Rampal Ahirwar Final Thesis

FORMULATION, DEVELOPMENT AND EVALUATION OF SOLID
DISPERSION FOR DISSOLUTION RATE ENHANCEMENT
M Pharm Dissertation 2020-2021
SUBMITTED TO
RAJIV GANDHI PROUDYOGIKI VISHWAVIDYALAYA, BHOPAL

(UNIVERSITY OF TECHNOLOGY OF MADHYA PRADESH)
In fulfillment of the requirements for the award of degree of
Master of Pharmacy in Pharmaceutics
Guide Co- Guide

Dr. Umesh K. Jain Miss. Dibya Kumari
(Director & Principal) ( Asst.Professor)
Submitted by:
RAM PAL AHIRWAR
M. Pharm-IV Semester
ENROLLMENT NO. 0139PY18MP09
BHOPAL INSTITUTEOF TECHNOLOGY&SCIENCE-PHARMACY,

BHOPAL(M.P.)
2020-2021
BHOPAL INSTITUTE OF TECHNOLOGY & SCIENCE- PHARMACY
(Ed society: Globus Institute of Engineering&Technology) Bhojpur Road,
Bangrasia Bhopal-462045(M.P.) Mailing Add: - BITS Bhopal
Phone (07480)262392; Fax (0755)4422050; Email: -
bitspharmacy@gmail.com
Approved by AICTE, New Delhi; Affiliated to RGPV, Bhopal (M.P.)
BITS-PH/19/ Date:
APPROVAL LETTER
The dissertation work entitled “FORMULATION, DEVELOPMENT AND EVALUATION OF

SOLID DISPERSION FOR DISSOLUTION RATE ENHANCEMENT” being submitted by Mr.
RAMPAL AHIRWAR (Enroll. no. 0139PY18MP09) student of M.Pharm. IV semester,
has been examined by us and has been submitted to Rajiv Gandhi Proudyogiki
Vishwavidyalaya, Bhopal (MP).
Internal Examiner: External Examiner:

Date: Date:
BHOPAL INSTITUTEOF TECHNOLOGY&SCIENCE-PHARMACY,

BHOPAL(M.P.)
2020-2021
BHOPAL INSTITUTE OF TECHNOLOGY & SCIENCE-
(Ed Society Globus Institute of Engineering & Technology)
Bhojpur Road, Bangrasia, Bhopal – 462045 (M.P.) Mailing Add: BITS Bhopal
Phone: (07480)-262392, Fax: (0755) 4422050, E- mail:
Approved by AICTE, New Delhi & PCI New Delhi
Affiliated to RGPV, Bhopal (M.P)
FORWARDING LETTER
This is to certify that Mr. RAMPAL AHIRWAR (Enroll. no. 0139PY18MP09) has sincerely
worked under the guidance of Dr. Umesh K. Jain & Co-guidance Miss Dibya Kumari for
his dissertation part-II entitled “FORMULATION, DEVELOPMENT AND EVALUATION
OF SOLID DISPERSION FOR DISSOLUTION RATE ENHANCEMENT’’ His work is
Appropriate and fulfills the requirement of the syllabus. I hereby forward his dissertation part -II.
Date: - Director
Place: - Bhopal Dr. UMESH K. JAIN
(M. Pharm., Ph.D.)

Director & Principal
BHOPAL INSTITUTE OF TECHNOLOGY &SCIENCE-PHARMACY,

BHOPAL(M.P.)
Bhojpur Road, Bangrasia, Bhopal – 462045 (M.P.) Mailing Add: BITS Bhopal Phone:
(07480)-262392, Fax: (0755) 4422050, E- mail: bitspharmacy@gmail.com
CERTIFICATE
This is to certify that ‘RAMPAL AHIRWAR’ has actively worked on his dissertation part-IIentitled
“FORMULATION, DEVELOPMENT AND EVALUATION OF SOLID DISPERSION FOR DISSOLUTION
RATE ENHANCEMENT” under our supervision. He is hard working and has carried out his scientific dissertation
part-II with full devotion. He has consulted us several times during working and preparation of dissertation part-II.
We strongly recommend his dissertation part- II for the award of degree of Masters of Pharmacy in Pharmaceutics.
Guide Co-Guide
Dr. Umesh K. Jain Miss Dibya Kumari
(Director & Principal) (Asst. Professor)
BHOPAL INSTITUTE OF TECHNOLOGY &SCIENCE-PHARMACY,

BHOPAL(M.P.)
BHOPAL INSTITUTE OF TECHNOLOGY & SCIENCE- PHARMACY
Bhojpur Road, Bangrasia, Bhopal – 462045 (M.P.) Mailing Add: BITS
Bhopal Phone: (07480)-262392, Fax: (0755) 4422050, Email:
DECLARATION
I hereby declare that the work, which is being presented in the dissertation, entitled
“FORMULATION, DEVELOPMENT AND EVALUATION OF SOLID DISPERSION FOR DISSOLUTION
RATE ENHANCEMENT’’ in partial fulfillment of the requirement for the award of degree of master of
pharmacy in pharmaceutics submitted in the Department of Bhopal Institute Of Technology And
Science- Pharmacy Bhopal (M.P.) is an authentic record of my own Works Carried under the guidance
of Prof. (Dr. Umesh Kumar Jain) I have not Submitted the Matter Embodied in this report for award
of any other degree. I also declared that "A Check for plagiarism has been carried on the
thesis/dissertation and is found within acceptable limit and report of which is enclosed herewith."
Co-Guide Guide
Miss Dibya Kumari Dr. Umesh K. Jain
(Asst. Professor) (Director & Principal)
Rampal Ahirwar
M. Pharmacy IV Sem
Enroll no. 0139PY18MP09
BHOPALINSTITUTEOFTECHNOLOGY&SCIENCE-PHARMACY,BHOPAL(M.P.)
2019-2020
PHARMACY
Phone: (07480)-262392, Fax: (0755) 4422050, E- mail:
Approved by AICTE, New Delhi & PCI New
DECLARATION
This work presented in the thesis entitled “FORMULATION, DEVELOPMENT AND

EVALUATION OF SOLID DISPERSION FOR DISSOLUTION RATE ENHANCEMENT”
was carried out by me, under the guidance of Dr. Umesh K Jain & Co- guidance of Miss
Dibya Kumari of ‘BITS Pharmacy, Bhopal..This work is original and has not been
submitted in part or full for the award of other degree or diploma of any other university.
Place:-
Date:- Rampal Ahirwar
Enroll.No.0139PY18MP09
Dept. of Pharmaceutics
BITS – Pharmacy
Bhopal (M.P.)
BHOPALINSTITUTEOFTECHNOLOGY&SCIENCE-PHARMACY,BHOPAL(M.P.)
2020-2021
PHARMACY
Phone: (07480)-262392, Fax: (0755) 4422050, E- mail:
Approved by AICTE, New Delhi & PCI New
ACKNOWLEDGEMENT
I am highly obliged to my guide Dr. Umesh K. Jain (Director & Pricnciple) Bhopal institute of
technology and science – pharmacy, Bhopal (M.P.), and my deepest gratitude to him for his constant
encouragement and cogent guidance during project work.
I am forever indebted to my co-guide Miss Dibya Kumari Asst. Professor, motivate
regularly to me for completion of research work. He provide me new ideas and inventions regarding
my topic and also provide me research articles, literature of various scientific journals.
I am thankful to the teaching staff Mr. Ajay Patel, Dr. Abhishek Jain, Mr. Anil Nagar,
Mr. Neeraj Patidar, Ms. Dibya Kumari, Mr. Manjesh Kumar, Mr. Dinkar Jayswal & Ms. Ashita
Pawaiya for their help and co-operation.
I am also thankful to all my supporting non-teaching staff of institute.
I also thankful and express my deepest heartiest parents & family members, those
regularly encourage me for completion of my thesis work.
I thank the almighty to make so many to extend their helping hands to complete my job
successful.
Date: Rampal Ahirwar

Place: Bhopal M.Pharm.IV SEMESTER
Enrollment No.:-0139PY18MP09
BHOPALINSTITUTE OF TECHNOLOGY& SCIENCE- PHARMACY, BHOPAL(M.P.)

2020-2021
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“FORMULATION, DEVELOPMENT
DISSOLUTION RATE ENHANCEMENT” A Dissertation Part-II submitted to Rajiv Gandhi
Proudyogiki Vishwavidyalaya, Bhopal (M.P.) In partial fulfillment for the award of degree of
Master of Pharmacy (Pharmaceutics)
bioavailability of poorly water soluble compounds. Various techniques are used for the improvement of t
Active Pharmaceutical Ingredients (APIs) have played a crucial role. To improve
bioavailability, stability and convenience to the patient, is the major objective of

formulation chemistry (Majerik et al., 2004). Bioavailability means the rate and extent to which the active
of an orally administered drug depends on its solubility in aqueous media over the pH
range of 1.0–7.5and the rate of mass transfer across biological membranes (Charbit et al.,
2004). In the oral bioavailability of poorly water soluble compounds, the insufficient
dissolution rate is the limiting factor (Rogers et al., 2001). Some new technologies have
been recently developed to improve wettability and aqueous solubility of APIs. These
methods are based on the use of compressed gases, supercritical fluids, and anti-solvent
(Jung and Perrut, (2001). The critical requirement for a poorly water-soluble drug for
absorption to be possible from the gastrointestinal (GI) tract is, achieving a solution of
drug in the GI fluid Horter and Dressman, 1997 defined a poorly water-soluble drug as the
one whose dissolution in the GI fluid under ordinary conditions takes a longer time than
its transition through the absorption sites in the GI tract. To increase dissolution rates of
drugs, salt formation, particle size . reduction etc., have commonly been used but
achieving desired bioavailability enhancement may not always be possible due to some
practical limitations with these techniques (Serajuddin, 1999). Solid dispersion systems
have shown promising results in increasing bioavailability of poorly water-soluble drugs in
which the drug is dispersed in solid water-soluble matrices either molecularly or as fine
particles
(Chiou and Riegelman, 1971; Ford, 1986; Serajuddin et al., 1988). 1.3 Methods for
solubility enhancement 1.3.1 Supercritical fluid technology Supercritical fluids are fluids
whose temperature and pressure are greater than their critical temperature (Tc) and
critical pressure (Tp). In the supercritical fluid (SCF) process, micronization is done by the
supercritical fluid which is highly compressible, and allows moderate changes in pressure
to greatly alter the density and mass transport characteristics that largely determine its
solvent power (Kakumanu and Bansal, 2004). The SCF process can create nanoparticle of
particles 5–2,000 nm in diameter (Pasquali et al., 2006; Reverchon and Adami, 2006).
Solvent extraction-evaporation, solvent diffusion and organic phase separation are some
conventional methods which require the use of organic solvents. These organic solvents are
hazardous to the environment as well as to physiological systems. Supercritical fluids are
environmentally safe. Therefore, to prepare biodegradable micro and nano-particles the
supercritical fluid technology has been investigated as an alternative (Ahuja et al., 2006).
1.3.2 Prodrug approach Throughout the past decades prodrug approaches have been used
to improve the pharmaceutical properties such as solubility, taste, odor, stability, etc.
Designing of prodrug is also used to improve the physicochemical properties such as
compound lipophilicity and solubility to prevail over the pharmacokinetic demerits
associated with drug molecules. The chemical decomposition and presystemic metabolism
is to be reduced by the use of prodrug approach. The basic principle associated with is to
cover the undesired functional group(s) with another functional group, which usually are
referred as promoiety. Designing prodrug for improving bioavailability is one of the
lucrative approaches especially for protein and peptide molecules. Designing of cyclic
prodrug using C and N terminal ends reduced the metabolic degradation caused by
exopeptidase. A recent study INTRODUCTION involved synthesis of cyclic hexapeptide to
improve the enzymatic stability and permeability through biological membranes. It showed
increased permeability of cyclic prodrug than parentmolecule. Derivatization is another
lucrative approach for synthesis of prodrug to improve bioavailability of drug molecules
especially for peptide

