room Temperature and at 40°C
6.1 IR Spectrum peak 80

List of figures…
LIST OF FIGURES
Fig. no. Title Page no.

A schematic representation of the bioavailability enhancement of a
1.1 poorly water-soluble drug by solid dispersion compared with 9
conventional tablet or capsule.
5.1 Standard calibration curve for Anagrelide HCl in Distilled water 49
5.2 Standard calibration curve for Anagrelide HCl in acidic buffer. 50

Phase solubility of study of Anagrelide HCl – PEG Complex
5.3 51
5.4 Phase solubility of study of Anagrelide HCl – PVP K30 Complex 52
5.5 Phase solubility of study of Anagrelide HCl –SSG Complex 52
5.6 Phase solubility of study of Anagrelide HCl 57
5.7 Percent Release of Anagrelide HCl 58

Percent Release of Anagrelide HCl from Solid Dispersions
5.8 containing PEG 59

5.9 60
containing PVP
5.10 containing SSG 61
in vitro drug release for pure drug, Physical mixture, Kneading

5.11 method, Fusion method and Solvent 62
5.12 FT-IR Spectrum of Formulation pure drug Anagrelide HCl. 63
5.13 FT-IR Spectrum of 4000 64
5.14 FT-IR Spectrum of SSG 64

List of figures…
5.15 FT-IR Spectrum of PVP K30 65
5.16 FT-IR Spectrum of Formulations F3 PM 65
5.17 FT-IR Spectrum of Formulations F6 SD 66
5.24 X-RD Spectrum of pure Anagrelide HCl 70
5.25 X-RD Spectrum of PEG 4000 71
5.26 X-RD Spectrum of Drug-PEG Physical Mixture 71
5.27 X-RD Spectrum of Anagrelide HCl-PEG Solid Dispersion 72
5.28 Scanning electron micrographs of a) Anagrelide HCl 73
5.29 Scanning electron micrographs of PEG 4000 73

Scanning electron micrographs of physical mixture of Anagrelide
5.30 HCl / PEG (F6) 74
scanning electron micrographs of solid dispersion of Anagrelide

5.31 HCl/PEG4000 (F6) 74

List of figures…
5.32 DSC Spectrum of pure drug 75
5.33 DSC Spectrum of PEG 4000 76
5.34 DSC Spectrum of Physical Mixture 76
5.35 DSC Spectrum of Solid Dispersion 77

Introduction…
CHAPTER–1
INTRODUCTION
1.1 SOLUBILIZATION:
Solubility is a measure of the maximum amount of solute that can be dissolved in a given
amount of solvent to form a stable solution the solution becomes saturated and the dissolved
solute is in equilibrium with the excess un-dissolved solute1.
Poorly water-soluble drugs are increasingly becoming a problem in terms of obtaining the
satisfactory dissolution within the gastrointestinal tract that is necessary for good bioavailability.
It is not only existing drugs that cause problems but it is the challenge of medicinal chemists to
ensure that new drugs are not only active pharmacologically but have enough solubility to ensure
fast enough dissolution at the site of administration, often gastrointestinal tract2.
The most important property of a dosage form is its ability to deliver the active ingredient
to its site of action at a rate and amount sufficient to elicit the desired pharmacological response3
Dissolution of solid dosage forms in gastrointestinal fluids is a prerequisite to the delivery

of the drug to the systemic circulation following oral administration. Dissolution depends in parts
on the solubility of the drug substance in the surrounding medium. Surface area of drug particle
is another parameter that influences drug dissolution, and in turn drug absorption. The
dissolution of a substance may be described by the modified
Noyes & Whitney equation (1);
Where dc/dt is the rate of increase in C, the concentration of drug in a bulk solution in
which dissolution of the solid particles is taking place, K is proportionality constant, D is the
diffusion coefficient of the drug in the solvent and S is the surface area of un-dissolved solid. V
Dept Of Pharmaceutics, DSCP, Bangalore Page 1

Introduction…
is the volume of the solution, h is the thickness of the diffusion layer around a particle and Cs is
the solubility of the drug in the solvent. If we consider a given drug under well-defined
conditions (such as controlled liquid intake) we may assume that D, V and h are relatively
constant values. Thus we can reduce equation to:

Equation (2) shows that the two variables, which can be controlled by the formulation are the
surface area and the solubility of the drug. These two variables can be altered by the following
techniques:
¾ Control the solubility of a weak acid or base by buffering the entire dissolution medium,
the “microenvironment”, or the diffusion layer surrounding a particle.
¾ Control the solubility of the drug through choice of the physical state, such as crystal
form, its hydrate and its amorphous form.
¾ Control the surface area of the drug through control of particle size.4

Introduction…
1.2 SOLUBILIZATION TECHNIQUES:
Solubilization is the process by which the apparent solubility of a poorly water soluble
substance is increased. The three approaches in overcoming the bioavailability problems due to
such causes are:
1. Pharmaceutical Approach which involves modification of formulation, manufacturing,

process or the physicochemical properties of drugs without changing the chemical structure.
2. Pharmacokinetic Approach in which the pharmacokinetics of drugs is altered by modifying

its chemical structure.
3. Biological Approach where by the route of drug administration may be changed such as
changing from oral to parenteral route.
The second approach of chemical structure modification has a number of drawbacks like very
expensive and time consuming, require repetition of studies and required regulatory approval.
The attempts, whether optimizing the formulation, manufacturing process or physicochemical
properties of the drug, are aimed at enhancement of dissolution rate.
Methods5 to enhance the dissolution rate of the drug:
1. Micronization:
The process involves reducing the size of the solid drug particles to 1 to 10 microns
commonly by spray drying or by use of air attrition methods. Examples of drugs whose
bioavailability have been increased by micronization include griesofulvin and several steroidal
and sulfa drugs.
2. Use of surfactants6:
The surface-active agents enhance dissolution rate primarily by promoting wetting and
penetration of dissolution fluid into the solid particles. They are generally used in concentration
below their cumulative mean concentration (CMC) values. Examples of the drugs whose

Introduction…
bioavailability have been increased by use of surfactants in the formulation include steroids like
spironolactone. A number of workers have used surfactants as the carrier material to achieve
enhanced dissolution effect. Surfactants have also been added to conventional drug-polymer
solid dispersions to further improve drug release properties.
Classification of Surfactants used:
a. Anionic surfactants, where the hydrophilic group carries a negative charge, such as carboxyl,
sulphonate or sulphate. Examples of pharmaceutically important include potassium laureate,
CH3 (CH2)10 COO–K+, and sodium lauryl sulphate, CH3 (CH2)11S4 O Na+.
b. Cationic surfactants, where the hydrophilic group carries a positive charge (e.g., quaternary
ammonium halides). Examples of pharmaceuticaly importante include cetrimide, a mixture
consisting mainly of tetradecyl (Ca 68%), dodecyl (ca 22%), and hexadecyl trimethyl ammonium
bromides (Ca 7%), as well as benzalkonium chloride, a mixture of aklylbenzyl dimethyl
ammonium chlorides of the general formula [C6H5CH2N+ (CH3)2R] Cl-, where R represents a
mixture of the alkyls from C8H17 to C18H37.
c. Ampholytic surfactants (also called Zwitter ionic surfactants), where the molecule contains, or
can potentially contain, both a negative and a positive charge (e.g., the sulfobetaines, RN+
(CH3)2 CH2 CH2 SO3). Examples of pharmaceutical importance include N-dodecyl-N, N-
dimethyl betaine, C12 H25 N+ (CH3)2 CH2 COO–.
d. Non-ionic surfactants, where the hydrophile carries no charge but derives its water solubility
from highly polar groups such as hydroxyl or polyoxyethylene (OCH2 CH2O-) groups. Examples
of pharmaceutical importance include polyoxy ethylated glycol mono-ethers (e.g., etomacrogol),
sorbitan esters (spans) and polysorbates (Tweens).

Introduction…
3. Use of salt Forms:

Salts have improved solubility and dissolution characteristics in comparison to the original
drug. Alkali metal salts of acidic drugs like penicillin and strong acid salts of basic drugs like
atropine are more water soluble than the parent drug.
4. Alteration of pH of the Drug Microenvironment:

This can be achieved in two ways-in situ salt formation, and addition of buffers to the
formulation Ex. Buffered aspirin tablets.
5. Use of Metastable polymorphs:

A Metastable polymorphs is more soluble than the stable polymorph of a drug that exhibit
polymorphism for example, the B form of chloramphenicol palpitate is more soluble than A and
C forms.
6. Solute-Solvent complexation:
Solvates of drugs with organic solvents have higher aqueous solubility than their respective
hydrates or the original drug. Much higher solubility can be attained by freeze drying such as
solute in solution with an organic solvent with which it is known to form a solvate. E.g.1:2
griesofulvin-benzene solvate.
7. Solvent deposition:
In this method, the poorly aqueous soluble drug such as nifedipine is dissolved in an
organic solvent like alcohol and deposited on an inert, hydrophilic, solid matrix such as starch or
micro-crystalline cellulose by evaporation of solvent.
8. Selective Adsorption on Insoluble Carriers:

A highly active adsorbent such as the inorganic clays like bentonite can enhance the
dissolution rate of poorly soluble drugs such as griesofulvin, indomethaciin and prednesolone by
maintaining the concentration gradient at its maximum. The two reasons suggested for the rapid

Introduction…
release of drugs from the surface of clay are the weak physical bonding between the adsorbate
and the adsorbent, and hydration and swelling of the clay in the aqueous media.
9. A solid solution:
It is the binary system comprising of a solid solute molecularly dispersed in a solid
solvent. Since the two components crystallize together in a homogeneous one phase system,
solid solutions are also called as molecular dispersions or mixed crystal. Because of reduction in
particle size to the molecular level, solid solution show greater aqueous solubility and faster
dissolution than eutectics mixture. They are generally prepared by fusion method where by a
physical mixture of solute and solvent are melted together followed by rapid solidification. E.g.
griseofulvin-succinic acid, the griesofulvin from such solid solution dissolves 6 to 7 times faster
than pure griesofulvin. The two mechanisms suggested for enhanced solubility and rapid
dissolution of molecular dispersions are:-
1. When the binary mixture is exposed to the water, the soluble carrier dissolves rapidly leaving
the insoluble drug in a state of micro-crystalline dispersion of very fine particles.
2. When the solid solution, which is said to be in a state of randomly, arranged solute and solvent
molecules in the crystalline lattice, is exposed to dissolution fluid, the soluble carrier dissolves
rapidly leaving the insoluble drug stranded at almost molecular level.
10. Eutectic Mixture:

These systems are also prepared by fusion method. Eutectic melts differ from solid
solution in that the fused melt of solute-solvent show complete miscibility but negligible solid-
solid solubility i.e. such systems are basically intimately blended physical mixture of two
crystalline components. The eutectic product is often tacky, intractable or irregular crystals.
The method however cannot be applied to:
- Drugs which fail to crystallize from the mixed melt,
- Themolabile drugs, and
- Carriers such as succinic acid that decompose at their melting point.

Introduction…
11. Molecular Encapsulation with Cyclodextrins:

The beta- and gamma Cyclodextrins and several of their derivatives are unique in having
the ability to form molecular inclusion complexes with hydrophobic drugs having poor
solubility. These cyclodexrtin molecules are versatile in having a hydrophobic cavity of size
suitable enough to accommodate the lipophilic drugs as guest the outside of the host molecule is
relatively hydrophilic. Thus molecularly encapsulated drug has greatly improved aqueous
solubility and dissolution rate. Among the possibilities, the preparation of inclusion complexes
with cyclodexrtin is of particular interest.
12. Solid dispersions:

These are generally prepared by solvent or co-precipitation method where by both the
guest solute and the solvent are dissolved in a common volatile liquid solvent. The liquid solvent
is removed by evaporation under reduced pressure or by freeze drying which results in
amorphous precipitation of guest in a crystalline carrier. Example is griesofulvin – PVP.

