Zolmi Final PDF

DESIGN AND EVALUATION OF BUCCAL PATCHES OF
ZOLMITRIPTAN
Dissertation Submitted to
Kakatiya University, Warangal,
In Partial Fulfillment for the degree of

Master of Pharmacy
in
PHARMACEUTICS
by
Ms. YARA NAGAMANI

B.Pharmacy
Under the guidance of
Prof. Y. MADHUSUDAN RAO
M.Pharm., Ph.D.
Department of Pharmaceutics
VAAGDEVI INSTITUTE OF PHARMACEUTICAL SCIENCES
Bollikunta, Warangal - 506 005
2019
DECLARATION
I hereby declare that the work described in this entitled “Design and
Evaluation of Buccal Patches of Zolmitriptan”, has been prepared by me under the
supervision of my guide Prof. Y. Madhusudan Rao, Director, Vaagdevi Institute of
Pharmaceutical Sciences, Bollikunta, Warangal, in partial fulfillment for the award of
the degree of Master of Pharmacy in Pharmaceutics. I further declare that I have not
submitted this dissertation previously for the award of any degree or diploma.
Date:
Place: (Ms. YARA NAGAMANI)

CERTIFICATE
This is to certify that the work presented in the thesis entitled, “Design and
Evaluation of Buccal Patches of Zolmitriptan” has been carried out in the
laboratories of Vaagdevi Institute of Pharmaceutical Sciences, Bollikunta, Warangal
for the partial fulfillment for the degree of Master of Pharmacy in Pharmacuetics by
Ms. Yara Nagamani under my guidance and supervision.
Prof. Y. MADHUSUDAN RAO

Date: Director, Department of Pharmaceutics
Place: VIPS, Bollikunta, Warangal
Date:
CERTIFICATE
This is to certify that the work presented in the thesis entitled, “Design and
Evaluation of Buccal Patches of Zolmitriptan” has been carried out in the
laboratories of Vaagdevi Institute of Pharmaceutical Sciences, Bollikunta, Warangal
for the partial fulfillment for the degree of Master of Pharmacy in Pharmacuetics by
Ms. Yara Nagamani.
Dr. K. Rajitha Dr. M. Radhakishan

M. Pharm. Ph.D, M. Pharm. Ph.D
HOD, Dept. of Pharmaceutics Principal
VIPS, Bollikunta, Warangal VIPS, Bollikunta, Warangal
ACKNOWLEDGEMENT
I owe my profound gratitude, indebtedness and heartfelt thanks to my guide

Prof Y. Madhusudhan Rao, Director, Vaagdevi Institute of pharmaceutical Sciences,
Bollikunta, Warangal for encouraging and permitting me to carry out my dissertation
work.
I am sincerely thankful to Dr. M. Radhakishan, Principal, Vaagdevi Institute

of Pharmaceutical Sciences, Bollikunta, Warangal for providing me necessary
facilities to carry out research work.
My special gratitude to Shri Ch. Devender Reddy,, Secretary and

Correspondent, Viswambhara Educational Society, Hanamkonda for his kind co-
operation and providing all the resources to complete my master’s successfully.
I wish to convey my deep sense of gratitude to Dr. K. Rajitha, HOD,

Department of Pharmaceutics, Vaagdevi Institute of Pharmaceutical Sciences,
Bollikunta, Warangal for his suggestions, encouragement and immense help
throughout my dissertation work.
My heartfelt thanks to Dr. Kiran Kumar, Mr. Kishore, Mr. K. Naresh, and
Mrs. S. Haraika for their co-operation during my project work.
(Ms. YARA NAGAMANI)

LIST OF FIGURES
F. no. Title of the figure
1 The two steps of the mucoadhesion process.

2 Dehydration theory of mucoadhesion
3 Schematic diagram showing influence of contact angle between device and
mucous membrane on bioadhesion.
4 Secondary interactions resulting from inter diffusion of polymer chains of
bioadhesive device and of mucus.
5 Regions where the mucoadhesive bond rupture can occur
6 Everted gut sac procedure
7 Different forces evaluated in mucoadhesion tests
8 Bioadhesion test using the texture analyzer.
9 Apparatus to determine mucoadhesion in vitro, using Wilhemy’s technique
10 Microbalance method for measuring mucoadhesion.
11 Constituents of AFM and the adaptations made for measuring the adhesive force
between polymer and mucus surface.
12 Elements of EFT. Adapted from Mathiowitz, Chickering and Lehr (1999).
13 Schematic representation of in vitro model used by Nielsen, Schubert and
Hansen (1998), adapted from Rango Rao and Buri (1989).
14 structural formula of Carboxymethylcellulose sodium
15 Structural formula of hydroxypropyl methylcellulose
16 Structural formula of eudragit
17 Standard Graph of Zolmitriptan in pH 6.8 Phosphate Buffer
18 Graphical representations for Tensile Strength of all formulations
19 Graphical representations for Percent Elongation of all formulations
20 Graphical representations for Folding Endurance of all formulations
21 % Cumulative drug release profile of formulations Z1, Z2, & Z3
23 % Cumulative Drug Release of formulations Z7, Z8, & Z9
LIST OF TABLES
Table no. Title of the table