molecules. Derivatization could be possible in C terminal amide group, N terminal amide
group and phenol group in various peptide molecules (Shah et al., 1994). 1.3.3
Microemulsion formulations Microemulsion is a lipid based delivery system whose major
advantages include high solubilization potential, thermodynamic stability, improved
dissolution of lipophilic drugs (Constantinides, 1995) and surfactant-induced permeability
enhancement. 1.3.4 Dissolution enhancement by physical modification of the drug The
solubility of a drug determines the dissolution behavior of an active pharmaceutical
ingredient (API) in the formulation as well as therapeutic efficacy of the drug. Reduction
of particle size, complexation, and solid dispersions of drug in suitable carriers are some
commonly used physical modifications of the API. In solubility limited absorption (intrinsic
solubility controlled), the formulation approach is commonly used to enhance the
solubility of the API and this approach also includes the use of surfactants in the
formulation (solid dispersions), non-crystalline materials, and different salt forms of API.
1.3.5 Micronization For many decades, the dissolution rate is being increased by reducing
the particle size of poorly water-soluble drugs. Conventional methods of particle size
reduction, such as comminution and spray drying, rely upon mechanical stress to
disaggregate the active compound. Today, micronization of drugs is widely done by milling
techniques using a jet mill, rotor stator, colloidal mill, and air attrition. Kornblum and
Hirschorn (1970) evaluated two specific methods of micronization, spray drying and air
attrition, which provided drug forms of different specific surface areas and particle size
ranges. With the aforementioned advantages, micronization has some limitations;
micronization of sparingly or poorly soluble drugs is by no means a guarantee of better
dissolution and absorption. 1.3.6 Nanotechnology
Nanotechnology will be used to improve drugs having poor solubility.
Nanotechnology is basically for the use of materials and structures at the nanoscale level of
approximately 100 nm or less than 100 nm (Valizadeh et al., 2004). For many new chemical
entities with very low solubility, oral bioavailability enhancement by micronizationis not
sufficient. Micronized product has the tendency to agglomerate, which leads to

decreased effective surface area for dissolution. So nanonisation is used. 1.3.7 Solid
Dispersions The dispersion method allows the preparation of physically modified forms of
the drug that are much more rapidly soluble in water than the pure compound. The most
commonly used hydrophilic carriers for solid dispersions include polyvinyl pyrrolidone,
polyethylene glycols, and plasdone-S630. Surfactants may also be used in the formation of
solid dispersions. Surfactants like Tween-80, Myrj-52, and Pluronic-F68 and sodium lauryl
sulfate are used. Chiou and Riegelman, (1969) recommended polyethylene glycol, a
water- soluble polymer, as an excellent universalcarrier for improving the dissolution rate
and oral absorption of water-insoluble drugs. They reported that the dissolution of
griseofulvin, as well as its absorption and total availability in both dog Chiou and
Riegelman, (1971) and man Chiou and Riegelman, (1971), was significantly higher when
the solid was dispersed in polyethylene glycol 4000, 6000, or 20,000, as compared with
the traditionally micronized form of the drug. 1.4 Classification of solid dispersion Based
on their molecular arrangement, six different types of solid dispersions can be
distinguished. Moreover, in various studies the designation of solid dispersions is based on
the method of preparation. 1However, since different preparation methods can result in
the same subtypes or similar preparation methods can result in different subtypes, it can
be argued that solid dispersions should preferably be designated according to their
molecular arrangement.
Moreover, not the preparation method but the molecular arrangement governs the
properties of solid dispersions. Therefore, it is essential to use terms that indicate the
molecular arrangement in the solid dispersion. Knowledge about the molecular
arrangement will enlarge comprehension of the properties and behavior of solid
dispersions. Furthermore, it will facilitate optimization of their properties required for

a
specific application
(Goldberg et al., 1965). Table 1.1: Types of solid dispersion
S. Solid dispersion type Matrix
* Drug** Remarks No. of No. phases I Eutectics C C The first
type of solid 2 dispersion prepared II Amorphous C A Rarely encountered 2 precipitations
in crystalline matrix III Solid solutions Continuous solid C M miscible composition, 1

solutions never prepared Discontinuous solid C M Partially mis cible, 2 2 solutions phases
even though drug is molecularly Substitutional solid C M Molecular diameter
of 1 or 2 solutions drug (solute) differs less than 15% from the matrix (solvent)
diameter. In that case the drug and matrix are substitutional. Can be continuous or
discontinuous.
When discontinuous: 2 phases even though drug is molecularly dispersed. IV Glass
suspension A C Particle size of 2 dispersed phase dependent on cooling/evaporation rate.
Obtained after crystallization of drug in amorphous matrix V Glass suspension A A Particle
size of 2 dispersed phase dependent on cooling/evaporation rate many solid dispersions
are this type VI Glass suspension A M Requires miscibility OR 1 solid solubility, complex o
formation or upon fast cooling OR evaporation during preparation, many (recent) examples
especially with PVP * A: matrix in the amorphous state, C: matrix in the crystalline state **
A: drug dispersed as amorphous clusters in the matrix, C: drug dispersed as crystalline
particles in the matrix, M: drug molecularly dispersed throughout the matrix 1.5
Manufacturing processes for preparation of solid dispersions There are two major methods
of preparing solid dispersions; melting method and
synonymous to melt method. 1.5.1 Meltsionlgvemnet

tehvoadpoMrealttiionngmmeeththoodd. Fwuasisofnirst
umsetdhotod pisrepare simple eutecticmixtures by 2Sekiguchi and Obi (1961). Leuner and
Dressman (2000) used to describe melting method as hot melt method. This method
consists of melting the drug within the carrier followed by cooling and pulverization of the
1The process has
obtained product. got some limitations like, use of high temperature and
chance of degradation of drug during melting, incomplete miscibility between drug and
carrier (Taylor and Zografi, 1997). To avoid these limitations several modifications were
introduced to the original process; i.e. hot stage extrusion, Meltrex®, melt agglomeration,
2hot melt extrusion was
injection molding, hot-spin-melting. Though a common processing
method in polymer industry it was first adapted for the pharmaceutical PAGE 6
INTRODUCTION purposes by Speiser
(El-Egakey and Speiser, 1971) and Hüttenrach (Tachibani and Nakamura, 1965). 1.5.2
Solvent evaporation method Solvent evaporation method is simple way to produce solid
d ispersio whe e the drug and is solubilized in a volatile solvent. The solvent is
n r carrie
later evaporated. Tachibani and Nakumara (1965) were the first to dissolve both the drug
and thecarrier in a common solvent
and then evaporate the solvent under vacuum to
produce a solid solution. The method was then taken up by Mayersohn and Gibaldi (1966).
many of the problems associated with
With the discovery of the solvent method, the
the method of
melting method were solved and for many years the solvent method was
choice for polymer-based systems. With time, however, the ecological and subsequent
econo ic p roblems associated with the use of rganic polymers began to make solvent
based methods more andmore problematic. F or these reasons, hot melt extrusion is the
currentmethod of choice for the manufacture of solid dispersions. Melt extrusion

method The drug/carrier mix is typically processed with a twinscrew extruder. The
drug/carrier mix is simultaneously melted, homogenized and then extruded and shaped as
nbe further
tablets, granules, pellets, sheets, sticks or powder. The intermediates can the
processed into important advantage of the hot melt extrusion
conventional tablets. An
method is that the an elevatedtemperature
drug/carrier mix is o ly subjected to for about
1 min, which enables drugs that are somewhat thermo labile to be processed (Narang and
Shrivastava, 2002). Solid dispersion by this method is composed of active ingredient and
carrier, and
prepare by hot-stage extrusion using a co-rotating twin-screw extruder.The
concentration of drug in the
dispersions is always 40% (w/w) (Breitenbach, 2002). The
screw-configuration consist of two mixing zones and three transport zones distribute over
the entire barrel length, the feeding rate is fix at 1 kg/h and the screw rate is set at 300
rpm. The five temperature zones are set at 100, 130, 170, 180, and 185C from feeder to
die. The extrudates are collect after cooling at ambient temperature on a conveyer belt.
Samples are milled for 1 min with a laboratory cutting mill and sieve to exclude particles
>355µm (Chokshi and Hossein, 2004).
Lyophilization Technique Lyophilization involves transfer of heat and mass to and fromthe
product under preparation.

proposed as an alternative technique to solvent evaporation. Lyophilization has been
thought of a molecular mixing technique where 1the drug and carrier are co dissolved in a
common solvent, frozen and sublimed to obtain a lyophilized molecular dispersion
(Perissutti et al., 2002). 1.5.5 Melt Agglomeration Process This technique has been used to
prepare solid dispersion wherein the binder acts as a carrier. In addition, solid dispersion is
prepared either by heating binder, drug and excipient to a temperature above the melting
point of the binder (melt- in procedure) or by spraying a dispersion of drug in molten
binder on the heated excipient (spray-on procedure) by using a high shear mixer
(Tsinontides et al., 2004). The rot ary processor might be pre erable to the high melt
agglomeration because it is easier to control the temperature and because a higher binder
content can be incorporated in the agglomerates. The effect of binder type, method of
manufacturing and particle size are critical parameters in preparation of solid dispersion
by melt agglomeration. 1.5.6 Melt Agglomeration Process The utility of the surfactant
systems in solubilization is very important. Adsorption of surfactant on solid surface can
modify their hydrophobicity, surface charge, and other key properties that govern
interfacial processes such as flocculation/dispersion, floatation, wetting, solubilization,
detergency, and enhanced oil recovery and corrosion inhibition. Surfactants have also been
reported to cause solvation/plasticization, manifesting in reduction of melting the active
pharmaceutical ingredients, glass transition temperature and the combined glass transition
temperature of solid dispersions. Because of these unique properties, surfactants have
attracted the attention of investigators for preparation of solid dispersions (Zhang and
Somasundaran, 2006). 1.6 Characterization of solid dispersion Several different molecular
structures of the drug in the matrix can be encountered in solid dispersions. Several
techniques have been available to investigate the molecular arrangement in solid
dispersions. However, most effort has been put into between amorphous
and crystalline material. Many techniques are available which detect the amount of
crystalline material in the dispersion (Kaushal et al., 2004). 1.6.1 Drug -carrier miscibility •
Hot stage microscopy • Differential scanning calorimetry
• Powder X-ray diffraction • NMR
1H Spin lattice relaxation time
Drug carrier interactions • FT-IR spectroscopy •
spectroscopy • Sol•id state NMR
Raman
Surface properties • Dynamic vapor
canning electron microscopy
sorption rface •areaanalysis
S •
microscopy Inverse gas chromatography • Atomic force
•
1.6.4 Amo
• Raman microscopy
microscopy Hot stagemicroscopy light optical
rphous content • Polarised
Powder X-ray diffraction
• • Humidity stage microscopy • DSC (MTDSC) • ITC •
• Humidity s udies • Isothermal Calorimetry • DSC (Tg,
Temperature recrystallization) • Dynamic vapor sorption • Saturated solubility studies 1.6.6
Dissolution enhancement • Dissolution • Intrinsic dissolution • Dynamic solubility •

Dissolution in bio-relevant media 1.6.7 Powder X-ray diffraction Powder X-ray diffraction can be used to qu
PAGE 10 INTRODUCTION 1.6.8Infrared spectroscopy (IR) Infrared spectroscopy (IR) can be used to detect th
Spectroscopy (FTIR) was used to accurately detect crystallinityranging from 1 to 99% in
pure material (Taylor and Zografi, 1997). 1.6.9 Water vapour sorption Water vapour
sorption can be used to discriminate between amorphous and crystalline ismaterial
method when
requirthe
hygroscopicity isdifferent (Buckton and Darcy, 1995). es accurate data
on the both completely crystalline and completely amo rphous samples.