Introduction…
1.3 INTRODUCTION TO SOLID DISPERSION TECHNOLOGY:
The enhancement of oral bioavailability of poorly water soluble drugs remains one of the
most challenging aspects of drug development. Although salt formation, solubilization and
particle size reduction have commonly been used to increase dissolution rate and thereby oral
absorption and bioavailability of such drugs7, there are practical limitations of these techniques.
The salt formation is not feasible for neutral compounds and the synthesis of appropriate salt
forms of drugs that are weakly acidic or weakly basic may often not be practical. Even when
salts can be prepared, an increased dissolution rate in the GIT may not be achieved in many cases
because of the reconversion of salts into aggregates of their respective acid or base forms. The
solubilization of drugs in organic solvents or in aqueous media by the use of surfactants and co
solvents leads to liquid formulations that are usually undesirable from the viewpoints of patient
acceptability and commercialization. Although particle size reduction is commonly used
to increase dissolution rate, there is a practical limit to how much size reduction can be achieved
by such commonly used methods as controlled crystallization, grinding, etc. The use of very fine
powders in a dosage form may also be problematic because of handling difficulties and poor
wettability.
In 1961, Sekiguchi and Obi8 developed a practical method whereby many of the
limitations with the bioavailability enhancement of poorly water-soluble drugs can be overcome,
which was termed as “Solid Dispersion”
The advantage of solid dispersion9 compared with conventional capsule or tablet

formulations is shown schematically in figure-1.1. From conventional capsules and tablets, the
dissolution rate is limited by the size of the primary particles formed after the disintegration of
dosage forms. In this case, an average particle size of 5µm is usually the lower limit, although
higher particle sizes are preferred for ease of handling, formulation and manufacturing. On the
other hand, if a solid dispersion or a solid solution is used, a portion of the drug dissolves
immediately to saturate the gastrointestinal fluid, and the excess drug precipitates out as fine

Introduction…
colloidal particle or oily globules of submicron size. Solid dispersion has become one of the most
active areas of research in the pharmaceutical field.
9
Figure-1.1: A schematic representation of the bioavailability enhancement of a poorly
water-soluble drug by solid dispersion compared with conventional tablet or capsule.

Introduction…
1.4 HISTORICAL BACKGROUND:

The effect of the particle size of the drugs on their dissolution rates and biological
availability was reviewed comprehensively by Fincher10,11. For drugs whose gastrointestinal
absorption is rate limited by dissolution, reduction of the particle size generally increases the rate
of absorption and or total bioavailability. This commonly occurs for drugs with poor water-
solubility. For example, the therapeutic dose of griesofulvin was reduced to 50% by
micronization and it also produced a more constant and reliable blood level. The commercial
dose of spironolactone was decreased to half by just a slight reduction of particle size. Such
enhancement of drug absorption could further be increased several fold if a micronized product
was used.
In 1961, a unique approach of solid dispersion to reduce the particle size and increase
rates of dissolution and absorption was first demonstrated by Sekiguchi and Obi. They proposed
the formation of a eutectic mixture of a poorly soluble drug such as sulfathiazole with a
physiologically inert, easily soluble carrier such as urea. The eutectic mixture was prepared by
melting the physical mixture of the drug and the carrier, followed by a rapid solidification
process. Upon exposure to aqueous fluids, the active drug was expected to be released into the
fluids as fine, dispersed particles because of the fine dispersion of the drug in the solid eutectic
mixture and the rapid dissolution of the soluble matrix.
Levy and Kanig12 subsequently noted the possibility of using a solid solution approach in
which a drug is dispersed molecularly in a soluble carrier. In a series of reports in 1965-66,
Goldberg et al presented a detailed experimental and theoretical discussion of advantages of
solid solution over the eutectic mixture.
In 1965, Tachibana and Nakamaru reported a novel method for preparing aqueous
colloidal dispersions of β-carotene by using water-soluble polymers such as polyvinyl
pyrrolidone. They dissolved the drug and the polymer carrier in a common solvent and then
evaporated the solvent completely. A colloidal dispersion was obtained when the coprecipitate
was exposed to water.

Introduction…
Chiou and Riegelman13 recently advocated the application of glass solution to increase
dissolution rates. They used PEG 6000 as a dispersion carrier. It is believed that this relatively
new field of pharmaceutical technique and principles will play an important role in increasing
dissolution, absorption and therapeutic efficacy of drugs in future dosage forms. Therefore, a
thorough understanding of its fast release principles, methods of preparation, selection of suitable
carriers, determination of physical properties, limitations and disadvantages will be essential in
the practical and effective application of this approach.
In addition to absorption enhancement, the solid dispersion technique may have numerous
pharmaceutical applications which remain to be further explored. It is possible that such a
technique can be used to obtain a homogeneous distribution of a small amount of drug at solid
state, to stabilize unstable drugs, to dispense liquid or gaseous compounds, to formulate a fast
release priming dose in a sustained release dosage form, and to formulate sustained release
regimens of soluble drugs by using poorly soluble or insoluble carriers.

Introduction…
1.5 DEFINITION AND TYPES OF SOLID DISPERSIONS
1.5.1 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 enhanced release of drugs from ointment and suppository bases,
and improved solubility and stability.
14
1.5.2 Types of solid dispersions :
a) Simple eutectic mixture: An-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.
b) 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.
Hence, this system would be expected to yield much higher rates of dissolution than simple
eutectic systems.
c) 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.
d) 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.

Introduction…
e) 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 drug14.
1.6 SELECTION OF A CARRIER:

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.
1. Be freely water-soluble with intrinsic rapid dissolution properties.
2. Be non-toxic and pharmacologically inert.
3. Be heat stable with a low melting point for the melt method.
4. Be soluble in a variety of solvents for the solvent method.
5. Be able to preferably increase the aqueous solubility of the drug and
6. Chemically compatible with the drug and not form a strongly bonded complex with the drug.
Table-1.1: Materials used as carrier for solid dispersion

Dextrose, sucrose, galactose, sorbitol, maltose, xylitol,
1
Sugars mannitol, lactose.
2
Acids Citric acid, succinic acid
Povidone (PVP), polyethylene glycol (PEG),
hydroxypropyl methyl cellulose, methyl cellulose,
3
Polymeric materials hydroxy ethyl cellulose, cyclodextrin, hydroxy propyl
cellulose, pectin, galactomannan.
Hydroxy propyl methyl cellulose phthalate, eudragit

4 Insoluble or enteric
L100, eudragit S100, Eudragit RL, Eudragit RS.
polymer
Polyoxyethylene stearate, renex, poloxamer 188,
5
Surfactants texafor AIP, deoxycholic acid, tweens, spans.
Pentaerythritol, pentaerythrityl tetraacetate, urea,

6
Miscellaneous urethane, hydroxy alkyl xanthins

Introduction…
1.7 POLYMERS USED IN SOLID DISPERSIONS:
a) Polyethylene glycols (PEG):

The term polyethylene glycols refer to compounds that are obtained by reacting ethylene
glycol with ethylene oxide. PEGs whose molecular weight is above 300000 are commonly
termed as polyethylene oxides.
Effect of PEG molecular weight: The dissolution rate of pure PEG decreases with increasing
molecular weight. The dissolution rate of the drug in solid dispersion can be increased with an
increase in molecular weight of PEG. In these cases, the rate at which the polymer dissolved
dictated the rate at which the drug dissolved. Lower molecular weight PEGs melt at 37ºC in the
dissolution medium prior to dissolution, further increasing the rate of dissolution. In some drug-
PEG solid dispersion systems, the rate dissolution decreases with molecular weight up to a
certain composition of the drug above which the trend becomes irregular.
b) Polyvinyl pyrrolidone (PVP):

PVP has a molecular weight ranging from 10,000 to 700,000. It is soluble in solvents like
water, ethanol, chloroform and isopropyl alcohol. PVP is not suitable for preparation of solid
dispersions prepared by melt method because of it melts at a very high temperature above 275ºC,
where it becomes decomposed.
The effect of molecular weight of PVP on the rate of dissolution of a drug is more consistent
than for PEG. An increase in molecular weight of PVP will decrease the dissolution rate of most
drugs. An increase in viscosity of PVP solution due to an increase in molecular weight decreases
diffusion of drug molecules from the surface of viscous material into the dissolution medium.
Lower molecular weight PVP has a short swelling time prior to dissolution resulting in an
increase in dissolution rate of the polymer and drug.

Introduction…
c) Polymers and surface active agent combinations:

The addition of surfactants to dissolution medium lowers the interfacial tension between the
drug and the dissolution medium and promote the wetting of the drug thereby they enhance the
solubility and dissolution of drugs. Ternary dispersion systems have higher dissolution rates than
binary dispersion system
d) Cyclodextrins:
Cyclodextrins are primarily used to enhance solubility, chemical protection, taste masking
and improved handling by the conversion of liquids into solids by entrapment. Oral
administration of cyclodextrins: Cyclodextrins play an important role in the bioavailability of
poorly water soluble drugs by increasing the rate and extent of dissolution of drug. Cyclodextrins
also have the advantage of:
¾ Increasing the stability of the drug.
¾ Release profile during gastrointestinal transit through modification of drug release site
and time profile.
¾ Decreasing local tissue irritation.
¾ Masking unpleasant taste.
e) Phospholipids:
Phospholipids are major structural components of cell membranes. Phosphotidylcholine
was first isolated from egg yolk and brain. Its chemical name is 1, 2-diacyl-in-glycero-3-
phosphocholine. In phosphatidyl ethanolamine and phosphatidyl serine, the choline moiety is
replaced by ethanolamine and serine respectively. Other phospholipids that occur in tissues
include phosphotidyl ethanolamide (PE), phosphotidyl serine (PS), and phosphotidyl glycerol
(PG). Naturally occuring lecithins contain both a saturated fatty acid and unsaturated fatty acids
with some exceptions.

Introduction…
1.8 METHODS OF PREPARING SOLID DISPERSIONS:
a) Fusion Process:
The fusion process is technically the less difficult method of preparing dispersions
provided the drug and carrier are miscible in the molten state.
Fusion was used by Sekiguchi and Obi, who melted 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 favored. Consequently the solidification process is often
affected on stainless-steel plates to favour rapid heat loss. A modification of the process involves
spray congealing from a modified spray drier onto cold metal surfaces and has been used for
dispersions containing mannitol or phenyl butanone urea.
Decomposition should be avoided during fusion but is often composition dependent, and
affected by fusion time and the rate of cooling. Therefore, to maintain decomposition at an
acceptable level, fusion may be effected at a temperature only just in excess of that which
completely melts both drug and carrier.
b) Solvent Process:
Solid dispersion prepared by solvent removal process was termed by Bate et al as “co
precipitates”. They are now termed as “co evaporates”
The solvent process used organic solvents, the agent to intimately mix the drug and carrier
molecules and was initially used by Tachibana and Nakamura by dissolving carotene and
polyvinylpyrrolidone in chloroform.