hygroscopicity
Dissolution calorimetry measures the energy of dissolution,
1.6.10 Dissolution calorimetry
which is dependent on the crystallinity of the sample(Pikal et al., 1978). Usually
,
dissolution of crystalline material is endothermic, whereas dissolution of amorphous
material is exothermic . 1.6.11 Macroscopic techniquesMacroscopic techniques that
measure mechanical properties that are different amorphous and crystalline material can
be indicative for the degree of crystallinity.Density measurements and Dynamic
Mechanical Analysis (DMA) determine the modulus of elasticity and viscosity and thus
for
affected by the degree ofcrystallinity.Ho
wever, also these techniques require k owledge
n
about the additivity of these properties in intimately mixed binary solids..6.12
1 Confocal
Raman Spectroscopy Confocal Raman Spectroscopy u

i ed to measure the homogeneity
of the solid mixture It is described that a standard deviation in drug content smalle
was indicative of homogeneous distribution. Because of the pixel size of 2

than10% µm3,
uncertainty remains about the presence of nano-sized amorphous drug particles.
PAGE 11 INTRODUCTION
IN VITRO Dissolution N VITRO dissolution s
1.6.13 Studies I tudies are done for the find out
dissolution behaviour. The IN-VITRO dissolution study c an be used demonstrate the
bioavailabil ty or of the drug

product through IN VITRO - IN VIVO
On the other hand i
bioequivalence correlation absorption of the drug is dissolution rate limited
(IVIVC). the drug in the
that means gastrointestinal fluid passes freely through the bio-membranes
at a rate higher than it dissolves or is released from the dosage form. The specifically
designed IN-VIVO dissolution study will be required in solid dispersion system to access
rate, andhence
the absor tion its bioavailability and to demonstrate the bioequivalence
There are some
ultimately. apparatus used in United States pharmacopoeia for dissolution
testing these are following. 1.6.14 Solubility Studies Solubility studies are done for the
finding out the solubility behaviour shown by the solid dispersion system indifferenttypes
of solvent system and body flui s. 1.7 Advantages of solid dispersion Ø Solid dispersion
results in particles with reducedparticle sizeand thus the surface area are improvedand
increased dissolution rate is attained. Hence bioavailability is increased. Ø The carrier
used in the solid dispersion plays a major role in improving the wettability of the
particles.
Improved wettability results in increased solubility thus improving the bioavailability. Ø In

solid dispersion drugs are presented as supersaturated solutions
which are considered to
metastable polymorphic form.Thus presenting the drug in amorphous form and
be
of solid dispersion
increases 1.8 Disadvantages Ø Major
the solubility of the
disadvantage is their instability. They show changes in crystallinity and a decrease in
dissolution rate with ageing. Ø Temperature and moisture have more deteriorating effect
“FORMULATION, DEVELOPMENT AND EVALUATION OF SOLID
DISPERSION FOR DISSOLUTION RATE ENHANCEMENT”
CONTENT
S. No. Chapter Page No.
1. Introduction 1-12
2. Review of Literature 13-17
3. Research Envisaged 18
4. Plan of Work 19
5. Drug Profile 20-25
6. Preformulation Study 26-33
7. Preparation and Characterization 34-46
8. Summary and Conclusion 47-48
9. Bibliography 49-53
INTRODUCTIO
1. INTRODUCTION
Solubility
Solubility is the phenomenon of dissolution of solid in liquid phase to give a homogenous
system and is one of the important parameter to achieve desired concentration of drug in
systemic circulation for pharmacological response. Poorly water-soluble drugs after oral
administration often require high doses in order to reach therapeutic plasma concentrations.
The bioavailability of an orally administered drug depends on its solubility in aqueous
media over different pH ranges. The insufficient dissolution rate of the drug is the limiting
factor in the oral bioavailability of poorly water soluble compounds. Various techniques are
used for the improvement of the aqueous solubility, dissolution rate, and bioavailability of
poorly water soluble drugs include micronization, chemical modification, pH adjustment,
solid dispersion, complexation, cosolvency, micellar solubilization, hydrotropy etc.
Bioavailability, stability and convenience
Throughout the past decade, in the development and commercialization of new

pharmaceutical products, the formulation and delivery of Active Pharmaceutical Ingredients
(APIs) have played a crucial role. To improve bioavailability, stability and convenience to
the patient, is the major objective of formulation chemistry (Majerik et. al., 2004).
Bioavailability means the rate and extent to which the active substance or therapeutic
moiety is absorbed from a pharmaceutical form and becomes available at the site of action
(Vemavarapu et. al.,2005). The bioavailability of an orally administered drug depends on its
solubility in aqueous media over the pH range of 1.0–7.5and the rate of mass transfer across
biological membranes (Charbit et. al., 2004). In the oral bioavailability of poorly water
soluble compounds, the insufficient dissolution rate is the limiting factor (Rogers et. al.,
2001). Some new technologies have been recently developed to improve wettability and
aqueous solubility of APIs. These methods are based on the use of compressed gases,
supercritical fluids, and anti-solvent (Jung and Perrut, (2001).
The critical requirement for a poorly water-soluble drug for absorption to be possible from
the gastrointestinal (GI) tract is, achieving a solution of drug in the GI fluid Horter and
Dressman, 1997 defined a poorly water-soluble drug as the one whose dissolution in the GI
fluid under ordinary conditions takes a longer time than its transition through the absorption
sites in the GI tract. To increase dissolution rates of drugs, salt formation, particle size
BITS
PAGE
INTRODUCTIO
reduction etc., have commonly been used but achieving desired bioavailability enhancement
may not always be possible due to some practical limitations with these techniques
(Serajuddin, 1999). Solid dispersion systems have shown promising results in increasing
bioavailability of poorly water-soluble drugs in which the drug is dispersed in solid water-
soluble matrices either molecularly or as fine particles (Chiou and Riegelman, 1971; Ford,
1986; Serajuddin et. al., 1988).
Methods for solubility enhancement
Supercritical fluid technology
Supercritical fluids are fluids whose temperature and pressure are greater than their critical
temperature (Tc) and critical pressure (Tp). In the supercritical fluid (SCF) process,
micronization is done by the supercritical fluid which is highly compressible, and allows
moderate changes in pressure to greatly alter the density and mass transport characteristics
that largely determine its solvent power (Kakumanu and Bansal, 2004). The SCF process
can create nanoparticle of particles 5–2,000 nm in diameter (Pasquali et. al., 2006;
Reverchon and Adami, 2006). Solvent extraction-evaporation, solvent diffusion and organic
phase separation are some conventional methods which require the use of organic solvents.
These organic solvents are hazardous to the environment as well as to physiological
systems. Supercritical fluids are environmentally safe. Therefore, to prepare biodegradable
micro and nano-particles the supercritical fluid technology has been investigated as an
alternative (Ahuja et. al.,, 2006).
Prodrug approach
Throughout the past decades prodrug approaches have been used to improve the
pharmaceutical properties such as solubility, taste, odor, stability, etc. Designing of prodrug
is also used to improve the physicochemical properties such as compound lipophilicity and
solubility to prevail over the pharmacokinetic demerits associated with drug molecules. The
chemical decomposition and presystemic metabolism is to be reduced by the use of prodrug
approach. The basic principle associated with is to cover the undesired functional group(s)
with another functional group, which usually are referred as promoiety.
Designing prodrug for improving bioavailability is one of the lucrative approaches

especially for protein and peptide molecules. Designing of cyclic prodrug using C and N
terminal ends reduced the metabolic degradation caused by exopeptidase. A recent study
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involved synthesis of cyclic hexapeptide to improve the enzymatic stability and permeability
through biological membranes. It showed increased permeability of cyclic prodrug than
parentmolecule. Derivatization is another lucrative approach for synthesis of prodrug to
improve bioavailability of drug molecules especially for peptide molecules. Derivatization
could be possible in C terminal amide group, N terminal amide group and phenol group in
various peptide molecules (Shah et. al., 1994).
Microemulsion formulations
Microemulsion is a lipid based delivery system whose major advantages include high
solubilization potential, thermodynamic stability, improved dissolution of lipophilic drugs
(Constantinides, 1995) and surfactant-induced permeability enhancement.
Dissolution enhancement by physical modification of the drug
The solubility of a drug determines the dissolution behavior of an active pharmaceutical

ingredient (API) in the formulation as well as therapeutic efficacy of the drug. Reduction of
particle size, complexation, and solid dispersions of drug in suitable carriers are some
commonly used physical modifications of the API. In solubility limited absorption (intrinsic
solubility controlled), the formulation approach is commonly used to enhance the solubility
of the API and this approach also includes the use of surfactants in the formulation (solid
dispersions), non-crystalline materials, and different salt forms of API.
Micronization
For many decades, the dissolution rate is being increased by reducing the particle size of
poorly water-soluble drugs. Conventional methods of particle size reduction, such as
comminution and spray drying, rely upon mechanical stress to disaggregate the active
compound. Today, micronization of drugs is widely done by milling techniques using a jet
.
mill, rotor stator, colloidal mill, and air attrition Kornblum and Hirschorn (1970) evaluated
two specific methods of micronization, spray drying and air attrition, which provided drug
forms of different specific surface areas and particle size ranges. With the aforementioned
advantages, micronization has some limitations; micronization of sparingly or poorly
soluble drugs is by no means a guarantee of better dissolution and absorption.
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Nanotechnology
Nanotechnology will be used to improve drugs having poor solubility. Nanotechnology is

basically for the use of materials and structures at the nanoscale level of approximately 100
nm or less than 100 nm (Valizadeh et. al., 2004). For many new chemical entities with very
low solubility, oral bioavailability enhancement by micronization is not sufficient.
Micronized product has the tendency to agglomerate, which leads to decreased effective
surface area for dissolution. So nanonisation is used.
Solid Dispersions
The dispersion method allows the preparation of physically modified forms of the drug that
are much more rapidly soluble in water than the pure compound. The most commonly used
hydrophilic carriers for solid dispersions include polyvinyl pyrrolidone, polyethylene
glycols, and plasdone-S630. Surfactants may also be used in the formation of solid
dispersions. Surfactants like Tween-80, Myrj-52, and Pluronic-F68 and sodium lauryl
sulfate are used. Chiou and Riegelman, (1969) recommended polyethylene glycol, a water-
soluble polymer, as an excellent universalcarrier for improving the dissolution rate and oral
absorption of water-insoluble drugs. They reported that the dissolution of griseofulvin, as
well as its absorption and total availability in both dog Chiou and Riegelman, (1971) and
man Chiou and Riegelman, (1971), was significantly higher when the solid was dispersed in
polyethylene glycol 4000, 6000, or 20,000, as compared with the traditionally micronized
form of the drug.
Classification of solid dispersion
Based on their molecular arrangement, six different types of solid dispersions can be
distinguished. Moreover, in various studies the designation of solid dispersions is based on
the method of preparation. However, since different preparation methods can result in the
same subtypes or similar preparation methods can result in different subtypes, it can be
argued that solid dispersions should preferably be designated according to their molecular
arrangement. Moreover, not the preparation method but the molecular arrangement governs
the properties of solid dispersions. Therefore, it is essential to use terms that indicate the
molecular arrangement in the solid dispersion. Knowledge about the molecular arrangement
will enlarge comprehension of the properties and behavior of solid dispersions. Furthermore,
it will facilitate optimization of their properties required for a specific application (Goldberg
et. al., 1965).