Introduction…
The choice of solvent and its removal rate are critical to the quality of the dispersion. Since
the chosen carriers are generally hydrophilic and the drugs are hydrophobic, the selection of a
common solvent is difficult. Vacuo-evaporation may be used for solvent removal at low
temperature and controlled rate. More rapid removal of the solvent may be accomplished by
freeze-drying.
Polyvinylpyrrolidone dispersions of Ketorpofen or dicoumarol were freeze-dried from their

ammonia solutions. The difficulties in selecting a solvent common to both drug and carrier may
be overcome by using an azeotropic mixture of solvent in water.
The bioavailability and stability of Nifedipine-enteric coating agents solid dispersion were
studied, using hydroxy propylmethyl cellulosephthalate (HP-55) and methacrylic methylester
copolymer (Eudragit-L) as carriers. These result suggested that these solid dispersion systems
might be useful for bioavailabiltiy enhancement and development of a sustained release
preparation of nifedipine. The solid dispersion systems were prepared by the solvent method.
Nifedipine (3g) and a polymer (9g.) were dissolved in about 90ml of mixed solvent (ethanol:
dichloromethane 1:1) and then the solvent was evaporated off under reduced pressure. The
residual solid was pulverized and the 32-80 mesh fractions were used. Solid dispersions of
Griseofulvin-PVP, Sulfathiazole-PVP, have been obtained by this method.
c) Fusion Solvent Method:

This method consists of dissolving the drug in a suitable liquid solvent and incorporating
the solution directly in the melt of PEG15. If the carrier is capable of holding a certain proportion
of liquid yet maintaining its solid properties and if the liquid is innocuous, the need for solvent
removal is eliminated. This method is particularly useful for drugs that have high melting points
or that are thermo-stable. Although there are advantages and disadvantages associated with all
these methods, the choice of a method of preparation could affect the intended purpose of Solid
dispersion formulations

Introduction…
d) Supercritical Fluid Process:

Supercritical CO2 is a good solvent for water insoluble as well as water soluble
compounds under suitable conditions of temperature and pressure. Therefore, supercritical CO2
has potential as an alternative for conventional organic solvents used in solvent based processes
for forming solid dispersions due to its favourable properties of being nontoxic and inexpensive.
The process developed by Ferro Corporation consists of the following steps:
1. Charging the bioactive material and suitable polymer into the autoclave.
2. Addition of supercritical CO2 under precise conditions of temperature and pressure, that
causes polymer to swell;
3. Mechanical stirring in the autoclave
4. Rapid depressurization of the autoclave vessel through a computer controlled orifice to
obtain desire particle size. The temperature conditions used in this process are fairly mild
(35–75°C), which allows handling of heat sensitive biomolecules, such as enzymes and
proteins.
5. Solid dispersion of cabamazepine-PEG800016 has been obtained by this method.
1.9 METHODS OF DETERMINATION OF TYPES OF SOLID

DISPERSION:
Various methods17, which are used to identify the physical nature of the solid dispersions, are
a) Thermo Analytical Methods
b) Thermal Analysis,
c) DSC,
d) SEM
e) X-ray Diffraction Methods,
f) FTIR-Spectroscopic Methods and
g) Microscopic Methods.

Introduction…
1.10 ADVANTAGES AND DISADVANTAGES OF SOLID DISPERSIONS:

Advantages
1. Rapid dissolution rates that result in an increase in the rate and extent of the absorption of
the drug,
2. Reduction in presystemic metabolism. This is because of the enzyme responsible for
biotransformation of the drug with inhibition of the enzyme by carrier thus it leads to
decrease in the dose of the drug.
3. Transformation of the liquid form of the drug into a solid Form which avoide
polymorphic changes and thereby bio-availability problems.
4. Decomposition by saliva to allow buckle absorption.
Disadvantages
1. The major disadvantages of solid dispersion are related to their instability of solid
dispersion. Several systems have shown changes in crystalline and a decrease in
dissolution rate with aging.
2. Moisture and temperature have more of a deteriorating effect on certain drugs in solid
dispersions than on physical mixtures.
3. Some solid dispersion may not lend them selves to easy handling because of tackiness.
1.11 Applications of solid dispersion
Apart from absorption enhancement, the solid dispersion technique may have numerous
pharmaceutical applications, which should be further explored.
¾ To obtain a homogeneous distribution of a small amount of drug in solid state.

¾ To stabilize the unstable drug and to reduce pre systemic inactivation of drugs like
morphine and progesterone.
¾ To dispense liquid (up to 10%) or gaseous compounds in a solid dosage.
¾ To formulate a fast release primary dose in a sustained released dosage form.
¾ To formulate sustained release regimen of soluble drugs by using poorly soluble or
insoluble carriers.

Introduction…
18
1.12 FUTURE PROSPECTS :
Despite many advantages of solid dispersion, issues related to preparation,

reproducibility, formulation, scale up and stability limited its use in commercial dosage forms for
poorly water soluble drugs. Successful development of solid dispersion systems for preclinical,
clinical and commercial use has been feasible in recent years due to the availability of surface-
active and self-emulsifying carriers with relatively low melting points. The preparation of dosage
forms involves the dissolving of drug in melted carriers and the filling of the hot solutions into
hard gelatin capsules because of the simplicity of manufacturing and scale up processes, the
physico-chemical properties and, as a result, the bioavailability of solid dispersions is not
expected to change significantly during the scale up. For this reason, the popularity of the solid
dispersion system to solve difficult bioavailability issues with respect to poorly water-soluble
drugs will grow rapidly. Because the dosage form can be developed and prepared using small
amounts of drug substances in early stages of the drug development process, the system might
have an advantage over such other commonly used bioavailability enhancement techniques as
micronization of drugs and soft gelatin encapsulation.
One major focus of future research will be the identification of new surface-active and self-
emulsifying carriers for solid dispersion. Only a small number of such carriers are currently
available for oral use. Some carriers that are used for topical application of drug only may be
qualified for oral use by conducting appropriate toxicological testing. One limitation in the
development of solid dispersion systems may the inadequate drug solubility in carrier, so a wider
choice of carriers will increase the success of dosage form development. Research should also be
directed toward identification of vehicles or recipients that would retard or prevent crystallization
of drugs from super-saturated systems. Attention must be given to any physiological and
pharmacological effects of carriers used. Many of the surface-active and self-emulsifying carriers
are lipid in nature, so potential roles of such carriers on drug absorption, especially on their
inhibitory effects on CYP-3 based drug metabolism and p-glycoprotein-mediated drug efflux
will require careful consideration. In addition to bioavailability enhancement, much recent

Introduction…
research on solid dispersion systems was directed toward the development of extended-release
dosage forms.
Physical and chemical stability of both the drug and the carrier in a solid dispersion are
major developmental issues, as exemplified by the recent withdrawal of ritonavir capsules from
the market so future research needs to be directed to address various stability issues. Predictive
methods will be necessary for the investigation of any potential crystallization of drugs and its
impact on dissolution and bioavailability, possible drug-carrier interactions must also be
investigated19.

Objectives…

CHAPTER–2
OBJECTIVES
By many estimates up to 40 percent of new chemical entities discovered by
the pharmaceutical industry today are poorly soluble or lipophilic compounds. The
solubility issues complicating the delivery of these new drugs also affect the delivery of
many existing drugs. Solid dispersion technology can be used to improve the in vitro
and in vivo dissolution properties of dissolution dependent poorly water soluble drugs.
PEG’s, PVP and surfactant like SLS have been reported to be used for increasing the
solubility of poorly soluble drugs.
Anagrelide HCl is anti platelet agent used for treatment of thrombocythemia

and which is administrated orally. Anagrelide HCl is very slightly soluble in water and
because of this it exhibits low bioavailability after oral administration. Therefore it is
important to improve the dissolution rate of oral dosage form and thus enhance the
therapeutic efficiency. Thus the objective of this work was to improve solubility and
dissolution rate of poorly water soluble drug Anagrelide HCl by solid dispersion
method.
OBJECTIVES OF THE STUDY: The objective of the study is to enhance solubility

of Anagrelide HCl by solid dispersion, which are expected to
¾ To enhance the dissolution rate of drug.

¾ Improve bioavailability
¾ To study in vitro drug release performance of different formulations.
¾ To study the phase solubility and stability constant for the intended complexes.
¾ Evaluate the potential of, polyethylene glycol 4000 and SSG as suitable drug
carrier systems for delivery of Anagrelide HCl.
¾ Determine the effect of change in polymer-polymer ratio on solubility of
Anagrelide HCl.
Department of Pharmaceutics, DSCP, Bangalore Page 22

Objectives…

2.1 PLAN OF WORK:
1. Preformulation studies
Infra-red spectroscopy. (FTIR)
2. Preparation of solid dispersions:

Preparation of solid dispersions employing different Carrier systems by
1. Physical mixture,
2. Solvent evaporation method
3. Fusion method.
Carrier Systems Used:
1. Polyethylene glycol 4000
2. Polyvinyl pyrrolidone.
3. Sodium Starch Glycolate
3. Evaluation of Anagrelide HCl. Solid Dispersions:

1. Physical appearance
2. Solubility study
3. Drug-content uniformity.
4. In vitro drug release studies.
5. Stability study.
6. Differential Scanning Calorimetri.(DSC)
7. X ray Diffratometry. (XRD)
8. Scanning Electron Microscopy ( SEM )

Department of Pharmaceutics, DSCP, Bangalore Page 23

Review of Literature…
CHAPTER–3
REVIEW OF LITERATURE
3.1 REVIEW OF LITERATURE:
An extensive work has been carried out on solid dispersion for many drugs with different
carrier as in order to improve their solubility and bioavailability. Some of them are cited below.
T.Kiraa20 et al formulated solid dispersions using water-insoluble carriers like

crospovidone, croscarmellose sodium, sodium starch glycolate, pre-gelatinized starch, potato
starch and avicel PH 10.1 with different ratios to enhance the dissolution rate of the glimepiride,
a poorly water insoluble drug. The surface solid dispersion of crospovidone with drug to carrier
ratio of 1:19 showed highest dissolution rate with the dissolution efficiency of 81.89% in
comparison to pure drug (22.88%) and physical mixture (35.96%). The surface solid dispersion
on crospovidone was characterized by powder X-ray diffractometry, differential scanning
calorimetry, Fourier transform infrared spectroscopy, gas chromatography and scanning electron
microscopy.
Deepa Pathak21 et al prepared solid dispersions of the poorly water-soluble drug

meloxicam with hydroxyethyl cellulose (HEC), mannitol and polyethylene glycol (PEG) 4000
and to develop a dosage form for geriatric population. Differential scanning calorimetry, X–ray
diffractometry, Fourier transform infrared spectroscopy and scanning electron microscopy were
used to investigate the solid-state physical structure of the prepared solid dispersions. Higher in
vitro dissolution was recorded with PEG 4000. Drug to carrier ratio (1:5) which are exhibited the
highest drug release (100.2%), followed by mannitol (98.2%) and HEC (89.5%) in the same ratio
Dept. of Pharmaceutics, DSCP, Bangalore Page 24

Moreshwar22 P. et al have studied the effect of polyethylene glycol 4000 (PEG 4000) on in
vitro dissolution of gliclazide3 from solid dispersion. Solid dispersions were prepared by the
melting or fusion method. Phase and saturation solubility study, in vitro dissolution of pure drug,
physical mixtures and solid dispersions were carried out. PEG was found to be effective in
increasing the dissolution of gliclazide in solid dispersions when compared to pure drug. FT-IR
spectroscopy, differential scanning calorimetry and X-ray diffractometry were studied to
characterization. Dissolution enhancement was attributed to decreased crystalline nature of the
drug and to the wetting and solubilizing effect of the carrier from the solid dispersions of
gliclazide.
Solubility behavior of solid dispersions of Valdecoxib (VLB) and etoricoxib23 (ETB) has
been studied. Solid dispersions were prepared with 1, 2, 5, 10, 15, and 20% w/w poly
(vinylpyrrolidone) (PVP) by the quench cooling method. The interactions between the drug and
polymer molecules were studied by Fourier transform infrared spectroscopy (FT-IR). Both the
drugs showed significant differences in their solubility behavior. In case of VLB, solubility was
found to increase significantly with increasing PVP concentration. ETB however did not show
any significant solubility enhancement but it shows decreased solubility at high PVP
concentrations.
Linyi24 Ma et al optimized the solid dispersions of ginkgolides to improve the drug

dissolution. The X-ray diffraction analysis (XRD) and differential scanning calorimetry (DSC)
were used to characterize the preparation. Solubilization using PVP k30 as carrier was better
than that poloxamer 188 or HPMC as matrix. The results of XRD and DSC showed that
ginkgolides existed in solid dispersion at amorphous form or solvates form. The dissolution rate
of ginkgolide B in solid dispersion was increased dramatically compared with raw material.