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Table 1.1: Types of solid dispersion
S. Solid dispersion type Matrix* Drug** Remarks No. of

No. phases
I Eutectics C C The first type of solid 2
dispersion prepared
II Amorphous C A Rarely encountered 2
precipitations in
crystalline matrix
III Solid solutions
Continuous solid C M Miscible composition, 1
solutions never prepared
Discontinuous solid C M Partially miscible, 2 2
solutions phases even though
drug is molecularly
dispersed.
Substitutional solid C M Molecular diameter of 1 or 2
solutions drug (solute) differs less
than 15% from the
matrix (solvent)
diameter. In that case
the drug and matrix are
substitutional. Can be
Continuous or
discontinuous. When
discontinuous: 2 phases
even though drug is
molecularly dispersed.
IV Glass suspension A C Particle size of 2
dispersed phase
dependent on
cooling/evaporation
rate. Obtained after
crystallization of drug in
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amorphous matrix
V Glass suspension A A Particle size of 2
dispersed phase
dependent on
cooling/evaporation rate
many solid dispersions
are of this type
VI Glass suspension A M Requires miscibility OR 1
Solid solubility,
complex formation or
upon fast cooling OR
evaporation during
preparation, many
(recent) examples
especially with PVP
* A: matrix in the amorphous state, C: matrix in the crystalline state
** A: drug dispersed as amorphous clusters in the matrix, C: drug dispersed as crystalline

particles in the matrix, M: drug molecularly dispersed throughout the matrix
Manufacturing processes for preparation of solid dispersions
There are two major methods of preparing solid dispersions; melting method and solvent
evaporation method. Fusion method is synonymous to melt method.
Melting method
Melting method was first used to prepare simple eutectic mixtures by Sekiguchi and Obi
(1961). Leuner and Dressman (2000) used to describe melting method as hot melt method.
This method consists of melting the drug within the carrier followed by cooling and
pulverization of the obtained product. The process has got some limitations like, use of high
temperature and chance of degradation of drug during melting, incomplete miscibility
between drug and carrier (Taylor and Zografi, 1997). To avoid these limitations several
modifications were introduced to the original process; i.e. hot stage extrusion, Meltrex®,
melt agglomeration, injection molding, hot-spin-melting. Though hot melt extrusion was a
common processing method in polymer industry it was first adapted for the pharmaceutical
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purposes by Speiser (El-Egakey and Speiser, 1971) and Hüttenrach (Tachibani and
Nakamura, 1965).
Solvent evaporation method
Solvent evaporation method is a simple way to produce solid dispersions where the drug
and carrier is solubilized in a volatile solvent. The solvent is later evaporated. Tachibani and
Nakumara (1965) were the first to dissolve both the drug and the carrier in a common
solvent and then evaporate the solvent under vacuum to produce a solid solution. The
method was then taken up by Mayersohn and Gibaldi (1966). With the discovery of the
solvent method, many of the problems associated with the melting method were solved and
for many years the solvent method was the method of choice for polymer-based systems.
With time, however, the ecological and subsequent economic problems associated with the
use of organic polymers began to make solvent based methods more and more problematic.
For these reasons, hot melt extrusion is the current method of choice for the manufacture of
solid dispersions.
Melt extrusion method
The drug/carrier mix is typically processed with a twinscrew extruder. The drug/carrier mix
is simultaneously melted, homogenized and then extruded and shaped as tablets, granules,
pellets, sheets, sticks or powder. The intermediates can then be further processed into
conventional tablets. An important advantage of the hot melt extrusion method is that the
drug/carrier mix is only subjected to an elevated temperature for about 1 min, which enables
drugs that are somewhat thermo labile to be processed (Narang and Shrivastava, 2002).
Solid dispersion by this method is composed of active ingredient and carrier, and prepare by
hot-stage extrusion using a co-rotating twin-screw extruder. The concentration of drug in the
dispersions is always 40% (w/w) (Breitenbach, 2002). The screw-configuration consist of
two mixing zones and three transport zones distribute over the entire barrel length, the
feeding rate is fix at 1 kg/h and the screw rate is set at 300 rpm. The five temperature zones
are set at 100, 130, 170, 180, and 185C from feeder to die. The extrudates are collect after
cooling at ambient temperature on a conveyer belt. Samples are milled for 1 min with a
laboratory cutting mill and sieve to exclude particles >355µm (Chokshi and Hossein, 2004).
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Lyophilization Technique
Lyophilization involves transfer of heat and mass to and from the product under preparation.
This technique was proposed as an alternative technique to solvent evaporation.
Lyophilization has been thought of a molecular mixing technique where the drug and carrier
are co dissolved in a common solvent, frozen and sublimed to obtain a lyophilized
molecular dispersion (Perissutti et. al., 2002).
Melt Agglomeration Process
This technique has been used to prepare solid dispersion wherein the binder acts as a carrier.
In addition, solid dispersion is prepared either by heating binder, drug and excipient to a
temperature above the melting point of the binder (melt- in procedure) or by spraying a
dispersion of drug in molten binder on the heated excipient (spray-on procedure) by using a
high shear mixer (Tsinontides et. al., 2004). The rotary processor might be preferable to the
high melt agglomeration because it is easier to control the temperature and because a higher
binder content can be incorporated in the agglomerates. The effect of binder type, method of
manufacturing and particle size are critical parameters in preparation of solid dispersion by
melt agglomeration.
Melt Agglomeration Process
The utility of the surfactant systems in solubilization is very important. Adsorption of

surfactant on solid surface can modify their hydrophobicity, surface charge, and other key
properties that govern interfacial processes such as flocculation/dispersion, floatation,
wetting, solubilization, detergency, and enhanced oil recovery and corrosion inhibition.
Surfactants have also been reported to cause solvation/plasticization, manifesting in
reduction of melting the active pharmaceutical ingredients, glass transition temperature and
the combined glass transition temperature of solid dispersions. Because of these unique
properties, surfactants have attracted the attention of investigators for preparation of solid
dispersions (Zhang and Somasundaran, 2006).
Characterization of solid dispersion
Several different molecular structures of the drug in the matrix can be encountered in solid
dispersions. Several techniques have been available to investigate the molecular
arrangement in solid dispersions. However, most effort has been put into differentiate
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between amorphous and crystalline material. Many techniques are available which detect
the amount of crystalline material in the dispersion (Kaushal et. al., 2004).
Drug -carrier miscibility
• Hot stage microscopy
• Differential scanning calorimetry
• Powder X-ray diffraction
• NMR 1H Spin lattice relaxation time
Drug carrier interactions
• FT-IR spectroscopy
• Raman spectroscopy
• Solid state NMR

• Scanning electron microscopy
• Surface area analysis
• Surface properties
• Dynamic vapor sorption
• Inverse gas chromatography
• Atomic force microscopy
• Raman microscopy

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1.6.4 Amorphous content
• Polarised light optical microscopy
• Hot stage microscopy
• Humidity stage microscopy
• DSC (MTDSC)
• ITC
• Powder X-ray diffraction
• Humidity studies
• Isothermal Calorimetry
• DSC (Tg, Temperature recrystallization)
• Dynamic vapor sorption
• Saturated solubility studies
Dissolution enhancement
• Dissolution
• Intrinsic dissolution
• Dynamic solubility
• Dissolution in bio-relevant media
Powder X-ray diffraction
Powder X-ray diffraction can be used to qualitatively detect material with long range order.
Sharper diffraction peaks indicate more crystalline material.

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INTRODUCTIO
Infrared spectroscopy (IR)
Infrared spectroscopy (IR) can be used to detect the variation in the energy distribution of
interactions between drug and matrix. Sharp vibrational bands indicate crystallinity. Fourier
Transformed Infrared Spectroscopy (FTIR) was used to accurately detect crystallinity
ranging from 1 to 99% in pure material (Taylor and Zografi, 1997).
Water vapour sorption
Water vapour sorption can be used to discriminate between amorphous and crystalline
material when the hygroscopicity is different (Buckton and Darcy, 1995). This method
requires accurate data on the hygroscopicity of both completely crystalline and completely
amorphous samples.
Dissolution calorimetry
Dissolution calorimetry measures the energy of dissolution, which is dependent on the

crystallinity of the sample (Pikal et. al., 1978). Usually, dissolution of crystalline material is
endothermic, whereas dissolution of amorphous material is exothermic.
Macroscopic techniques
Macroscopic techniques that measure mechanical properties that are different amorphous
and crystalline material can be indicative for the degree of crystallinity. Density
measurements and Dynamic Mechanical Analysis (DMA) determine the modulus of
elasticity for and viscosity and thus affected by the degree of crystallinity. However,
also these techniques require knowledge about the additivity of these properties in
intimately mixed binary solids.
Confocal Raman Spectroscopy
Confocal Raman Spectroscopy is used to measure the homogeneity of the solid mixture. It is
described that a standard deviation in drug content smaller than10% was indicative of
homogeneous distribution. Because of the pixel size of 2 µm3, uncertainty remains about
the presence of nano-sized amorphous drug particles.
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IN VITRO Dissolution Studies
IN VITRO dissolution studies are done for the find out dissolution behaviour. The IN-VITRO
dissolution study can be used to demonstrate the bioavailability or bioequivalence of the

drug product through IN VITRO - IN VIVO correlation (IVIVC). On the other hand if absorption
of the drug is dissolution rate limited that means the drug in the gastrointestinal fluid passes
freely through the bio-membranes at a rate higher than it dissolves or is released from the
dosage form. The specifically designed IN-VIVO dissolution study will be required in solid
dispersion system to access the absorption rate, and hence its bioavailability and to
demonstrate the bioequivalence ultimately. There are some apparatus used in United States
pharmacopoeia for dissolution testing these are following.
Solubility Studies
Solubility studies are done for the finding out the solubility behaviour shown by the solid
dispersion system in different types of solvent system and body fluids.
Advantages of solid dispersion
 Solid dispersion results in particles with reduced particle size and thus the surface
area are improved and increased dissolution rate is attained. Hence bioavailability is
increased.
 The carrier used in the solid dispersion plays a major role in improving the
wettability of the particles. Improved wettability results in increased solubility thus
improving the bioavailability.
 In solid dispersion drugs are presented as supersaturated solutions which are
considered to be metastable polymorphic form. Thus presenting the drug in
amorphous form and increases the solubility of the particles.
Disadvantages of solid dispersion
 Major disadvantage is their instability. They show changes in crystallinity and a

decrease in dissolution rate with ageing.
 Temperature and moisture have more deteriorating effect on solid dispersions than
on physical mixtures.
 Difficulty in handling because of tackiness.
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REVIEW OF LITERATURE
2. REVIEW OF LITERATURE
MJ Humayun , Samanta D and Carson RP, (2020) Clobazam was first synthesized in
1966 and first published in 1969. The primary goal for developing this drug was to provide
greater efficacy with fewer benzodiazepine (BZD) related side effects.
Patil, (2016) prepared orally dissolving formulation of clobazam is to control the epileptic
attack in shortest possible time. During the seizure attack, it is highly unlikely that clinician
will use orally dissolving tablet. Injection of benzodiazepine becomes the choice in urgent
situation to control ongoing seizures.
Bala et. al., (2014) Clobazam orally dissolving strips were prepared by solvent casting
method. A full 32 factorial design was applied for optimization using different
concentration of film forming polymer and disintegrating agent as independent variable and
disintegration time, % cumulative drug release, and tensile strength as dependent variable.
In addition the prepared films were also evaluated for surface pH, folding endurance, and
content uniformity. The optimized film formulation showing the maximum IN VITRO drug
release, satisfactory IN VITRO disintegration time, and tensile strength was selected for
bioavailability study and compared with a reference marketed product (frisium 5 tablets) in
rabbits.
Fazil et. al., (2016) SD of spironolactone (SPL) was developed using an inert carrier
polyethylene glycol 4000 (PEG 4000) by the conventional fusion method and characterized
for various characterization parameters. Solubility of pure drug and SD of SPL in water
was found to be 23.54 ± 1.75 μg/mL and 61.73 ± 1.26 μg/mL, respectively. The maximum
cumulative percentage release from pure drug, SPL marketed product (tablet), physical
mixture, and SPL SD at 60 min was 27.25 ± 1.83%, 35.64 ± 3.65%, 47.72 ± 2.45%, and
74.24 ± 3.25%, respectively in 0.1 N HCl.
Chaulang et. al., (2009) determined if a solid dispersion of furosemide in sodium starch
glycolate (SSG) would enhance the dissolution properties of the drug. FTIR spectroscopy,
DSC, and XRD showed a change in crystal structure toward an amorphous form of
furosemide. Dissolution data indicated that furosemide dissolution was enhanced. 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.
Jafari et. al., (2013) improve the solubility and dissolution rate of a poorly water-soluble
drug, diclofenac sodium, by SD technique as using Eudragit E100. SD was prepared by
solvent
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REVIEW OF
evaporation technique. The SD was characterized for particle size, particle size distribution
and solubility studies. Solid state characterizations i.e., Differential Scanning Calorimetry
and Scanning Electron Microscopy were also carried out for the best formulation. It was
concluded that the SD prepared by solvent evaporation technique using Eudragit E100
enhanced solubility and dissolution and hence better patient compliance and effective
therapy.
Varalakshmi et. al., (2015) formulated solid dispersions of Valsartan using hydrophilic
carriers in different concentrations and to determine their effect on solubility of drug. The
prepared physical mixtures and Solid dispersions of Valsartan showed good flow property
and uniformity in drug content. From the saturated solubility studies and IN-VITRO
dissolution studies it was observed that there was increase in solubility of drug and
enhanced dissolution rate in solid dispersions compared to physical mixtures respectively.
Formulation containing 1:4 ratio of drug: PEG4000 is considered as best formulation as it
has shown highest drug release in short time i.e. 99.86 % in 20min. Our studies showed
that the solubility of the drug can be significantly enhanced with solid dispersions of the
studied polymers. With increase in the carrier content there is increase in the solubility
resulting in enhanced dissolution rate.
Mir-ali molaei et. al., (2018) the study was conducted to enhance the dissolution rate of
ketoconazole (KCZ) (a poorly water-soluble drug) using the liquisolid technique.
Dhobale et. al., (2018) Solubility is not to be confused with the ability to dissolve or liquefy
a substance, since this process may occur not only because of dissolution but also because
of a chemical reaction Solubility is the phenomenon of dissolute on of solid in liquid phase
to give a homogenous system. There are many techniques which are used to enhance the
aqueous solubility. The ability to increase aqueous solubility can thus be a valuable aid to
increasing efficiency and/or reducing side effects for drugs.
Rana et. al., (2017) enhanced the solubility of poorly soluble drug Ibuprofen using spherical
crystallization technique. Spherical agglomerates were prepared using diethyl ether as
bridging liquid by neutralizing technique, spherical agglomeration technique, Quasi
emulsion solvent diffusion technique. Spherical agglomerates were evaluated for
morphology, production yield, drug content, particle size and dissolution behaviour

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REVIEW OF
compared with pure drug. The result of phase solubility studies revealed that there is
enhancement of solubility by PEG 4000. Rod shaped crystals of pure drug converted to
spherical was confirmed by optical microscopy. The dissolution of agglomerates of
optimum batch exhibited 88.24% release compare to 47.18% of pure drug within 60
minute.. Ibuprofen spherical agglomerates can be prepared with PEG 4000. It exhibited
excellent physicochemical, solubility, dissolution rate in comparison with pure drug.
Among other spherical crystallization technique, QESD proved to be excellent technique
for enhancement of solubility and dissolution.
Maghsoodi and Nokhodchi, (2016) the quasi-emulsion solvent diffusion (QESD) has
evolved into an effective technique to manufacture agglomerates of Celecoxib crystals. The
combination of different solvents and stabilizers were compared to investigate any
connections between the solvents and stabilizers. The results showed that the effectiveness
of stabilizer in terms of particle size and particle size distribution is specific to each solvent
candidate. A stabilizer with a lower HLB value is preferred which actually increased its
effectiveness with the solvent candidates with higher lipophilicity. HPMC appeared to be
the most versatile stabilizer because it showed a better stabilizing effect compared to other
stabilizers in all solvents used. This study demonstrated that the efficiency of stabilizers in
forming the celecoxib agglomerates by QESD was influenced by the HLB of the stabilizer
and lipophilicity of the solvents.
Fazil et. al., (2016) solid dispersion (SD) of spironolactone (SPL) was developed using an
inert carrier polyethylene glycol 4000 (PEG 4000) by the conventional fusion method and
characterized for various characterization parameters. Solubility of pure drug and SD of SPL in
water was found to be 23.54 ± 1.75 μg/mL and 61.73 ± 1.26 μg/mL, respectively.
The maximum cumulative percentage release from pure drug, SPL marketed product
(tablet), physical mixture, and SPL SD at 60 min was 27.25 ± 1.83%, 35.64 ± 3.65%, 47.72
± 2.45%, and 74.24 ± 3.25%, respectively in 0.1 N HCl.
Varalakshmi et. al., (2015) formulated solid dispersions of Valsartan using hydrophilic
carriers in different concentrations and to determine their effect on solubility of drug. The
prepared physical mixtures and Solid dispersions of Valsartan showed good flow property
and uniformity in drug content. From the saturated solubility studies and IN-VITRO
dissolution studies it was observed that there

REVIEW OF
was increase in solubility of drug and enhanced dissolution rate in solid dispersions
compared to physical mixtures respectively. Formulation containing 1:4 ratio of drug:
PEG4000 is considered as best formulation as it has shown highest drug release in short
time i.e. 99.86 % in 20min. Our studies showed that the solubility of the drug can be
significantly enhanced with solid dispersions of the studied polymers. With increase in the
carrier content there is increase in the solubility resulting in enhanced dissolution rate.
Jafari, (2013) improve the solubility and dissolution rate of a poorly water-soluble drug,
diclofenac sodium, by SD technique as using Eudragit E100. SD was prepared
by solvent evaporation technique. The SD was characterized for particle size, particle size
distribution and solubility studies. Solid state characterizations i.e., Differential Scanning
Calorimetry and Scanning Electron Microscopy were also carried out for the best
formulation. It was concluded that the SD prepared by solvent evaporation technique using
Eudragit E100 enhanced solubility and dissolution and hence better patient compliance and
effective therapy.
Vemula et. al., (2010) described the techniques of solubilizaton for the attainment of
effective absorption and improved bioavailability. Solubility is the phenomenon of
dissolution of solid in liquid phase to give a homogenous system. Solubility is one of the
important parameter to achieve desired concentration of drug in systemic circulation for
pharmacological response to be shown. Poorly water-soluble drugs often require high doses
in order to reach therapeutic plasma concentrations after oral administration. Low aqueous
solubility is the major problem encountered with formulation development of new chemical
entities. Any drug to be absorbed must be present in the form of an aqueous solution at the
site of absorption. Water is the solvent of choice for liquid pharmaceutical formulations.
Most of drugs weakly acidic and weakly basic with poor aqueous solubility. Hence various
techniques are used for the improvement of the solubility of poorly water-soluble drugs
include micronization, chemical modification, pH adjustment, solid dispersion,
complexation, co‐solvency, micellar solubilization, hydrotropy etc.
Tapas et. al., (2009) improved the dissolution rate of felodipine using spherical
agglomeration technique with acetone, water and dichloromethane as good solvent, poor
solvent and bridging liquid, respectively. The quasi emulsion solvent diffusion technique
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was used as a method for spherical agglomeration. Inutec SP1 was used as an emulsion
stabilizer and as hydrophilic polymer in agglomeration process. The FTIR and DSC results
showed no change in the drug after crystallization process. PXRD studies showed sharp
peaks in the diffractograms of spherical agglomerates with minor reduction in height of the
peaks. The particle size of spherical agglomerates (FI-2) was about 134.33 ± 13.57 µm,
n=3 and the dissolution efficiency of felodipine up to 120 min increased to about 4-fold in
phosphate buffer containing 1.8% Tween 80 (pH 6.8). Spherical agglomerates showed
enhanced solubility compared to untreated powder possibly due to the partial conversion to
amorphous form.
Chaulang et. al., (2009) determined if a solid dispersion of furosemide in sodium starch
glycolate (SSG) would enhance the dissolution properties of the drug. FTIR spectroscopy,
DSC, and XRD showed a change in crystal structure toward an amorphous form of
furosemide. Dissolution data indicated that furosemide dissolution was enhanced. XRD,
DSC, FTIR spectroscopy and dissolution studies indicated that the solid dispersion
formulated in 1:2 ratios showed a 5.40-fold increase in dissolution and also exhibited
superior dissolution characteristics to commercial furosemide tablets.
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RESEARCH ENVISAGED
3. RESEARCH ENVISAGED
The oral route of drug administration is the most common and preferred method of delivery.
However, several orally administered drugs have a reduced bioavailability due to poor water
solubility. In biopharmaceutical classification system drugs with low aqueous solubility, slow
dissolution rate, high dose, and high membrane permeability are categorized as Class II drug. To
overcome low bioavailability, many of the modern oral drug delivery systems emphasize on
formulation strategies such as alteration of solvent composition, carrier systems as well as chemical
and physical modifications. Solid dispersion of drug in a water soluble polymer has been shown to
be one of the most promising strategy to improve solubility.
Increasing the Bioavailability of a poorly soluble drug is a challenging aspect of drug

development. Because of the poor aqueous solubility the drug possess dissolution problems
due to which the in vivo absorption of the drug is reduced and thus the bioavailability is
reduced, making the drug inappropriate for oral consumption and therefore solubility
enhancement become necessary for such drug candidate. Solid dispersion is a most simple
and efficient technique for increasing the aqueous solubility of a drug
For treatment and management of epilepsy and seizures associated with Lennox-Gastaut
syndrome, a difficult-to-treat form of childhood epilepsy. Hence the objective of the
present work was to obtained faster onset of action and successfully enhanced the
bioavailability by developing solid dispersion.
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PLAN OF WORK
4. PLAN OF WORK
1. Extensive literature survey

2. Selection of drug
3. Preformulation studies on drug which includes following parameter:
 Physical appearance
 Melting point determination
 Solubility analysis
 FT-IR analysis of drug sample
 UV spectroscopic analysis: by preparing its calibration curve
Formulation and evaluation of solid dispersion
 Selection of suitable method for formulation by employing experimental design
 Formulation of batch: Pre-compression characterization by
 General physical characterization
 Bulk density
 Tapped density
 Hausner’s ratio
 Carr’s index
 Angle of repose
 Percentage drug content of solid dispersion
 Dissolution rate study of solid dispersion
 Stability study us
5. Compilation and interpretation of work.

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DRUG AND EXCIPIENT
5. DRUG AND EXCIPIENT PROFILE
Drug Profile
Clobazam
Clobazam belongs to the 1,5-benzodiazepine class of drugs and is expected to have a better
side-effect profile compared to older 1,4-benzodiazepines. It has been marketed as an
anxiolytic since 1975 and an anticonvulsant since 1984. The oral preparation was FDA
approved on October 21, 2011.
Figure 5.1: Structure of Clobazam
Molecular formula: C16H13ClN2O2
Molecular weight: 300.74
Indication
For treatment and management of epilepsy and seizures associated with Lennox-Gastaut
syndrome, a difficult-to-treat form of childhood epilepsy.
Pharmacodynamics
Similar to other benzodiazepines, clobazam binds to the interface of the α and γ2-
subunit of the GABA-A receptor. However, it is considered a partial agonist to GABA-A
receptors which sets clobazam apart from 1,4-benzodiazepines which are full agonist. The
significance of this difference is that one may experience less sedation with clobazam than
with other benzodiazepines. Unlike the endogenous GABA ligand, clobazam binds
allosterically to the GABA receptor to increase the frequency of the chloride channel
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DRUG AND EXCIPIENT
opening and membrane permeability to chloride ions. Pharmacodynamic tolerance has been
demonstrated in animal models.
Mechanism of action
Clobazam binds at distinct binding sites associated with the chloride ionopore at the post-
synaptic GABA receptor. These GABA receptors are in various locations in the CNS
(limbic, reticular formation) and clobazam increases the duration of time for which the
chloride ionopore is open. As a result, hyper polarization and stabilization of the membrane
occur as the post-synaptic inhibitory effect of GABA is enhanced.
Metabolism
Clobazam is extensively metabolized in the liver via N-demethylation and hydroxylation.

Clobazam has two major metabolites: N-desmethylclobazam (norclobazam) and 4'-
hydroxyclobazam, the former of which is active. Norclobazam is one-fourth the potency of
clobazam. The main enzyme that facilitates the process of N-demethylation is CYP3A4,
and to a lesser extent by CYP2C19 and CYP2B6. Norclobazam itself is also metabolized
via hydroxylation, primarily by CYP2C19. The formation of 4'-hydroxyclobazam is
facilitated by CYP2C18 and CYP2C19. A factor in determining extent of metabolism is the
genetic profile of the individual patient as CYP2C19 is a polymorphic enzyme.
Route of elimination: Clobazam is eliminated via the urine (~94%) as metabolites.
Toxicity: The most common adverse effects include somnolence, pyrexia, upper
respiratory tract infection, and lethargy.
Description
This compound belongs to the class of organic compounds known as benzodiazepines.