Physicochemical characteristics of solid dispersions of pizotifen malate25 and povidone

(Kollidon 12) at different proportions have been analyzed by X-ray diffraction, infrared
spectrometry, and differential scanning calorimetry (DSC) were used to test the solubility of the
solid dispersions. The results were compared with findings for physical mixtures with the same
proportions. A solid dispersion with a drug proportion of 16%–17% formed a eutectic mixture.
Solubility of pizotifen malate increased with the proportion of drug in the solid dispersion up to a
drug: polymer ratio of 40:60. The hydrotropic effect of the polymer also favored solubility in
physical mixtures this effect was greatest at a drug: polymer ratio of 10:90. Solubility at this
proportion was equal to that of the solid dispersion
DM Patel26 et al studied the solid dispersions of piroxicam with polyethylene glycol 400
and polyvinyl pyrrolidone k- 30 was prepared to increase its water solubility. Solid dispersions
of piroxicam were prepared using polyethylene glycol 400 as a water soluble carrier (1:4, 1:8,
1:12, 1:16, and 1:20 by weight) employing solvent evaporation method
Solid dispersion of poorly water soluble Glyburide27 (GLY) was prepared to enhance the
solubility. Solid dispersions of GLY were prepared using polyethylene glycol 4000 (PEG 4000),
PEG 6000 and a mixture of PEG 4000 and PEG 6000 (h1 mixture). The effect of melt and
solvent methods of preparation of solid dispersion on dissolution behavior was also investigated.
Dissolution studies indicated a significant increase in dissolution of GLY when dispersed in
PEG.
Solid dispersion and physical mixture of Meloxicam28 (MLX) with skimmed milk were
prepared to enhance the aqueous solubility and dissolution. Differential scanning Calorimetry,
X-ray diffraction and scanning electron microscopic analysis were revealed the formation of
solid dispersion of the drug with skimmed milk. Results showed that the solubility of solid
dispersion of the drug was almost three times greater than the pure drug.

Ganesh Chaulang29 et al prepared solid dispersion of furosemide in sodium starch

glycolate (SSG) in ratios of 1:1 by kneading method. The solid dispersion was characterized by
Fourier transform infrared (FTIR) spectroscopy, differential scanning Calorimetry (DSC), and X-
ray diffraction (XRD) to ascertain physicochemical interactions between drug and carrier. Solid
dispersion was formulated and their dissolution characteristics compared with commercial
furosemide tablets. The dissolution was performed at 37 ± 0.5oC and 50 rpm in (1.2 pH) gastric
fluid. XRD, DSC, FTIR spectroscopy and dissolution studies indicated that the solid dispersion
formulated in 1:2 ratio showed a 5.40-fold increase in dissolution and also exhibited superior
dissolution characteristics to commercial furosemide tablets.
Physico-chemical stability and drug dissolution profiles of the prepared solid dispersions
containing Verapamil30 HCl as active substance were evaluated using different experimental
methods during 6 months real-time stability studies. During the stability studies no drug
decomposition or changes in the active substance content appeared. Physical characterization of
the solid dispersions showed no changes in the drug/polymer network during ageing. The initial
amorphous appearance of the drug substance in the solid dispersions was maintained during
ageing. Although the drug dissolution profiles showed differences compared to series tested
immediately after preparation, the drug release dependence upon HPMCP HP 55 was maintained
even more pronounced at higher pH values.
Adinarayana31 G. et al studied the solubility and dissolution rate of a poorly water-soluble

drug, Nimodipine by a solid dispersion technique. The solid dispersions were prepared with
melting method by using polyethylene glycol 4000 (PEG- 4000) and polyvinylpyrrolidone K30
(PVPK30) in different drug-to-carrier ratios. Morphology of solid dispersions was characterized
by scanning electron microscope. The pure drug, physical mixtures and solid dispersions were
characterized by in vitro dissolution study by using pH 4.5 acetate buffer containing 0.3% SDS.
Solid dispersions prepared with PEG-4000 and PVPK30 showed the highest improvement in

wetability and dissolution rate of nimodipine. Even physical mixtures of nimodipine prepared
with both polymers also showed better dissolution profile than that of pure nimodipine. In
conclusion, dissolution of nimodipine was enhanced by the use of hydrophilic carriers PEG-4000
and PVPK30
NG Raghavendra32 Rao et al developed the fast dissolving tablets of the carbamazepine by

solid dispersion methods, using different concentrations of croscarmellose sodium as super
disintegrating agent and study the effect of various carriers on solid dispersion technique. The
formulations prepared with mannitol solid dispersion was in the disintegration time between the
ranges of 11.83 – 17.79 sec and drug release was in the ranges of 08 – 10 min. However the
formulations prepared with PEG‐6000 and PVP solid dispersions did not disintegrate in specified
limit of time for fast dissolving tablet. Among all formulations SM4 prepared with mannitol as
carrier showed 99.71 % drug release within 8 minutes. The prepared tablets were characterized
by DSC and FTIR Studies. No chemical interaction between drug and recipient was confirmed
by DSC and FTIR studies. The stability study was conducted as per the ICH guidelines for 3
months and the formulations were found to be stable. The results concluded that fast dissolving
tablets of poorly soluble drug, carbamazepine showed enhanced dissolution and bioavailability.
Ganesh Chaulang33 et al investigate the enhancement of the dissolution profile of

furosemide using solid dispersion technique. Solid dispersions were prepared by kneading
method using solvent water and ethanol in 1:1 ratio. Dissolution studies were performed by using
the USP paddle method at 37 ± 0.5oC and 50 rpm in simulated gastric fluid of pH 1.2. Fourier
transformer infrared (FTIR) spectroscopy, differential scanning Calorimetry (DSC), and x-ray
Diffratometry (XRD) were performed to identify the physicochemical interaction between drug
and carrier. IR spectroscopy, XRD, and DSC showed change in the crystal structure towards
amorphous. Dissolution of furosemide improved significantly in solid dispersion. The 1:2 solid
dispersion indicated increase in dissolution 5.11 fold. Tablets containing solid dispersion
exhibited better dissolution profile than commercial tablets.

Dabbagh34 MA et al prepared Ibuprofen solid dispersions by solvent and fusion-solvent

methods using polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), eudragit RS PO,
eudragit RL PO and hydroxypropylmethylcellulose (HPMC) as carriers to improve
physicochemical characteristics of ibuprofen. Prepared solid dispersions were evaluated for the
flowability, solubility characteristics and dissolution behavior. Flowability studies of powders
showed that solid dispersion technique was improve flow properties compared with the physical
mixtures. Dissolution was carried out in phosphate buffer (pH 6.8) using a standard USP II
dissolution apparatus. Solid dispersion technique was found to be effective in increasing the
aqueous solubility. Solid dispersion of Ibuprofen/PEG 6000 prepared in 1:1.5 ratio showed
excellent physicochemical characteristics and was found to be described by the zero order
kinetic, and was selected as the best formulation in this study.
Gerrit35 S. Z et al prepared cyclosporine A (CsA) solid dispersions by spray freeze-drying.

The solid dispersion was characterized by water vapor uptake, specific surface area analysis;
particle size analysis and Fourier transform infrared spectroscopy. Finally the dissolution
behavior was determined. The solid dispersion was a combination of a solid solution and solid
suspension. At a 10% drug load, 55% of the CsA in the powder was in the form of a solid
solution and 45% as solid suspension. The solid dispersions dissolved faster than the physical
mixture and CsA
Terbinafine36 HCl solid dispersion was formulated by using polyethylene glycol 6000
(by elating method) and polyvinyl pyrrolidone K 30 (by solvent method) in the drug carrier ratio
of 1:1, 1:2 and 1:3. The prepared solid aspersions were characterized for their drug content,
thermal studies, infrared spectral studies, differential scanning calorimetric studies, solubility
studies and in-vitro release studies. From the results it was clear that solid dispersion formulation
showed improved dissolution rate than pure drug and physical mixture. The tablets compressed
were evaluated for its physical parameters like thickness, hardness, weight variation, friability,
drug content and disintegration tests. The dissolution profile of formulated tablet was compared

with the marketed product and the formulated tablet showed better release profile than the
marketed product.
Patil37 CC et al studied the enhancement of dissolution efficiency of naproxen using

solid dispersions. Solid dispersions were prepared by melting method as well as common solvent
method using three hydrophilic carrier viz., PEG 6000, PEG 4000 and polyvinyl pyrrolidone,
employing chloroform as a common solvent. Naproxen showed only 56.51% dissolution at the
end of 90 minutes in pH 7.4 phosphate buffer, whereas solid dispersions showed enhanced drug
release. The increase in carrier ratio in the formulation increased the drug release. Dispersion
prepared by melting methods showed faster dissolution rate than common solvent method.
Dhanaraju38 MD et al studied Griseofulvin solid dispersions was prepared using

polyethylene glycol 6000 (PEG) and polysorbate 80 (Tween 80) mixture using fusion technique.
The in vitro dissolution release studies indicated that drug release from PEG with Tween 80
provided dissolution rates faster than dispersion prepared with PEG alone. The incorporation of
surface active agent such as tween 80 has a considerable effect in the in vitro dissolution profile
of Griseofulvin.
Gopal Rao39 M et al conducted a study to improve the dissolution rate of naproxen using
carrier such as PVP, PEG 4000, PEG 6000, PEG 20000, methyl cellulose and cyclodextrin with
a view to develop fast release formulations of naproxen. Solid dispersions of naproxen were
prepared by solvent evaporation method and dispersions were evaluated for drug content
uniformity, dissolution rates, moisture absorption, thin layer chromatography and X-ray
diffraction analysis. A marked increase in dissolution rate was observed with all solid
dispersions.

Inclusion complexes of tolbutamide40 with β-cyclodextrin and hydroxypropyl β

cyclodextrin were prepared using different methods like kneading, co-precipitation and freeze-
drying. Inclusion complexation in aqueous solution and in solid phase state was studied by the
solubility method, X-ray Diffratometry, and thermal analysis and Raman spectroscopy. The
solubility of tolbutamide increased as a function of cyclodextrin concentration, showing Bs and
AL type diagrams for β cyclodextrin and hydroxypropyl β cyclodextrin, respectively. The
dissolution rate of tolbutamide/cyclodextrin complexes were investigated and compared with
those of the physical mixtures and pure drug. The dissolution rate of tolbutamide from the
inclusion complexes was much more rapid than tolbutamide alone.
Gangadharappa41 HV et al studied the enhancement of solubility and dissolution of

rofecoxib by solid dispersion (SD) technique using various hydrophilic excipients like PEG
4000, PEG 6000 and PVP at different ratios by melting method and solvent evaporation method.
The prepared SD was characterized to various physico-chemical properties and in vitro drug
dissolution studies in 0.1N HCl with 0.25% SLS (pH 1.1) media for a period of 90 min using.
The result of study indicated that there was no drug-polymer interaction found. The drug
dissolution was found to enhance percent in PEG 4000, PEG 6000 and PVP, after 90mins of
dissolution study 79.02%, 88.02%, 98.57% respectively.
M.D.Dhanaraju42 prepared Solid dispersions by using polyethylene glycol 6000 (PEG),

talc and their combinations as carriers by the combination of melting and solvent method to
enhance the solubility of poorly soluble nimesulide as a model drug. The dissolution of
nimesulide from these dispersions was studied and it was evaluated by thermal behavior (DSC).
It was found that in these carriers the drug dissolution rate was a function of drug loading.
Dispersions of PEG and PEG / talc provided dissolution rates faster than those from dispersion
of talc. The incorporation of talc in PEG yielded dispersions with proportions of less tackiness
and ease of handling.

Solid dispersion of Glibenclamide43 was prepared by using different carriers such as PEG
6000, polyvinyl pyrrolidone (PVP) and Poloxamer in different ratios (1:1, 1:2, 1:3, 1:4 and 1:5)
by Solvent Evaporation method. Drug carrier interactions were analyzed by X‐ray diffraction
and Infra‐Red Spectroscopy. Dissolution studies using the USP paddle method were performed
for all solid dispersions. All solid dispersions showed increased dissolution rate as compared to
pure
Glibenclamide and PVP were found to be better than PEG and Poloxamer. Prepared tablets
containing solid dispersion exhibited better dissolution profile than commercial tablets.
Nala Chandana44 et al design the solid dispersion In order to improve the solubility and
oral absorption of the Efavirenz in gastric fluid and to enhance its dissolution rate. Solid
dispersions of Efavirenz were prepared using PEG 6000. The effect of fusion-solvent methods of
preparation of solid dispersion on dissolution behavior was also investigated. Dissolution studies
indicated a significant increase in dissolution of Efavirenz when dispersed in PEG6000. Solid
dispersions containing Efavirenz / PEG 6000 in 1: 8 ratio showed a 2-fold increase in dissolution
after 180 min in the 0.1 N HCl systems.