These are organic compounds containing a benzene ring fused to either isomers of
diazepine (unsaturated seven-member heterocycle with two nitrogen atoms replacing two
carbon atoms).
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DRUG AND EXCIPIENT
EXCIPIENT PROFILE
Polyethyleneglycol
Name Polyethyleneglycol
Structure
IUPAC Name Poly(oxyethylene), poly(ethylene oxide
Carbowax, Golytely, GlycoLax, Fortrans, TriLyte,

Other Name
Colyte, Halflytely, Macrogol, Miralax, Movis
Properties
1) Formula C2nH4n+2On+1
2) Molecular mass Variable
3) Flash point 182 to 287 °C
4) Solubility In water, methanol, ethanol, acetonitrile, benzene
Uses
PEG is the basis of a number of laxatives. Whole bowel irrigation with

polyethylene glycol and added electrolytes is used for bowel preparation before
surgery or colonoscopy.
PEG is also used as an excipient in many pharmaceutical products.
When attached to various protein medications, polyethylene glycol allows a slowed

clearance of the carried protein from the blood.
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DRUG AND EXCIPIENT
The possibility that PEG could be used to fuse nerve cells is being explored by
researchers studying spinal cord injury.
Because PEG is a hydrophilic molecule, it has been used to passivate microscope

glass slides for avoiding non-specific sticking of proteins in single-molecule
fluorescence studies.
 Polyethylene glycol has a low toxicity and is used in a variety of products. The
polymer is used as a lubricating coating for various surfaces in aqueous and non-
aqueous environments.
Since PEG is a flexible, water-soluble polymer, it can be used to create very high
osmotic pressures (on the order of tens of atmospheres). It also is unlikely to have
specific interactions with biological chemicals. These properties make PEG one of
the most useful molecules for applying osmotic pressure in biochemistry and
biomembranes experiments, in particular when using the osmotic stress technique.
Polyethylene glycol is also commonly used as a polar stationary phase for gas
chromatography, as well as a heat transfer fluid in electronic testers.
PEG has also been used to preserve objects that have been salvaged from
underwater, as was the case with the warship Vasa in Stockholm, and similar cases.
It replaces water in wooden objects, making the wood dimensionally stable and
preventing warping or shrinking of the wood when it dries. In addition, PEG is used
when working with green wood as a stabilizer, and to prevent shrinkage.
 PEG is commonly used as a crowding agent in in vitro assays to mimic highly

crowded cellular conditions.
PEG is commonly used as a precipitant for plasmid DNA isolation and protein
crystallization. X-ray diffraction of protein crystals can reveal the atomic structure
of the proteins.
PEG is used to fuse two different types of cells, most often B-cells and myelomas in
order to create hybridomas. César Milstein and Georges J. F. Köhler originated this
technique, which they used for antibody production, winning a Nobel Prize in
Physiology or Medicine in 1984.
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DRUG AND EXCIPIENT
Polymer segments derived from PEG polyols impart flexibility to polyurethanes for
applications such as elastomeric fibers (spandex) and foam cushions.
In microbiology, PEG precipitation is used to concentrate viruses. PEG is also used

to induce complete fusion (mixing of both inner and outer leaflets) in liposomes
reconstituted in vitro.
Sodium dodecyl sulfate
Sodium dodecyl sulfate (SDS), synonymously, sodium lauryl sulfate (SLS), or sodium
laurilsulfate, is a synthetic organic compound with the formula CH3(CH2)11SO4Na. It is an
anionic surfactant used in many cleaning and hygiene products. The sodium salt is of an
organosulfate class of organics. It consists of a 12-carbon tail attached to a sulfate group,
that is, it is the sodium salt of dodecyl hydrogen sulfate, the ester of dodecyl alcohol and
sulfuric acid. Its hydrocarbon tail combined with a polar "headgroup" give the compound
amphiphilic properties and so make it useful as a detergent. Also derived as a component of
mixtures produced from inexpensive coconut and palm oils, SDS is a common component
of many domestic cleaning, personal hygiene and cosmetic, pharmaceutical, and food
products, as well as of industrial and commercial cleaning and product formulations.
Applications
 Cleaning and hygiene
SDS is mainly used in detergents for laundry with many cleaning applications. It is a highly
effective surfactant and is used in any task requiring the removal of oily stains and residues;
for example, it is found in higher concentrations with industrial products including engine
degreasers, floor cleaners, and car wash soaps.
In lower concentrations, it is found in toothpastes, shampoos, shaving creams, and bubble

bath formulations, for its ability to create a foam (lather), for its surfactant properties, and
in part for its thickening effect.

DRUG AND EXCIPIENT
 Food additive
Sodium dodecyl sulfate, appearing as its synonym sodium lauryl sulfate (SLS), is
considered as a generally recognized as safe (GRAS) ingredient, for food use according to
the guidelines published in 21 CFR 172.822. It is used as an emulsifying agent and
whipping aid. SLS is reported to temporarily diminish perception of sweetness.
Laboratory applications
Sodium lauryl sulfate, in science referred to as sodium dodecyl sulfate (SDS), is used in
cleaning procedures, and is commonly used as a component for lysing cells during RNA
extraction and/or DNA extraction, and for denaturing proteins in preparation for
electrophoresis in the SDS-PAGE technique.
In the case of the SDS-PAGE application, the compound works by disrupting non-covalent
bonds in the proteins, and so denaturing them, i.e., causing the protein molecules to lose
their native conformations and shapes. By binding to the proteins with high affinity and in
high concentrations, the negatively charged detergent provides all proteins with a similar
net negative charge and therefore a similar charge-to-mass ratio. In this way, the difference
in mobility of the polypeptide chains in the gel can be attributed solely to their size as
opposed to both their size and charge. It is possible to make separation based on the size of
the polypeptide chain to simplify the analysis of protein molecules, this can be achieved by
denaturing proteins with the detergent SDS. The association of SDS molecules with protein
molecules imparts an associated negative charge to the molecular aggregate formed; this
negative charge is significantly greater than the original charge of that protein. The
electrostatic repulsion that is created by SDS binding forces proteins into a rod-like shape,
thereby eliminating differences in shape as a factor for electrophoretic separation in gels.
Dodecyl sulfate molecule has two negative charges at the pH value used for
electrophoresis, this will lead the net charge of coated polypeptide chains to be much more
negative than uncoated chains. The charge-to-mass ratio is essentially identical for different
proteins because SDS coating dominates the charge.
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PREFORMULATION
6. PREFORMULATION STUDY
Preformulation study
Physiochemical Properties of Clobazam
A) Physical evaluation
It refers to the evaluation by sensory characters-taste, appearance, odor, feel of the drug,
etc.
Table 6.1 List of Sensory characters
S. No. Sensory characters Result
1. Colour White or off-white powder
2. Odor Odorless
B) Solubility: Solubility of the drug was determined by taking some quantity of drug
(about 1-2 mg) in the test tube separately and added the 5 ml of the solvent (water, ethanol,
methanol, 0.1N HCl, 0.1 N NaOH and Chloroform) Shake vigorously and kept for some
time. Note the solubility of the drug in various solvents (at room temperature) (Indian
pharmacopeia. 2007).
Table 6.2 Solubility of Clobazam
Solvent used Clobazam
Distilled Water Slightly Soluble
0.1 N Hydrochloric acid Slightly Soluble
Ethanol Soluble
Methanol Freely soluble
Chloroform Slightly Soluble
C) Melting point:
It is one of the parameters to judge the purity of drugs. In case of pure chemicals,
melting points are very sharp and constant. Since the drugs contain the mixed chemicals,
they are described with certain range of melting point (Reddy ET AL., 2016).
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PREFORMULATION
Procedure for determine melting point:

A small quantity of powder was placed into a fusion tube. That tube was placed in
the melting point determining apparatus (Chemline) containing castor oil. The temperature
of the castor oil was gradual increased automatically and read the temperature at which
powder started to melt and the temperature when all the powder gets melted.
Table 6.3 Melting point of the Clobazam
S. No. Melting Point of Clobazam Average Melting Point of Clobazam
1. 182 ºC-184 ºC 181 - 183°C
2. 181 ºC -183 ºC
3. 181 ºC -183 ºC
D) Identification Test
FTIR Spectroscopy
Infra- red spectrum is an important record which gives sufficient information about
the structure of a compound. This technique provides a spectrum containing a large number
of absorption band from which a wealth of information can be derived about the structure
-1
of an organic compound. The region from 400-4000 cm infra-red region.
Identification of Clobazam was done by FTIR Spectroscopy with respect to marker

compound. Clobazam was obtained as White or off-white powder. It was identified from
the result of IR spectrum as per specification.
Sample of pure Clobazam

The IR spectrum of sample drug shows the peak values which are characteristics of
the drug and the graph were shown in figure no. 6.1
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PREFORMULATION
Figure 6.1: FT-IR Spectrum of Pure Drug (Clobazam)

E) Loss on drying: The moisture in a solid can be expressed on a wet weight or dry wet
basis. On a wet weight basis, the water content of a material is calculated as a percentage of
the weight of the weight solid. The term loss on drying is an expression of moisture content
on a wet weight basis.
Procedure:
Loss on drying is directly measured by IR moisture balance. Firstly calibrated the
instrument by knob then taken 1.000 gm sample (powder) and set the temp at 100°C to
105°C for 15 minutes and constant reading set the knob and check % moisture.
Table 6.4 Loss of drying of drug sample
S. No. Initial weight Final weight after 15 % loss of drying Avg. %

loss
Minutes
of drying
1. 1gm 0.998 gm 0.2 % 0.466
2. 1gm 0.992 gm 0.8 %
3. 1gm 0.996 gm 0.4 %
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PREFORMULATION
F) Bulk properties
Bulk density is defined as the mass of powder divided by the bulk volume. Bulk
density largely depends on particle shape, as the particles become more spherical in shape,
bulk density is increase. In addition as granules size increase, bulk density decrease. Bulk
properties such as particle size, bulk density etc. of a solid form, are likely to change during
process development. Therefore, comprehensive characterization of all Preformulation lots
is necessary to avoid misleading predictions (Newman, 1995).
Bulk Density, Hygroscopicity and Compressibility, these properties are important in
designing reliable manufacturing method.
Bulk density is determined by measuring the volume of a known mass of powder
sample that has been passed through a screen into a graduated cylinder or through a
volumetric measuring apparatus into a cup.
Procedure:
Accurately weighed 10mg of powder was poured into the measuring cylinder
carefully level the powder without compacting, if necessary and read the unsettled apparent
volume, Vo, to the nearest graduated unit. Calculate the bulk density in gm per ml, gm/cc
by the formula.
Bulk density = Bulk Mass/ Bulk Volume
Table 6.5 Bulk density of Clobazam
S. No. Bulk mass Bulk volume Bulk density Avg. bulk
density
1. 1 gm 1.52 ml 0.657 g/ml 0.660±0.0094
2. 1 gm 1.49 ml 0.671 g/ml
3. 1 gm 1.53 ml 0.653 g/ml
G) Tapped density:
Tapped density is determined by measuring the volume of a known mass of powder
sample before and after the tapping that has been passed through a screen into a graduated
cylinder or through a volumetric measuring apparatus into a cup (Newman, 1995).
Procedure:
Accurately weighed 10mg of powder was poured into the measuring cylinder
carefully level the powder and read the tapped volume (after 50-60 times tapping), Vt to the
3
nearest graduated unit. Calculate the tapped density in gm per ml, gm/ cm by the formula:
Tapped density = Bulk Mass/ Tapped Volume
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PREFORMULATION
Table 6.6 Tapped density of Clobazam
S. No. Bulk mass Tapped volume Tapped density Avg. tapped

density
1. 1 gm 1.12 ml 0.892 g/ ml 0.885±0.008
2. 1 gm 1.13 ml 0.885 g/ ml
3. 1 gm 1.14 ml 0.877g/ ml
H) Compressibility index (Carr’s index):
Compressibility index (C.I.) is an important measure that can be obtained from the
bulk and tapped densities. Carr’s index a material having values of less than 20% to 30% is
defined as the free flowing material (Wells, 1998). It can be calculated as per given formula:
100 (V0-Vf) Tapped density- Bulk density

C.I. = ORC.I. = x100
V0 Tapped density
Table 6.7 C.I. of Clobazam
S. No. Bulk density Tapped density C.I.
1. 0.660±0.0094 0.885±0.008 25.42
I) Hausner ratio:
It indicates the flow properties of the powder and is measured by the ratio of tapped
density to bulk density.
Hausner ratio = Tapped density / Bulk Density
Table 6.8 Hausner ratio of Clobazam
S. No. Bulk density Tapped density Hausner ratio
1. 0.660±0.0094 0.885±0.008 1.340
J) Moisture content determination:

Principle: The titrimetric determination of water is based upon the quantitative reaction of
water with an anhydrous solution of sulphur dioxide and iodine in the presence of a buffer
that reacts with hydrogen ions.
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PREFORMULATION
In the original titrimetric solution, known as Karl Fisher Reagents, the sulfur
dioxide and iodine was dissolved in pyridine and methanol. The test specimen may be
titrated with the reagent directly, or the analysis may be carried out by a residual titration
procedure. The stoichiometry of the reaction is not exact, and the reproducibility of a
determination depends upon such factors as the relative concentration of the reagent
ingredients, the nature of the inert solvent used to dissolve the test specimen, and the
technique used in the particular determination. Therefore, an empirically standardized
technique is used in order to achieve the desired accuracy. Precision in the method is
governed largely by the extent to which atmospheric moisture is excluded from the system.
The titration of water is usually carried out with the use of anhydrous methanol as the
solvent for the test specimen; however other suitable solvents may be used for special or
unusual test specimens. (Note: Now-a-days pyridine free KF reagents are coming in which
pyridine is replaced by the imidazole, because pyridine has carcinogenic effects).
Procedure
Karl Fischer volumetry is used for samples with high water content, I.E. 1-100 mg
per sample. An iodine-containing solution serves as titrating agent. The water content of the
sample is calculated using titration volume and titer of the titrating agent. One- component
reagents conveniently contain all reactants (iodine, sulfur dioxide and a base) dissolved in a
suitable alcohol in one solution, whereas two-component reagents contain all necessary
reactants separated in two different solutions to enhance the rapidity of the Karl Fischer
reaction and the titer stability of the titrating agent.
Karl Fischer coulometry is a micro-method and is particularly suitable for samples
with low water content, from 10 µg up to 10 mg. Here, the required iodine is generated
electrochemically in the titration vessel by anodic oxidation from iodide contained in the
coulometric reagents. The amount of consumed electric charge is used to calculate the
consumption of iodine and therefore the amount of water in the sample.
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PREFORMULATION
Table 6.9 Moisture content determination
S. No. Drug KF Factor Amount of KF Reagent Moisture content

consumed
1 Clobazam 0.545 0.2ml 0.109
K) Determination of λ max of Clobazam:

The λmax of Clobazam was determined by running the spectrum of drug solution in
double beam ultraviolet spectrophotometer.
Procedure:
Accurately weighed 10 mg of drug was dissolved in 10 ml of ethanol solutions in
10ml of volumetric flask. The resulted solution 1000µg/ml and from this solution 1 ml
pipette out and transfer into 10 ml volumetric flask and volume make up with ethanol
solution prepare suitable dilution to make it to a concentration range of 5-25 μg/ml. The
spectrum of this solution was run in 200-400 nm range in U.V. spectrophotometer
(Labindia-3000+). The spectrum peak point graph of absorbance of Clobazam versus wave
length was found 238.00 nm and shown in figure 6.2:
200.0250.0300.0350.0400.
00
Figure 6.2: Wavelength maxima of Clobazam in Ethanol
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PREFORMULATION
L) Calibration curve of
Clobazam Observation table:
Table 6.10 Calibration curve of Clobazam
S. No. Conc. (µg/ml ) Absorbance
1 5 0.125±0.005
2 10 0.248±0.003
3 15 0.369±0.004
4 20 0.478±0.006
5 25 0.598±0.004
Figure 6.3: Calibration curve of Clobazam in methanol

The linear regression analysis was done on Absorbance data points. The results are as
follow for standard curve
Slope = 0.030
The intercept = 0.002
2
The correlation coefficient (r ) = 0.999
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PREPARATION AND
7. PREPARATION AND CHARACTERIZATION
Preparation of solid dispersions

Preparation of sold dispersion using PEG 8000, PVP K 30 and SLS
PEG 8000, PVP K 30 and SLS solid dispersion were used to prepare at weight ratios of 1:1,
1:2, 1:4 and 1:8, using three different preparation methods, physical trituration, kneading
and solvent evaporation.
Table 7.1: Preparation of solid dispersion complexes
S. No. Solid Dispersion

Drug: PEG 8000 Drug: PVP K30 Drug: SLS
1. 1:1 1:1 1:1
2. 1:2 1:2 1:2
3. 1:4 1:4 1:4
4. 1:8 1:8 1:8
Method of preparation of Solid Dispersion

Physical trituration method
In the physical trituration method, drug and PEG 8000, PVP K 30 and SLS were weighed,
sieved and mixed evenly by slowly adding drug into PEG 8000, PVP K 30 and SLS
separately in a mortar with light trituration. The mixture was continuously mixed for an
hour until a homogeneous mixture was obtained. The mixtures were passed through a #65
mesh sieve and kept in a closed container.
Kneading method
In the kneading method, PEG 8000, PVP K 30 and SLS in a mortar was wetted with
sufficient amount of water (10% w/w) to obtain a paste and drug was slowly added into
the paste. Kneading was performed manually for an hour and suitable amount of water was
added from time to time to maintain the consistency of the paste. The mixture was dried
overnight for 24 hr in an oven (Electronic India) at 50°C. The dried complex was ground
using mortar and pestle. After sieving through a #65 mesh sieve, the complex was kept in
a closed container.
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PREPARATION AND
Solvent evaporation method
8000, PVP K 30 and SLS were dissolved in 50 mL of distilled water. The two solutions
were mixed together and stirred for 1 hr (Magnetic stirrer, Electronic India) methanol was
evaporated off by heating at 40°C under constant stirring. Water was then removed under
reduced pressure using rotary evaporator. The mixture was placed overnight for 24 hr in an
oven at 40°C to remove the residual solvent. The inclusion complex was ground using
mortar and pestle. After sieving through a #65 mesh sieve, the solid dispersion was kept in
a closed container.
Solubility study was performed by adding an excess amount of solid dispersions in 50 mL

of distilled water. The flasks were vortex-mixed for 3 min and agitated at 120 rounds per
minute in a water bath maintained at 30°C for 72 hours. Samples of 3 mL were withdrawn
and filtered through a 0.45 µm nylon membrane filter. Filtrate (0.1ml) was diluted
appropriately and measured spectrophotometrically (Labindia 3000+) at 238nm. Each
measurement was repeated three times.
Solubility studies
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PREPARATION AND
Results of solubility study

Table 7.2: Solubility of different solid dispersion complexes
F. code Complex Solubility (mg/ml)
Physical method Kneading Solvent evaporation
method method
Pure drug 0.188 mg/ml
CSDF1 Drug: PEG 8000 0.190 0.225 0.332
(1:1)
CSDF2 Drug: PEG 8000 0.196 0.325 0.365
(1:2)
CSDF3 Drug: PEG 8000 0.223 0.365 0.421
(1:4)
CSDF4 Drug: PEG 8000 0.245 0.378 0.565
1:8)
CSDF5 Drug: PVP K 30 0.223 0.332 0.356
(1:1)
CSDF6 Drug: PVP K 30 0.256 0.356 0.458
(1:2)
CSDF7 Drug: PVP K 30 0.325 0.385 0.556
(1:4)
CSDF8 Drug: PVP K 30 0.456 0.398 0.658
(1:8)
CSDF9 Drug: SLS (1:1) 0.321 0.325 0.221
CSDF10 Drug: SLS (1:2) 0.456 0.395 0.265
CSDF11 Drug: SLS (1:4) 0.569 0.421 0.369
CSDF12 Drug: SLS (1:8) 0.625 0.485 0.421
*CSDF – (Complex of Solid Dispersion Formulation)
Intraction of complex CSDF8 with solvent is maximum because of intermolecular force
between complex and solvent in compasison to other complex.
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PREPARATION AND
Evaluation of dispersion granules of optimized formulation SDF8
Percentage drug content:
For the determination of Clobazam content, dispersion granules equivalent to 10 mg of

drug, were weighed and extracted with 10 ml of methanol by mechanical mixing for 5min
followed by centrifugation at 10,000 rpm for 5 min on a centrifuge. The supernant was
filtered through 0.45µ membrane filter, and the filtered solutions were suitably diluted and
analyzed for albendazole at 238nm using a validated UV spectrophotometric method.
Drug content
Table No. 7.3: Results of drug content
Formulation Label Amount Label claim %

claim Found (%) RSD
(mg) (mg) Mean ± S.D.

CSDF8 10 9.92 99.20 ±0.03 0.125
Drug: PVP K 30 (1:8)
*Average of three determination
Differential scanning calorimetry (DSC)
Thermal analysis was carried out with a DSC instrument. Sample was weighed into a non-
hermetically sealed aluminum pan. The samples were heated from 25 to 400 °C at a heating
rate of 5°C/min for drug and solid dispersion. The instrument was calibrated by using
indium.
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PREPARATION AND
Figure 7.1: DSC analysis of pure Clobazam
Figure 7.2: DSC analysis of optimized batch SDF8
As the solid dispersion exhibited no endothermic peak corresponding to the melting point
of drug that the drug is dispersed amorphously in solid matrix.
Evaluation of Flow properties
Angle of repose (θ): The frictional forces in a loose powder or granules can be measured
by the angle of repose. This is the maximum angle possible between the surface of a pile of
powder or granules and the horizontal plane.
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PREPARATION AND
Where, θ is the angle of repose, h is the height, r is the radius.
The granules were allowed to flow through the funnel fixed to a stand at definit
height. The angle of repose was then calculated by measuring the height and radius of
the heap of granules formed
Table 7.4 Relationship between Angle of Repose (θ) and flow properties
Angle of Repose (θ)

S. No. Flow
(degrees)
1. <25 Excellent
2. 25-30 Good
3. 30-40 Passable*
4. >40 Very poor
*Adding glidant E.g. Talc may improve flow properties
Bulk density: Both loose bulk density (LBD) and tapped bulk density (TBD) were
determined. Accurately weighed amount of granules taken in a 50 ml capacity measuring
cylinder was tapped for 100 times on a plane hard wooden surface and estimated the LBD
and TBD, calculated by using following formulas.
Carr’s Compressibility index: Percent compressibility of powder mix was determined by
Carr’s compressibility index, calculated by using following formula:-
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PREPARATION AND
Table 7.5 Grading of the powders for their flow properties according to Carr’s Index
Carr’s Compressibility
S. No. Flow
index
1. 5–15 Excellent
2. 12–16 Good
3. *18 – 21 Fair to passable
4. *23 – 35 Poor
5. 33–38 Very poor
6. >40 Very very poor
*Adding glidant E.g. Talc should improve the flow properties
Hausners ratio: It is determined by comparing tapped density to the bulk density by using
following equation:-
Housner’s ratio = Tapped bulk density/loose Bulk density
Hausner’s ratio value <1.25 shows better flow properties
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PREPARATION AND
Table 7.6 Results of pre-compression parameters of Clobazam
Parameters
Formulation Carr’s
Loose Bulk Tapped bulk Hausner’s
Code Index
density(gm/ml) density(gm/ml) Ratio
(%)
SDF1 0.465 0.568 18.134 1.222
SDF2 0.469 0.561 16.399 1.196
SDF3 0.472 0.573 17.627 1.214
SDF4 0.475 0.574 17.247 1.208
SDF5 0.468 0.569 17.750 1.216
SDF6 0.469 0.572 18.007 1.220
SDF7 0.471 0.572 17.657 1.214
SDF8 0.465 0.576 19.271 1.239
SDF9 0.463 0.574 19.338 1.240
SDF10 0.471 0.573 17.801 1.217
SDF11 0.469 0.572 18.007 1.220
SDF12 0.471 0.573 17.801 1.217
Dissolution rate studies of optimized solid dispersion SDF8

The prepared tablets were evaluated for IN VITRO drug release. The drug release studies were
carried out using USP XXII paddle type Dissolution test apparatus. The dissolution study
was carried out in 900 ml dissolution medium which was stirred at 75 rpm maintained at
37±0.2C. The scheme of using the simulated fluids at different timing was as follows:
A solid dispersion equivalent to 10mg placed in dissolution media (900 ml) at