3.2 DRUG PROFILE:
Drug: AGRYLIN /Anagrelide Hydrochloride.
Pharmacological Classification: Platelet-reducing agent,

Thrombocytopenic agent and
Phosphodiesterase inhibitor
Structural formula:
Chemical Name: 6, 7-dichloro-1, 5-dihydroimidazo [2, 1-b] quinazolin-2(3H)-one

Monohydrochloride monohydrate.
Molecular formula: C10H7Cl2N3O•HCl•H2O
Description: A white or almost white amorphous powder
Appearance: Off-white powder
Physical state: Solid
Odor: Odorless
Dosage Form: 0.5 mg capsules for oral administration
Molecular weight: 310.55 gms
Melting point: 280

Solubility:
Water……………………….. Very slightly soluble

Dimethyl Sulfoxide………… Sparingly soluble
Dimethylformamide………... Sparingly soluble
Predicted Water Solubility: 2.50-01 mg/mL
Standard:
It contains not less than 99.0 percent and not more than the equivalent of 101.0 percent Of 6, 7-
dichloro-1, 5-dihydroimidazo [2, 1-b] quinazolin-2(3H)-one-Mono-hydrochloride-monohydrate.
Calculated with reference to the dried substance
Storage:
Store Anagrelide HCl at room temperature at 770F (ie.250 C) and store Anagrelide HCl away
from heat and light.
Pharmacokinetics:
Dosage Form: 0.5 mg.
Half-life45:- 1.3 hours.
Routes: Oral (capsules).
Absorption46: - well absorbed from the gastrointestinal tract
Protein Binding: Not Available
Metabolism: Extensive, Metabolized primarily in the liver by cytochrome P450 1A2 (CYP1A2).
Excretion: 75% in urine and 10% in feces. With < 1% recovered unchanged in the urine47, 48
Bioavailability: well absorbed following oral administration. Following oral administration,
peak plasma concentrations attained within 1–2 hours. No evidence of drug accumulation
following multiple dosing49

Pharmacological Profile
The mechanism by which Anagrelide HCl50, 51 reduces blood platelet count is still under
investigation. Studies in patients support a hypothesis of dose-related reduction in platelet
production resulting from a decrease in megakaryocytic hyper maturation. In blood withdrawn
from normal volunteers treated with Anagrelide HCl, a disruption was found in the post mitotic
phase of megakaryocytic development and a reduction in megakaryocytic size and plaids. At
therapeutic doses, Anagrelide HCL does not produce significant changes in white cell counts or
coagulation Parameters, and may have a small, but clinically insignificant effect on red cell
parameters. Anagrelide HCl inhibits cyclic AMP phosphodiesterase III (PDEIII). PDEIII
inhibitors can also inhibit platelet aggregation. However, significant inhibition of platelet
aggregation is observed only at doses of Anagrelide HCl higher than those required to reduce
platelet count.
Adverse52 Effect:
Common side effects are headache, diarrhea, unusual weakness/fatigue, hair loss, nausea
and dizziness.
Less common side effects include: congestive heart failure, myocardial infarction,
cardiomyopathy, cardiomegaly, complete heart block, arterial fibrillation, cerebrovascular
accident, pericarditis, pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension,
pancreatitis, gastric/duodenal ulceration, renal impairment/failure and seizure. Due to these
issues, Anagrelide HCl should not generally be considered for first line therapy in ET.

Drug Interactions:
In vivo interaction studies in humans have demonstrated that digoxin and warfarin do not
affect the PK properties of Anagrelide HCl, nor does Anagrelide HCl affect the PK properties of
digoxin or warfarin though additional drug interaction studies have not been conducted, the most
common medications used concomitantly with Anagrelide HCl in clinical trials were aspirin,
acetaminophen, furosemide, iron, ranitidine, ydroxyurea, and allopurinol. There is no clinical
evidence to suggest that Anagrelide HCL interacts with any of these compounds. Anagrelide
alone had no effect on platelet aggregation, but did slightly enhance the inhibition of platelet
aggregation by aspirin.
Anagrelide HCl is an inhibitor of cyclic AMP PDE III. The effects of medicinal products
with similar properties such as inotropes milrinone, enoximone, amrinone, olprinone and
cilostazol may be exacerbated by Anagrelide HCl. There is a single case report which suggests
that sucralfate may interfere with Anagrelide HCl absorption. Food has no clinically significant
effect on the bioavailability of Anagrelide HCl.
Dosage52 and Administration:
Treatment with Anagrelide HCl hydrochloride capsules should be initiated under close
medical supervision. The recommended starting dosage of Anagrelide hydrochloride capsules is
0.5 mg or 1 mg, which should be maintained for at least one week. Dosage should then be
adjusted to the lowest effective dosage required to reduce and maintain platelet count below
600,000/µL, and ideally to the normal range. The dosage should be increased by not more than
0.5 mg/day in any one week. Dosage should not exceed 10 mg/day or 2.5 mg in a single dose.
There are no special requirements for dosing the geriatric population

Uses:
Anagrelide HCl is used in the treatment of thrombocythemia; chronic myelogenous

leukemia and belongs to the drug class miscellaneous uncategorized agents. Risk cannot be ruled
out during pregnancy.

Methodology…
CHAPTER–4
METHODOLOGY
4.1 Materials and Equipment:
The following materials that were either AR/LR grade or the best possible pharma grade
available were used as supplied by the manufacturer.
Materials:
Sl. No. Materials/ Chemicals Source
Gift sample from cipla Pvt. Ltd,

1 Anagrelide HCl
Virgonagar, Bangalore
2 Polyethylene Glycol 4000 S.d. Fine chemicals limited, Mumbai
3 Sodium Starch Glycolate Loba Chemie Pvt. Ltd., Mumbai
Polyvinyl Pyrrolidone.
4 Sisco research lab. Pvt. Ltd. Mumbai
(PVP K30)
5 Dimethyl Sulfoxide (DMSO) S.d Fine Chemicals Pvt.Ltd., Mumbai
Potassium Dihydrogen
6 S.d Fine Chemicals Pvt.Ltd., Mumbai
Orthophosphate
7 Sodium Hydroxide S.d Fine Chemicals Pvt.Ltd., Mumbai
8 Hydrochloric acid Spectrum reagent and chemicals Pvt. Ltd., India.
9 Potassium bromide Merck specialities Pvt. Ltd., Germany
10 Potassium chloride Thomas baker, Mumbai, India.
Table No- 4.1, Materials Used for solid dispersion

Methodology…
Equipments:
Sl. No. Instruments/Equipments Source
1 Digital Balance Acculab Sartorius Group, Bangalore, India
2 Dissolution apparatus LabIndia, India
3 UV Spectrophotometer Shimadzu, Japan
4 FTIR Spectrophotometer Shimadzu, Japan
5 Differential Scanning Mettler-Toledo, USA

Colorimeter
6 pH meter Elico, India.
7 Hot air Oven Serwell Instrument Inc., Bangalore, India.
Borosil (A)-grade
8 Glassware
9 Mechanical Shaker Remi Motors Ltd, Mumbai, India
10 SEM JEOL, Tokyo, Japan
Table No – 4.2. INSTRUMENTS & EQUIPMENTS USED FOR SOLID DISPERSION

Methodology…
4.2 STANDARDIZATION OF DRUG:
Tests were carried out on the sample of the drug to establish its identity and purity as per USP
2001 specifications.
Calibration curve of Anagrelide HCl for in distilled water

Procedure: 100 mg of Anagrelide HCl was accurately weighed into 100ml volumetric flask and
dissolved in small quantity of (5%) percent DMSO. The volume was made up to 100ml with the
water to get a concentration of (1000 μg/ml.) Stock Solution-I (SS- I). From this, 2 ml was
withdrawn and diluted to 100ml to get a concentration of (20 μg/ml) SS-II. From the standard
stock solution (SS-II), 1,2,4,6 and 8ml were withdrawn and volume was made up to 10 ml with
Distilled water to give a concentration of 2,4,8,12 and 16μg/ml. Absorbance of these solutions
was measured against a blank of Distilled water at 275nm for Anagrelide HCl and the
absorbance values are summarized in Table 6. Calibration curve was plotted.
Calibration curve for Anagrelide HCl in 1.2 pH acidic Buffer:

Procedure: 100 mg of Anagrelide HCl was accurately weighed into 100ml volumetric flask and
dissolved in small quantity of (5%) percent DMSO. The volume was made up to 100ml with the
1.2 pH acidic Buffer to get a concentration of (1000 μg/ml.) Stock Solution-I (SS- I). From this,
2 ml was withdrawn and diluted to 100ml to get a concentration of (20 μg/ml) SS-II. From the
standard stock solution (SS-II), 1,2,4,6 and 8ml were withdrawn and volume was made up to 10
ml with Distilled water to give a concentration of 2,4,8,12 and 16μg/ml. Absorbance of these
solutions was measured against a blank of Distilled water at 275nm for Anagrelide HCl.

Methodology…
4.3 METHODS OF PREPARATION OF ANAGRELIDE HCl SOLID DISPERSION
A) Preparation of Anagrelide HCl Solid Dispersions with PEG 4000

Solid dispersions of Anagrelide HCl were prepared with PEG 4000. The methods used
for the preparation of Anagrelide HCl with PEG53 are physical mixture, solvent evaporation
method54, 55 and fusion method56
variables (1:1) (1:3) (1:5)

Anagrelide HCl (mg) 150 200 150
PEG 6000 (mg) 150 600 750
i) Physical Mixture: The physical mixtures were prepared by weighing the calculated
amount of Anagrelide HCl and the carriers and then mixing them in a glass mortar by
triturating. The resultant physical mixtures was passed through 44-mesh sieve and
stored in dessicator until used for further studies.
ii) Solvent Evaporation Method: The required amount of Anagrelide HCl and the carrier
were dissolved in sufficient volume of methanol with continuous stirring. The solvent
was then completely evaporated at 45º C with continuous stirring to obtain dry mass.
The dried mass was pulverized passed through 44 mesh sieve and stored in dessicator
until used for further studies.
iii) Fusion Method: Accurately weighed amount of carrier was melted in a porcelain dish at
80-85º C and to this calculated amount of Anagrelide HCl was added with thorough
mixing for 1-2 minutes followed by quick cooling. The dried mass was then
pulverized passed through 44-mesh sieve and stored in a dessicator until used for
.
further studies

Methodology…
B) Preparation of Anagrelide HCl Solid Dispersions with PVP K30:
Solid dispersions of Anagrelide HCl were prepared with PVP K30. The methods used for
the preparation of these solid dispersions were physical mixture and solvent evaporation method.
PVP57 containing solid dispersions were not prepared by the melt method, because PVP melts
above 250ºC and degrades before its melting point.
Variables (1:1) (1:2) (1:3)

PVP K30 (mg) 150 500 600

Methodology…
C) Preparation of Anagrelide HCl Solid Dispersions with SSG:

Solid dispersions of Anagrelide HCl in SSG were prepared with SSG. The methods used
for the preparation of these solid dispersions were physical mixtures, solvent evaporation method
and fusion method.
variables (1:1) (1:5) (1:7)

SSG (mg) 150 625 700
iii) Fusion Method: Accurately weighed amount of carrier was melted in a porcelain dish at
80-85º C and to this calculated amount of Anagrelide HCl was added with thorough
mixing for 1-2 minutes followed by quick cooling. The dried mass was then
pulverized passed through 44-mesh sieve and stored in a dessicator until used for
further studies.