37±0.2C. Samples were withdrawn at different time interval and compensated with same
amount of fresh dissolution medium. Volume of sample withdrawn was made up to 10ml
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PREPARATION AND
0.1 N HCl. The samples withdrawn were assayed spectrophotometrically at 238nm using
UV visible spectrophotometer. The release of drug was calculated with the help of standard
curve of Clobazam.
Mathematical treatment of IN-VITRO release data: The quantitative analysis of

the values obtained in dissolution/release tests is easier when mathematical formulas
that express the dissolution results as a function of some of the dosage forms
characteristics are used.
1. Zero-order kinetics: The pharmaceutical dosage forms following this profile release
the same amount of drug by unit of time and it is the ideal method of drug release in order
to achieve a pharmacological prolonged action. The following relation can, in a simple
way, express this model:
Qt = Qo + Ko t
where Qt is the amount of drug dissolved in time t, Qo is the initial amount of drug in the
solution (most times, Qo=0) and Ko is the zero order release constant.
2. First-order kinetics: The following relation expresses this model:
Where Qt is the amount of drug dissolved in time t, Qo is the initial amount of drug in the
solution and K1 is the zero order release constant.
In this way a graphic of the decimal logarithm of the released amount of drug versus time
will be linear. The pharmaceutical dosage forms following this dissolution profile, such as
those containing water-soluble drugs in porous matrices, release drug in a way that is
proportional to the amount of drug remaining in its interior, in such way, that the amount of
drug released by unit of time diminish.
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PREPARATION AND
3. Higuchi model: Higuchi developed several theoretical models to study the release of
water-soluble and low soluble drugs in semi-solid and/or solid matrixes. Mathematical
expressions were obtained for drug particles dispersed in a uniform matrix behaving as the
diffusion media.
The simplified Higuchi model is expressed as:
Where Q is the amount of drug released in time t and K H is the Higuchi dissolution
constant. Higuchi model describes drug release as a diffusion process based in the Fick’s
law, square root time dependent. This relation can be used to describe the drug dissolution
from several types of modified release pharmaceutical dosage forms such as transdermal
systems and matrix tablets with water-soluble drugs.
4. Korsmeyer-Peppas model: Korsmeyer ET AL. used a simple empirical equation
to describe general solute release behaviour from controlled release polymer
matrices:
Where Mt/M is fraction of drug released, a is kinetic constant, t is release time and n is the
diffusional exponent for drug release. ’n’ is the slope value of log Mt/M versus log time
curve. Peppas stated that the above equation could adequately describe the release of
solutes from slabs, spheres, cylinders and discs, regardless of the release mechanism.
Peppas used this n value in order to characterize different release mechanisms, concluding
for values for a slab, of N =0.5 for fickian diffusion and higher values of N, between 0.5
and 1.0, or N =1.0, for mass transfer following a non-fickian model. In case of a cylinder N
=0.45 instead of 0.5, and 0.89 instead of 1.0. This equation can only be used in systems
with a drug diffusion coefficient fairly concentration independent. To the determination of
the exponent N the portion of the release curve where Mt/M < 0.6 should only be used. To
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PREPARATION AND
use this equation it is also necessary that release occurs in a one-dimensional way and that
the system width-thickness or length-thickness relation be at least 10. A modified form of
this equation was developed to accommodate the lag time ( L) in the beginning of the drug
release from the pharmaceutical dosage form:
When there is the possibility of a burst effect, b, this equation becomes:
In the absence of lag time or burst effect, l and b value would be zero and only at N is used.
This mathematical model, also known as Power Law, has been used very frequently to
describe release from several different pharmaceutical modified release dosage forms.
Release kinetics of Clobazam solid dispersion
Table 7.7 IN-VITRO drug release data for optimized formulation CSDF8
Log Log
Square Cumulative
Time Log Cumulative*% Cumulative Cumulative
Root of % Drug
(min) Time Drug Release % Drug % Drug
Time(h)1/2 Remaining
Release Remaining
15 3.873 1.176 11.23 1.050 88.77 1.948
30 5.477 1.477 22.23 1.347 77.77 1.891
60 7.746 1.778 36.65 1.564 63.35 1.802
120 10.954 2.079 43.32 1.637 56.68 1.753
240 15.492 2.380 49.98 1.699 50.02 1.699
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PREPARATION AND
Zero order release kinetics of formulation CSDF8
Figure 7.3: Graph of zero order release Kinetics of formulation CSDF8
First order release Kinetics of formulation CSDF8
Figure 7.4: Graph of first order release kinetics of formulation CSDF8
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PREPARATION AND
Table 7.8 Regression analysis data
Zero Order First Order

Batch
r² r²
CSDF8 0.757 0.817
When the regression coefficient values of were compared, it was observed that ‘r’ values of
First order was maximum i.e. 0.817 hence indicating drug release from formulations was
found to follow first order kinetics.
The higher oral bioavailability and longer half life of clobazam can be additive in terms of
tolerance, drug administered orally with water or 50% ethanol to seven healthy subjects and
found satisficantly increased bioavailability resulting in doubling of Cmax. Ethanol
increased clobazam Cmax and AUC.
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SUMMARY AND
8. SUMMARY AND CONCLUSION
Aqueous solubility is one of the key determinants in development technologies, such as

combinational chemistry and high throughput screening are based on the basic principles of
medicinal chemistry, teaching that the most reliable method to increase in vitro potency is
to add lipophilic moiety at appropriate positions of the lead structure. This has led to an
increase in number of lipophilic and poorly soluble molecules being investigated for their
therapeutic activity. Various formulation techniques are applied to compensate for their
insolubility slow dissolution rate consequently poor therapeutic efficacy. These include
formulation of the amorphous solid form, nanoparticles, microemulsions, solid dispersions;
melt extrusion, salt formation and formation of water soluble complexes.
Preformulation of drug and excipient was performed in which physiochemical properties

and other parameters of drug were studied. Physiochemical parameters such determination of
solubility, melting point, λmax scan using
UV-spectrophotometry, FT-IR spectrophotometry were performed in this study. The

obtained data from these studies were matched with the data given in standard monographs
to confirm the authenticity of procured drug.
Procured Clobazam drug was odorless and White to off-white powder in nature. In
solubility study it was found that drug was freely soluble in methanol and soluble in
ethanol, It was slightly soluble in distilled water, 0.1 N Hydrochloric acid Chloroform.
Melting point of drug was found 181 - 183°C.
The obtained FT-IR characteristic peaks of drug was matched with the peaks of drug given
in standard monograph was revealed similar. Identification of Clobazam sample was done
by infrared spectroscopy. Moisture content of Clobazam was found 0.109mg.
The drug solution was scan on UV-spectrophotometer at 200-400 nm in Wavelength range

to determine the maximum absorbance (λ max) and it was found at 238nm. The calibration
2
curve was prepared in methanol. The regression coefficient (R ) was 0.998 which was
shows the linearity of curve. The line of equation for the standard curve was y = 0.030x -
0.002.
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SUMMARY AND
The solubility of pure drug was significantly increased in the presence of different
hydrophilic carriers lite. PEG 8000, PVP K 30 and SLS solid dispersion were used on the
prepare at weight ratios of 1:1, 1:2, 1:4 and 1:8, using three different preparation methods,
physical trituration, kneading and solvent evaporation in various weight ratios to enhance
the solubility of pure drug and dissolution.The increased dissolution rate was observed with
increase in hydrophilic carrier concentration. From the selected hydrophilic carrier, PVP K
30 in the ratio of (1:8) has shown significant impact on the aqueous solubility and
dissolution rate of Clobazam when compared to the reaming two hydrophilic carriers. It
means solid dispersion of clobazam with increased solubility of dissolution increased the
bioavailability of the drug.
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BIBLIOGRAPH
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Rampal Ahirwar Final Thesis

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FORMULATION, DEVELOPMENT AND EVALUATION OF SOLID

DISPERSION FOR DISSOLUTION RATE ENHANCEMENT

M Pharm Dissertation 2020-2021

RAJIV GANDHI PROUDYOGIKI VISHWAVIDYALAYA, BHOPAL

Guide Co- Guide

BHOPAL INSTITUTEOF TECHNOLOGY&SCIENCE-PHARMACY,

The dissertation work entitled “FORMULATION, DEVELOPMENT AND EVALUATION OF

Internal Examiner: External Examiner:

BHOPAL INSTITUTEOF TECHNOLOGY&SCIENCE-PHARMACY,

Place: - Bhopal Dr. UMESH K. JAIN

(M. Pharm., Ph.D.)

BHOPAL INSTITUTE OF TECHNOLOGY &SCIENCE-PHARMACY,

BHOPAL INSTITUTE OF TECHNOLOGY &SCIENCE-PHARMACY,

This work presented in the thesis entitled “FORMULATION, DEVELOPMENT AND

Date: Rampal Ahirwar

BHOPALINSTITUTE OF TECHNOLOGY& SCIENCE- PHARMACY, BHOPAL(M.P.)

Overall Similarity: 19%

DISSOLUTION RATE ENHANCEMENT” A Dissertation Part-II submitted to Rajiv Gandhi

Master of Pharmacy (Pharmaceutics)

bioavailability, stability and convenience to the patient, is the major objective of

have shown promising results in increasing bioavailability of poorly water-soluble drugs in

hazardous to the environment as well as to physiological systems. Supercritical fluids are

environmentally safe. Therefore, to prepare biodegradable micro and nano-particles the

Designing of prodrug is also used to improve the physicochemical properties such as

compound lipophilicity and solubility to prevail over the pharmacokinetic demerits

referred as promoiety. Designing prodrug for improving bioavailability is one of the

exopeptidase. A recent study INTRODUCTION involved synthesis of cyclic hexapeptide to

increased permeability of cyclic prodrug than parentmolecule. Derivatization is another

lucrative approach for synthesis of prodrug to improve bioavailability of drug molecules

especially for peptide

Microemulsion formulations Microemulsion is a lipid based delivery system whose major

advantages include high solubilization potential, thermodynamic stability, improved

dissolution of lipophilic drugs (Constantinides, 1995) and surfactant-induced permeability

enhancement. 1.3.4 Dissolution enhancement by physical modification of the drug The

solubility of a drug determines the dissolution behavior of an active pharmaceutical

solubility controlled), the formulation approach is commonly used to enhance the

ranges. With the aforementioned advantages, micronization has some limitations;

micronization of sparingly or poorly soluble drugs is by no means a guarantee of better

dissolution and absorption. 1.3.6 Nanotechnology

Nanotechnology will be used to improve drugs having poor solubility.

sufficient. Micronized product has the tendency to agglomerate, which leads to

on their molecular arrangement, six different types of solid dispersions can be

distinguished. Moreover, in various studies the designation of solid dispersions is based on

be argued that solid dispersions should preferably be designated according to their

arrangement will enlarge comprehension of the properties and behavior of solid

dispersions. Furthermore, it will facilitate optimization of their properties required for

type of solid 2 dispersion prepared II Amorphous C A Rarely encountered 2 precipitations

in crystalline matrix III Solid solutions Continuous solid C M miscible composition, 1

even though drug is molecularly Substitutional solid C M Molecular diameter

When discontinuous: 2 phases even though drug is molecularly dispersed. IV Glass

suspension A C Particle size of 2 dispersed phase dependent on cooling/evaporation rate.

Obtained after crystallization of drug in amorphous matrix V Glass suspension A A Particle

size of 2 dispersed phase dependent on cooling/evaporation rate many solid dispersions

A: drug dispersed as amorphous clusters in the matrix, C: drug dispersed as crystalline

of preparing solid dispersions; melting method and

synonymous to melt method. 1.5.1 Meltsionlgvemnet

INTRODUCTION purposes by Speiser

currentmethod of choice for the manufacture of solid dispersions. Melt extrusion

>355µm (Chokshi and Hossein, 2004).

product under preparation.

common solvent, frozen and sublimed to obtain a lyophilized molecular dispersion

point of the binder (melt- in procedure) or by spraying a dispersion of drug in molten