Methodology…
4.4 EVALUATION OF ANAGRELIDE HCl SOLID DISPERSION SYSTEMS:
4.4.1 Physical Appearance:

All the batches of Anagrelide HCl solid dispersions were evaluated for colour and
appearance.
4.4.3 Determination of Anagrelide HCl Content:

An accurately weighed amount of each preparation was dissolved in small volume of
5% DMSO and further diluted with 1.2 pH buffered solution. The content of Anagrelide HCl
was determined spectrophotometrically at 275 nm using Shimadzu UV-visible
spectrophotometer.
4.4.2 Solubility of Anagrelide HCl
The most widely used approach to study inclusion complexation is the phase solubility
method described by Higuchi and Connors, which examines the effect of a solubilizer, i.e., the
drug being solubilized,
The solubility of Anagrelide HCl in various carriers was carried out and the solubility was
determined. Phase solubility58 studies on Anagrelide HCl with different carriers like PVP, PEG
4000 and SSG were performed by the method described by Higuchi and Connors. Excess
amount of Anagrelide HCl (10 mg) was added to 25 ml of distilled water containing various
concentrations of carriers (0, 0.25, 0.50, 0.75, 1.00 and 1.25% w/v). The suspensions were
shaken for 3 hours on a rotary flask at 37±1ºC and filtered through a whatman filter paper. The
filtrate so obtained was analyzed spectrophotometrically at 275 nm and corresponding
concentrations of the drug were computed from the standard curve.

Methodology…
The apparent solubility constant (Kc) according the hypothesis of 1:1 stoichiometric
ratio of complexes was calculated from the phase-solubility diagram using following equation.

The slope is obtained from the initial straight line portion of the plot of Anagrelide HCl against
solid dispersion concentration, and S0 is the equilibrium solubility of Anagrelide HCl in water.
4.4.4 in Vitro Dissolution:

The dissolution study was carried out using USP XXIII apparatus type-II. The
dissolution medium was 900 ml 1.2 pH acidic buffer along with 5% DMSO kept at 37±1ºC. The
drug or physical mixture or solid dispersions was taken in capsule and kept in the basket of
dissolution apparatus, the basket was rotated at 100 rpm. Samples of 1ml were withdrawn at
specified time intervals and analyzed spectrophotometrically at 275 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.
4.4.6 Stability Studies:

The purpose of stability testing is to provide evidence on how the quality of a drug
substance or drug product varies with time under the influence of a variety of environmental
factors such as temperature, humidity and light, and to establish a retest period for the drug
substance or a shelf-life for the drug product and recommended storage conditions. Stress testing
of the drug substance can help to identify the likely degradation products, which can in-turn help
to establish the degradation pathways and the intrinsic stability of the molecule and validated the
stability indicating power of analytical procedure used. The nature of the stress testing will
depend upon the individual drug substance and the type of drug-product involved.

Methodology…
The stability studies should be conducted on the drug substance packaged in container
closure systems is the same as or simulates the packing proposed for storage and distribution.
Stability studies on various batches were carried out by storing 500 mg of solid dispersions in an
Amber colored screw capped bottle at different temperatures for a period of 3 months.
The solid dispersions were visually examined for any physical change and drug content was
59
estimated at the end of 3 months .
4.4.7 COMPATIBILITY STUDY
Differential Scanning Calorimetry:

Differential scanning60 Calorimetry (DSC) of some selected preparations was compared
with plain Anagrelide HCl i.e. PEG 4000, solid dispersion & physical mixture were carried out.
The DSC thermograms were recorded at a heating of 10ºC/ min from 100ºC to 270ºC.
Infrared Spectroscopy:
The infrared spectra (IR) of Anagrelide HCl, PVP K30, PEG 4000 and SSG and some
selected preparations were obtained using FTIR. The IR spectra were carried by KBr pellet
method.
4.4.8 CHARACTERIZATION OF COMPLEXES
X-ray diffraction study:

X-ray diffraction study was done to study the powder characteristics of Anagrelide HCl and its
inclusion complexes with PEG 4000. X-ray diffractogram 61were obtained by Philips

Methodology…
Diffractometer (PW 1140) and Cu-K radiation diffractograms were run at a scanning speed of
2o/min and a chart speed of 2o/ 2cm/ 2θ
Scanning Electron Microscopy (SEM):

62
Scanning Electron Microscopy photograph of Anagrelide HCl and its solid dispersion with
PEG 4000 obtained using an optical microscope (JEOL, Tokyo, Japan) to observe the
morphology of Anagrelide HCl powder.

Results…
CHAPTER–5
RESULTS
5.1 Standard Calibration of Anagrelide HCl.
5.1.1 Standard Calibration Curve of Anagrelide HCl in Distilled Water:

Standard graph for the drug Anagrelide HCl was done in distilled water. Table 5.1 shows
the concentrations of Anagrelide HCl in distilled water and the respective absorbance. The
Figure 5.1 shows the standard graph of Anagrelide HCl in distilled water.
Table No. 5.1. Calibration data of Anagrelide HCl in distilled water at λ max 275 nm
Concentration
Sl. No. Absorbance
(µg/ml)
1 0 0
2 2 0.101
3 4 0.208
4 8 0.414
5 12 0.596
6 16 0.791
Dept of pharmaceutics, DSCP, Bangalore Page 48

Results…
Fig. 5.1: Standard calibration curve for Anagrelide HCl in Distilled water.
5.1.2: Standard Calibration Curve Data of Anagrelide HCl in 1.2 Acidic Buffers
Standard graph for the drug Anagrelide HCl was done in 1.2 Acidic Buffer with 5%
DMSO. Table 5.2 which show the concentrations of Anagrelide HCl with respective absorbance.
The Figure 5.2 shows the standard graph of Anagrelide HCl in 1.2 Acidic Buffer.

Results…
Table 5.2: Standard Calibration Curve Data of Anagrelide HCl in 1.2 Acidic Buffers
Concentration
Sl. No. Absorbance
(µg/ml)
1 2 0.049
2 4 0.114
3 6 0.167
4 8 0.242
5 10 0.312
6 12 0.374
7 14 0.442
8 16 0.506
Fig. 5.2: Standard calibration curve for Anagrelide HCl in acidic buffer

Results…
5.2 Phase solubility studies:
The phase-solubility diagram for the complexes of Anagrelide HCl with polymer is shown
in Fig.5.3, 5. The phase-solubility diagrams were of all according to Higuchi and Connors. The
amount of drug dissolved with respect to amount of polymer taken is given in table no 5.3.
Table 5.3 Phase solubility studies data
Solubility of Anagrelide HCl (µg/ml)

Concentration
Carrier (% w/v)
PEG 4000 PVP K30 SSG
0.00 22.17 22.17

22.17
0.25 25.68 23.70
27.87
0.50 29.63 26.55
32.48
0.75 33.14 28.53
37.75
1.00 36.65 30.51
41.92
1.25 47.63 41.26 32.48
Figure No 5.3: Phase solubility of study of Anagrelide HCl – PEG Complex

Results…
Figure No 5.4: Phase solubility of study of Anagrelide HCl – PVP K30 Complex
Figure No 5.5: Phase solubility of study of Anagrelide HCl –SSG Complex

Results…
5.3 EVALUATION AND CHARECTERIZATION OF ANAGRELIDE HCL

COMPLEXES:
Table No 5.4: Different formulations of Anagrelide HCl in molar ratio.

Drug to carrier
Drug to carrier Method Code
Ratio
Drug : PEG Physical Mixture 1:1 , 1:3 , 1:5 F1 , F2 , F3
Drug : PEG Solvent evaporation 1:1 , 1:3 , 1:5 F4 , F5 , F6
Drug : PEG Fusion Method 1:1 , 1:3 , 1:5 F7 , F8 , F9
Drug : PVP Physical Mixture 1:1 , 1:2 , 1:3 F10 , F11 , F12
Drug : PVP Solvent evaporation 1:1 , 1:3 , 1:3 F13 , F14 , F15
Drug : SSG Physical Mixture 1:1 , 1:5 , 1:7 F16 , F17 , F18
Drug : SSG Kneading method 1:1 , 1:5 , 1:7 F19 , F20 , F21
Drug : SSG Fusion Method 1:1 , 1:5 , 1:7 F22 , F23 , F24
Table No 5.5: Physical Appearance of Anagrelide HCl Solid Dispersions
Physical properties of solid dispersions

Method
Colour Appearance
White Fine powder

Physical mixture
White Fine powder
Solvent evaporation method
White Fine powder
Fusion method
White Fine powder
Kneading method

Results…
Drug Content Uniformity

The percentage of drug content was found to be between 80.12% and 92.59% which was
within acceptable limits. Table No 5.6 shows the results of drug content uniformity in each
formulation.
Table No 5.6: Determination of Anagrelide HCl Content Uniformity:
SR. Formulations Quantity Theoretical Practical % drug

NO. of complex drug drug Content
taken content content
(mg) (mg) (mg)
1 F1 50 14.3 12.6 88.18 ± 2.6
2 F2 50 8.3 7.6 92.59 ±1.6
3 F2 50 11.5 10.08 87.72 ±1.9
4 F4 50 6.5 5.83 89.81 ±3.4
5 F5 50 14.3 11.45 80.12 ±2.5
6 F6 50 8.3 7.66 92.35 ± 0.4
7 F7 50 11.5 10.50 91.34 ±1.8
8 F8 50 6.5 5.85 90.12 ±2.3
9 F9 50 14.3 11.75 82.20 ±3.1
10 F10 50 8.3 7.54 90.91 ±4.8
11 F11 50 11.5 10.42 90.65 ±1.6
12 F12 50 6.5 5.67 87.37 ±1.4
13 F13 50 14.3 11.45 80.12 ±3.8
14 F14 50 8.3 7.66 92.35 ±1.4

Results…
15 F15 50 11.5 10.50 91.34 ±1.7
16 F16 50 6.5 5.85 90.12 ±2.2
17 F17 50 14.3 11.75 82.20 ±2.4
18 F18 50 8.3 7.54 90.91 ±0.9
19 F19 50 11.5 10.42 90.65 ±1.4
20 F20 50 6.5 5.67 87.37 ±2.5
21 F21 50 14.3 11.45 80.12 ±1.5
22 F22 50 8.3 7.66 92.35 ±3.1
23 F23 50 11.5 10.50 91.34 ±2.9
24 F24 50 6.5 5.85 90.12 ±2.4
*Average of 3 determinations

Results…
Phase solubility of study of inclusive complex.
The phase-solubility diagram for the complexes of Anagrelide HCl with PEG is shown in
Fig.8. The phase Solubility study Data is given in table no (5.7). The aqueous solubility of
Anagrelide HCl, physical mixture and solid dispersion with PEG 4000 was 28.47, 51.72 and
99.88μg/ml respectively
Table No. 5.7: Phase solubility of study of Anagrelide HCl
Sr.
Sample Absorbance Conc. Concentration Concentration
No
(μg/ml) (mg/ml)
1 Pure drug 0.024 0.2847 28.47 0.028
Physical
2 0.436 5.172 51.72 0.051
mixture
Inclusion
3 0.842 9.988 99.88 0.0998
complex

Results…
Figure No 5.6: Phase solubility of study of Anagrelide HCl
IN-VITRO Dissolution study.
The dissolution data of Anagrelide HCl with PEG 4000 SSG and PVPK 30 systems are
given in table 5.4 to 5.8. The dissolution rate profiles of pure Anagrelide HCl and inclusion
complexes prepared by physical method, Solvent evaporation method, kneading method and
fusion method It is evident that the complexes prepared by all method exhibited a faster
dissolution when compared to pure drug. The percent drug release from various inclusion
complexes was found in the range of 67.055% to 91.33% within 90 minutes, where as the pure
drug exhibited only 1 to 38.84%.

Results…
Table-5.8: Percent Release of Pure Anagrelide HCl
Time Absorbance Concentration Conc. Conc. CDA CDR % CDR

(min) (μg/ml) (mg/ml) 900ml
0 0.000 0.000 0.000 0.000 ‐ 0.000 0.000
15 0.025 1.090 0.01090 17.10 0.000 17.10 17.10
30 0.058 2.6362 0.02630 23.67 0.0109 23.68 23.68
45 0.068 3.0901 0.030901 27.81 0.045 27.85 27.85
60 0.074 3.3634 0.033634 30.24 0.075 30.31 30.31
90 0.082 3.7278 0.037278 33.30 0.108 33.40 33.40
120 0.096 4.3632 0.043632 38.70 0.145 38.84 38.84
150 0.102 4.634 0.046340 41.40 0.188 41.58 41.58
180 0.107 4.863 0.04863 43.74 0.234 43.97 43.97
Figure-5.7: Percent Release of Anagrelide HCl

Results…
Table-5.9: In vitro Percent Release of Anagrelide HCl from Solid Dispersions containing
PEG 4000
Time Solvent
Physical Mixture Fusion method
(min) Evaporation
F1 F2 F3 F4 F5 F6 F7 F8 F9
0
0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000
05
10.593 11.864 20.868 30.154 27.125 37.214 22.560 21.532 25.731
15
21.949 23.737 37.605 48.726 44.562 56.586 34.803 35.214 43.361
30
27.372 42.266 56.461 59.36 64.486 78.608 49.791 51.438 49.791
45
33.220 53.250 62.288 78.608 77.699 85.875 60.546 62.818 62.935
60
42.203 61.453 65.995 84.687 81.152 87.758 62.935 65.424 72.668
90
52.627 68.544 67.055 85.787 87.519 91.337 71.043 74.948 76.149
Figure-5.8: Percent Release of Anagrelide HCl from Solid Dispersions containing PEG

Results…
PVP K30
Time Solvent
Physical Mixture
(min) Evaporation
F10 F11 F12 F13 F14 F15
0
0.000 0.000 0.000 0.000 0.000 0.000
05
15.367 18.655 19.477 19.272 24.820 25.642
15
26.138 27.801 28.833 33.352 36.443 49.211
30
37.174 37.202 39.678 43.812 45.481 60.153
45
46.421 46.038 49.349 54.123 63.462 69.749
60
53.663 54.305 57.635 63.462 70.023 78.146
90
61.529 62.617 63.499 78.146 82.125 83.651
Figure-5.9: Percent Release of Anagrelide HCl from Solid Dispersions containing PVP

Results…
SSG
Time
Physical Mixture Solvent Evaporation Fusion method
(min)
F16 F17 F18 F19 F20 F21 F22 F23 F24
0
0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000

05
16.806 20.505 21.121 25.231 25.231 27.902 22.149 24.615 25.642
15
30.667 34.585 38.089 40.167 40.167 41.620 38.514 40.574 42.635
30
40.495 48.339 51.657 54.157 54.157 53.769 52.084 54.156 56.292
45
49.760 57.031 59.340 66.374 66.374 66.806 61.413 60.620 69.210
60
55.377 61.249 63.570 73.315 73.315 74.571 67.080 67.734 74.932
90
59.996 63.845 66.795 76.594 76.594 81.761 70.969 72.215 75.965
Figure-5.10: Percent Release of Anagrelide HCl from Solid Dispersions containing SSG

Results…
Table No. 5.12: In vitro drug release for pure drug, Physical mixture, Fusion method and
Solvent evaporation method
Time (min) Pure Physical Solvent Solvent Fusion

Drug Mixture (F3) Evaporation Evaporation method (F9)
With PEG with PEG (F6) with SSG (F21) With PEG
0
0.000 0.000 0.000 0.000 0.000

05 17.10 20.868 37.214 27.902 25.731
15 23.68 37.605 56.586 41.620 43.361
30 27.85 56.461 78.608 53.769 49.791
45 30.31 62.288 85.875 66.806 62.935
60 33.40 65.995 87.758 74.571 72.668
90 38.84 67.055 91.337 81.761 76.149
Figure-5.11: in vitro drug release for pure drug, Physical mixture, solvent evaporation
method and Fusion method,

Results…
FT-IR SPECTRUM ANALYSIS
An FT-IR spectroscopy study was carried out separately to check the compatibility
between the drug (Anagrelide HCl) and the carrier used for the preparation of solid dispersion.
The FT-IR was performed for drugs, polymer, physical mixture and solids dispersion of drug and
polymer.
The spectra obtained from FT-IR spectroscopy studies at wavelength from 4000 cm-1 to
400 cm-1 are shown in Figures 5.12 to 5.23 and the characteristic peaks obtained are shown in
Table 6.1.
Figure No- 5.12: FT-IR Spectrum of Formulation pure drug Anagrelide HCl.

Results…
Figure No- 5.13: FT-IR Spectrum of PEG 4000
Figure No- 5.14: FT-IR Spectrum of SSG

Results…
Figure No- 5.15: FT-IR Spectrum of PVP K30
Figure No- 5.16: FT-IR Spectrum of Formulations F3 PM

Results…
Figure No- 5.17: FT-IR Spectrum of Formulations F6 SD

Results…

Results…

Results…

Results…
XRD SPECTRUM ANALYSIS:-
The X-RD patterns of pure drug Anagrelide HCl, PEG 4000, physical mixture (Drug-
PEG), solid dispersion (Drug-PEG) systems are represented in figure 5.24 to 5.27. The
diffractograms of Anagrelide HCl and PEG 4000 exhibited a series of intense peaks, which is an
indicative of their amorphous nature. X-RD pattern of physical mixture is simply the
superimposition of each component indicating no formation of new structure. Complex prepared
by solvent evaporation method showed a diffraction pattern quite similar to that of physical
mixture, while those obtained from physical mixture and fusion method showed less peaks with
low intensity. This indicates that the inclusion complex prepared by this method is less
crystalline than the complexes prepared by physical mixture and solvent evaporation method.
Figure No- 5.24: X-RD Spectrum of pure Anagrelide HCl

Results…
Figure No- 5.25: X-RD Spectrum of PEG 4000
Figure No- 5.26: X-RD Spectrum of Drug-PEG Physical Mixture

Results…
Figure No- 5.27: X-RD Spectrum of Anagrelide HCl-PEG Solid Dispersion
SCANNING ELECTRON MICROSCOPY ANALYSIS:
The morphology of Anagrelide HCl/ PEG 4000 solid dispersion was studied by SEM.
PEG 4000 particals were attached on to the surface of Anagrelide HCl in case of physical
mixture and in solid dispersion there were no distinguishable drug and PEG 4000 particles,
suggesting total miscibility of drug with the carrier.

Results…
Fig.5.28: Scanning electron micrographs of a) Anagrelide HCl
Fig.5.29: Scanning electron micrographs of PEG 4000

Results…
Fig.5.30: Scanning electron micrographs of physical mixture of Anagrelide HCl / PEG (F6)
Fig.5.31: scanning electron micrographs of solid dispersion of Anagrelide HCl/PEG4000

(F6).

Results…
DSC SPECTRUM ANALYSIS:
The thermal behavior of the Anagrelide HCl inclusion complexes was studied using
DSC in order to confirm the formation of solid inclusion complexes. When the guest molecules
are incorporated in polymer cavity or in the crystal lattice, their melting, boiling and sublimation
points usually shifted to a different temperature or disappear within the temperature range, where
the polymer lattice is decomposed. The thermograms of pure Anagrelide HCl PEG 4000,
physical mixture (Drug-PEG) and solid dispersion (Drug-PEG) are presented in figure 5.32 to
5.35.
Figure No- 5.32: DSC Spectrum of pure drug

Results…
Figure No- 5.33: DSC Spectrum of PEG 4000
Figure No- 5.34: DSC Spectrum of Physical Mixture

Results…
Figure No- 5.35: DSC Spectrum of Solid Dispersion

Results…
STABILITY STUDIES OF ANAGRELIDE HCl
The inclusion complexes of Anagrelide HCl (F6) were subjected to short-term stability
testing by storing the complexes at room temperature and at 40ºC
Table- 5.13: Short term stability studies of Anagrelide HCl complex at room Temperature
and at 40°C
Percent drug content ± SD at Percent drug content ± SD

Time Colour
Room Temperature at 40°C
First day white 100.03 ± 0.91 100.03 ± 0.91
1st week white 99.045 ± 0.19 99.15 ± 0.63
3rd week white 99.938 ± 0.62 99.13 ± 0.68
6th week white 98.204 ± 0.31 98.67 ± 0.38

Discussion…
CHAPTER– 6
DISCUSSION
EVALUATION AND CHARECTERIZATION OF ANAGRELIDE HCl COMPLEXES
Anagrelide HCl Complexes
In the present work inclusion complexes of Anagrelide HCl were prepared with PEG
4000, PVP K30 and SSG by physical mixture, Solvent evaporation method and fusion method.
The complexes were prepared in different molar ratios of drug and carrier PEG (1:1, 1:3 and
1:5), PVP K30 (1:1, 1:2 and 1:3) and SSG (1:1, 1:5, and 1:7) respectively. The prepared
complexes were characterized by differential scanning colorimetry (DSC), scanning electron
microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR) and powder x-ray
diffratometry (PX-RD). Prepared complexes were evaluated for in vitro drug release and short-
term stability studies and the results of all these evaluations are given in table-5.1 to 5.17. All the
prepared inclusion complexes were white and fine without any stickiness. The drug content of
the inclusion complexes was quite uniform (table-5.6). The percent drug content of the
complexes was found to be in the range of 80.12% to 92.59%
Phase solubility study.
The phase-solubility diagram for the complexes of Anagrelide HCl with polymer is
shown in Fig.5.3, 5.4, 5.4 and 5.6. The phase-solubility diagrams were of all according to
Higuchi and Connors. The amount of drug dissolved with respect to amount of polymer taken is
given in table no 5.3. The aqueous solubility of Anagrelide HCl was increased linearly as a
function of the polymer concentration showing that the increase in the solubility was due to the
formation of complex. The apparent solubility constant (Kc) was obtained from the slope of the
linear phase solubility diagrams. This value of stability constant (Kc) indicated that complexes
formed is quite stable.

Discussion…
The phase-solubility diagram for the complexes of Anagrelide HCl with PEG is shown in
Fig.8. The phase-solubility diagrams were of all according to Higuchi and Connors. The phase
Solubility study Data is given in table no (5.7). The aqueous solubility of Anagrelide HCl,
physical mixture and solid dispersion with PEG 4000 was 28.47, 51.72 and 99.88 μg/ml
respectively. The aqueous solubility of Anagrelide HCl increased linearly due to the formation of
complex. The apparent solubility constant (Kc) obtained from the slope of the linear phase
solubility diagrams increased linearly.
Compatibility study:
Compatibility studies were performed using FT-IR spectrophotometer. The IR spectrum of
pure drug, physical mixture of drug and polymer and solid dispersion of drug and polymer were
studied by making a KBr disc. The characteristic absorption peaks of Anagrelide HCl were
obtained at different wave numbers in different samples as shown in figure 5.12 to 5.23. The
peaks obtained in the spectra of each formulation correlates with the peaks of drug spectrum.
This indicates that the drug is compatible with the formulation components.
Table 6.1: IR Spectrum peak
Cl C-H C-N C=C C =N C=O N-H

Indications
FT-IR Pure
659.68 2844.85 1147.68 1570.11 1627.97 1799.00 3377.47
DRUG peaks at
FT-IR PEG SD
659.68 2842.85 1147.68 1570.11 1631.97 1799.00 3377.47
peaks at
FT-IR PVP SD
659.68 2844.85 1157.68 1570.11 1627.97 1799.00 3412.47
peaks at
FT-IR SSG SD
659.68 2844.85 1147.68 1570.11 1627.97 1799.00 3437.47
peaks at

Discussion…
Drug content uniformity
The percentage of drug content was found to be between 80.12% and 92.59% which was
within acceptable limits. Table No 5.6 shows the results of drug content uniformity in each
formulation.
IN-VITRO Dissolution study.
The dissolution data of Anagrelide HCl with PEG 4000 SSG and PVPK 30 systems are
given in table 5.4 to 5.8. The dissolution rate profiles of pure Anagrelide HCl and inclusion
complexes prepared by physical method, Solvent evaporation method and fusion method It is
evident that the complexes prepared by all method exhibited a faster dissolution when compared
to pure drug. The percent drug release from various inclusion complexes was found in the range
of 67.055% to 91.33% within 90 minutes, where as the pure drug exhibited only 1 to 38.84%.
Inclusion complexes of drug with PEG 4000, exhibited release in 1.2 pH buffer in the
following order, 67.055%, 91.33%, 76.14% from formulations F3, F6, & F9 respectively in 90
minutes in case 1:5 M ratio. Whereas in the formulations F1, F4, & F7 showed 52.627%,
85.78%, 71.04% of drug release respectively in case of 1:1 M ratio.
Inclusion complexes of Anagrelide HCl prepared with PVP K30 showed release 63.49%
83.65%, of Anagrelide HCl from F12 and F15 in 90 minutes using 1.2 pH buffer as a dissolution
medium in case of 1:3 M ratio. Formulations F4, F8, & F12 showed 62.61% and 82.12 % release
respectively in 1:2 M ratio.
Inclusion complexes of drug with SSG exhibited release in 1.2 pH buffer in the following
order, 66.795%, 81.761%, 75.965%% from formulations F18, F21, & F24 respectively in 90
minutes in case 1:7 M ratio. Whereas in the formulations F16, F19, & F22 showed 59.996%,
76.594%, 70.969%, and of drug release respectively in case of 1:1 M ratio.

Discussion…
A marked improvement in dissolution rates of Anagrelide HCl was observed with F6 and
F21 prepared by Solvent evaporation method and kneading method. The higher dissolution rates
observed with inclusion complexes prepared by Solvent evaporation and kneading method may
be due to better interaction of drug and polymer.
X-RD Study:
The X-RD patterns of pure drug Anagrelide HCl, PEG 4000, physical mixture (Drug-
PEG), solid dispersion (Drug-PEG) systems are represented in figure 5.24 to 5.27. The
diffractograms of Anagrelide HCl and PEG 4000 exhibited a series of intense peaks, which is an
indicative of their amorphous nature. X-RD pattern of physical mixture is simply the
superimposition of each component indicating no formation of new structure. Complex prepared
by solvent evaporation method method showed a diffraction pattern quite similar to that of
physical mixture, while those obtained from physical mixture and fusion method showed less
peaks with low intensity. This indicates that the inclusion complex prepared by this method is
less crystalline than the complexes prepared by physical mixture and solvent evaporation
method.
SCANNING ELECTRON MICROSCOPY ANALYSIS:
The morphology of Anagrelide HCl/ PEG 4000 solid dispersion was studied by SEM.
PEG 4000 particals were attached on to the surface of Anagrelide HCl in case of physical
mixture and in solid dispersion there were no distinguishable drug and PEG 4000 particles,
suggesting total miscibility of drug with the carrier.

Discussion…
DSC Study:
The thermal behavior of the Anagrelide HCl inclusion complexes was studied using
DSC in order to confirm the formation of solid inclusion complexes. When the guest molecules
are incorporated in polymer cavity or in the crystal lattice, their melting, boiling and sublimation
points usually shifted to a different temperature or disappear within the temperature range, where
the polymer lattice is decomposed. The thermograms of pure Anagrelide HCl PEG 4000,
physical mixture (Drug-PEG) and solid dispersion (Drug-PEG) are presented in figure 5.32 to
5.35. The DSC thermo gram of Anagrelide HCl showed an endothermic peak at 134.82°C
corresponding to its melting point. The thermograms of PEG showed a very broad peak at
59.87°C corresponding to its melting point. The thermograms of Anagrelide HCl and PEG (1:5
M) prepared by physical and solvent evaporation method i.e., F3 and F6, respectively showed
endothermic peaks 59.22°C and 61.31°C. This may be due to shift of characteristic peak of
Anagrelide HCl which was observed at 134.82°, indicates a strong interaction of drug and PEG
4000.
Short-term stability study

The inclusion complexes of Anagrelide HCl (F6) were subjected to short-term stability testing by
storing the complexes at room temperature and at 40ºC with 75% (RH) humidity. The samples
were analyzed at an interval of one week, three weeks and six weeks for their physical
appearance, drug content values and dissolution profiles. No appreciable changes observed with
the above parameters and are given in table 5.13.

Conclusion…
Chapter 7
CONCLUSION
FROM THE PRESENT STUDY, THE FOLLOWING CONCLUSIONS CAN BE
DRAWN:
¾ Polymers like PEG 4000, PVP K30 and SSG can be used to prepare inclusion complexes
of Anagrelide HCl with improved solubility of the drug. Phase solubility studies of drug
with PEG 4000 illustrate the solubility enhancement. The phase solubility of pure drug,
physical mixture and solid dispersion was found to be 28.47 μg/ml, 51.72 μg/ml and
99.88 μg/ml respectively
¾ FT-IR and DSC studies indicated the formation of true complexes of Anagrelide HCl and
PEG 4000 in 1:5 molar ratio prepared by Solvent evaporation method.
¾ The dissolution of Anagrelide HCl from inclusion complex prepared by kneading, solvent
evaporation method was found to be higher than the pure drug and other prepared
complexes.
¾ The inclusion complexes of Anagrelide HCl prepared by Solvent evaporation method
(F6) were subjected to short-term accelerated stability studies had no appreciable change
in its physical appearance, drug content value and dissolution profiles were observed.

Conclusion…
¾ All prepared complexes showed improved dissolution when compared to drug alone and
this was characterized by XRD, DSC and FT-IR studies
¾ Enhancement of the solubility of Anagrelide HCl- PEG 4000 Solvent evaporation
evaporation complex was 92.33% in 90 min with 3-fold increase in its dissolution rate.
¾ Hence from the above results it can be concluded that PEG4000 and SSG PVP k30 can
be used to formulate fast releasing formulations of drug.

Summary…
Chapter 8
SUMMARY
The poor dissolution of relatively water insoluble drugs as for long had been a
problem in the formulation of oral dosage forms. This limits such as absorption and
Bioavailability. Several approaches have been followed in improving solubility of the
drugs, one of them is solid dispersion to increase the solubility and bioavailability,
Anagrelide HCl can be formulated in the form of complexes with carrier such as PEG
4000 PVP K30 and SSG.
The scheme of the work followed was as under:
Chapter 1: Introduction:
In this chapter, the various methods to improve the solubility, solubility improvement by
complexation with carrier has been explained.
Chapter 2: Objective of the work:
The aims and objectives involved in the proposed work were given.
Chapter 3: Review of Literature:
Past work in connection with the solubility improvement by solid dispersion which were
reported in different scientific journals.
Department of Pharmaceutics, DSCP, Bangalore. Page 86

Summary…
Chapter 4: Methodology:
In this chapter the materials used throughout the work was entitled and the methods
followed in the investigation were discussed.
Chapter 5: Results and Discussion:
In this chapter all the results were presented in the form of tables, graphs and figures. The
results obtained are explained and discussed in detail.
Chapter 6: Conclusion:
Conclusions were entitled.


Reference…
Chapter 9
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Annexure…
10. ANNEXURE
10.1 Poster Presentation
Study Of Solubility Enhancement Of Anagrelide Hydrochloride By Solid Dispersion, at

2nd International conference on drug delivery, PSG college of pharmacy, 21st,&22nd
January, 2011, Coimbatore. Tamil Nadu. India.
Abstract code: PP 026

STUDY OF SOLUBILITY ENHANCEMENT OF ANAGRELIDE HYDROCHLORIDE
BY SOLID DISPERSION
Morge Ganesh Vasantrao*, Brahmani Priyadarshini SR,

Pankaj Patel, Nagabhushan BS, Wilson B.
Department of Pharmaceutics, Dayananda Sagar College

of Pharmacy, Bangalore-78.
The objective of the present study was to enhance the solubility of Anagrelide
hydrochloride by solid dispersion. Anagrelide hydrochloride is an ant platelet agent
having poor water solubility. Solid dispersion is the one of the most commonly used
techniques to improve the aqueous solubility of poorly water soluble drugs. Solid
dispersions of Anagrelide hydrochloride were prepared using different carriers such as
poly ethylene glycol - 4000 (PEG-4000) and sodium starch glycolate by melting/ fusion
method and kneading method. The prepared solid dispersions of Anagrelide
hydrochloride and the physical mixtures were evaluated for phase and saturation
solubility study, FT-IR studies, differential scanning Calorimetry (DSC), scanning
electron microscopy (SEM), X-ray diffraction (X-RD) and in vitro dissolution studies.
The results revealed that the solid dispersions prepared with carrier PEG-4000
significantly increased the dissolution of drug Anagrelide hydrochloride in comparison
with the carrier sodium starch glycolate. In conclusion, solid dispersion technique can be
successfully used to improve the dissolution of Anagrelide hydrochloride.

Anagrelide Dispersion Solida

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STUDY OF SOLUBILITY ENHANCEMENT

Dissertation submitted to the Rajiv Gandhi University of

In partial fulfillment of the requirements for the degree of

MORGE GANESH VASANTRAO B. Pharm.

Dayananda Sagar College of pharmacy

© Rajiv Gandhi University of Health Sciences, Karnataka.

JAYANAGAR 4th T- Block, BANGALORE,

DECLARATION BY THE CANDIDATE

I hereby declare that this dissertation entitled “Study of solubility enhancement of

Anagrelide hydrochloride by solid dispersion” is a bonafide and genuine research

Associate Professor, Department of Pharmaceutics, Dayananda Sagar College of

Pharmacy, Bangalore -78.

Date: Signature of the Candidate

Place: Bangalore Mr. Morge Ganesh Vasantrao

KUMARASWAMY LAYOUT, BANGALORE-560078,

CERTIFICATE BY THE GUIDE

I hereby declare that this dissertation entitled “Study of solubility enhancement of

Anagrelide hydrochloride by solid dispersion” is a bonafide research work done

degree of “Master of Pharmacy in Pharmaceutics”

Date: Signature of the Guide

Place: Bangalore Mrs. BRAHMANI PRIYADARSHINI SR.

ENDORSEMENT BY THE HOD, PRINCIPAL/HEAD

This is to certify that the dissertation entitled “Study of solubility enhancement of

Anagrelide hydrochloride by solid dispersion” is a bonafide research work done

by Mr. Morge Ganesh Vasantrao under the guidance of Mrs. BRAHMANI

PRIYADARSHINI SR. Associate Professor, Department of Pharmaceutics.

Dayananda Sagar College of Pharmacy, Bangalore-78.

Place: Bangalore Place: Bangalore

Declaration by the Candidate

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

dissertation in print or electronic format for academic/research purpose.

Date: Signature of the candidate

Place: Bangalore Mr. Morge Ganesh Vasantrao

© Rajiv Gandhi University of Health Sciences, Karnataka.

I take this privilege and pleasure to acknowledge the contributions of

It is with pleasure of immense gratitude that I express my most

I am gratefully indebted to Dr. V. Murugan, M. Pharm., Ph.D.

I consider it as a great privilege to express my heartfelt gratitude and

I will not forget the help and company given by my classmates

My special thanks and appreciation goes to all my seniors, especially,

Words are not sufficient to express my deepest love and appreciation

I express my deep sense of gratitude to Cipla Pvt. Ltd, Virgonagar,

Finally I consider this as an opportunity to express my gratitude to all

Solid dispersions of Anagrelide hydrochloride were prepared using

The prepared solid dispersions of Anagrelide hydrochloride and the

PEG Poly ethylene glycol

PVP Polyvinyl pyrrolidone

SSG Sodium starch glycolate

DMSO Dimethyl sulfoxide

FTIR Fourier Transform Infrared

SEM Scanning Electron Microscopy

DSC Differential Scanning Calorimetry

XRD X-ray diffraction

GIT Gastro Intestinal Tract

USP United States Pharmacopoeia

rpm Revolutions Per Minute

CDR Cumulative drug release

Department of Pharmaceutics, DSCP, Bangalore.

pH Negative Logarithm of Hydrogen Ion Concentration

Percent weight / volume

Department of Pharmaceutics, DSCP, Bangalore.

F1 Solid dispersions of Anagrelide HCl containing PEG4000

F2 Solid dispersions of Anagrelide HCl containing PEG4000

F3 Solid dispersions of Anagrelide HCl containing PEG4000