1 List of Material used in the formulation development
2 List of equipments used in the study
3 Different HPMC grades (Methocel) and their properties (Colorcon, Asia
ltd)
4 HPMC grades and their molecular units
5 Solubility chart
6 Composition of film formulated with HPMC E5
7 Composition of film formulated with Sodium CMC
8 Composition of film formulated with Carbopol 934p
9 Composition of film formulated with Eudragit RS-100
10 Zolmitriptan Standard Graph Parameters
11 Different combinations of API and Excipients for Drug-Excipient
compatibility study. (Exposed conditions 40ºc)
12 Physical evaluation parameters of all formulations
13 Mechanical properties of all formulations
14 % Cumulative drug release of formulations Z1, Z2, & Z3
15 % Cumulative drug release of formulations Z4, Z5, & Z6
16 % Cumulative Drug Release of formulations Z10, Z11, & Z12
LIST OF ABBREVIATIONS
C : Celsius
Cps : Centipoise
Cm : Centimeter
F : Formulations
Mcc : Microcrystalline cellulose
Pvp : Polyvinyl pyrrolidone
HPMC : Hydroxy propyl methyl cellulose
PEG : Poly ethylene glycol
Csd : Colloidal silicon dioxide
Ssg : Sodium starch glycolate
PG : Propylene Glycol
CMC : Critical micelle concentration
Bp : British Pharmacopoeia
Ip : Indian Pharmacopoeia
USP : United States Pharmacopeia
FTIR : Fourier Transform Infrared
IR : Infrared
SD : Standard Deviation
RPM : Revolutions per minute
UV : Ultraviolet
Gm : Gram
mg : Milligram
mm : milli meter
pH : Negative logarithm of hydrogen ion concentration
min : Minutes
sec : Seconds
Cc : Cubic centimeter
Kg : Kilogram
% : Percentage
o
C : Degree Celsius
nm : Nanometer
FDA : Food and drug administration of USA
BCS : Bio pharmaceutics classification system
TABLE OF CONTENTS
Sl. No CONTENTS Page No.
1 Introduction 01
2 Review of Literature 27
3 Objectives 34
4 Materials & Method 36
5 Results & Discussion 54
6 Summary & Conclusion 68
7 References 69
Design And Evaluation Of Buccal Patches Of Zolmitriptan
1. INTRODUCTION
The effect of a drug can now be reinforced as a result of the development of new
release systems. Controlled release consists of techniques that make the active chemical
agents available for a target, providing an adequate release rate and duration to produce
the desired effect. The main controlled drug delivery systems currently available include
matrices, pellets, floating systems, liposomes, microemulsions, liquid crystals, solid
dispersions, nanosuspensions, transdermal systems, cyclodextrin inclusion complexes,
osmotic pumps and bioadhesive systems (Wise, 2000).
Bioadhesion can be defined as the state in which two materials, at least one of which
is biological in nature, are maintained together for a prolonged time period by means of
interfacial forces (Smart, 2005). During the 1980s, this concept began to be applied to
drug delivery systems. It consists of the incorporation of adhesive molecules into some
kind of pharmaceutical formulation intended to stay in close contact with the absorption
tissue, releasing the drug near to the action site, thereby increasing its bioavailability and
promoting local or systemic effects (Hägerström, 2003; Woodley, 2001). An extensive
review on mucoadhesive systems was compiled by Andrews, Laverty and Jones (2008).
The potential use for mucoadhesive systems as drug carriers lies in its prolongation of
the residence time at the absorption site, allowing intensified contact with the epithelial
barrier (Hägerström, 2003). On the other hand, adhesion of preparations onto mucous
membrane can be impaired by the mucociliary clearance system. This clearance, a natural
defense mechanism of the body against the deposition of impurities onto the mucous
membrane, can also remove the preparation. Thus, by using bioadhesive molecules, it is
possible to retain the preparation at the action site and to direct the drug to a specific site
or tissue. Other features associated with the development of controlled drug delivery
systems using bioadhesive molecules include a decrease in drug administration frequency
and an increase in patient compliance to the therapy (Woodley, 2001). Therefore, a
bioadhesive system controlling drug release could improve the treatment of diseases,
helping to maintain an effective concentration of the drug at the action site (Huang et al.,
2000).
Mucous membrane is the main administration site for bioadhesive systems, although
the need for new bioadhesive formulations for dermal administration has also been
Department of Pharmaceutics- VIPS, Bollikunta Page 1

reported when prolonged cutaneous action is desired. A prolonged effect upon the dermal
administration of creams, solutions, and lotions is unexpected, since such preparations
can be easily removed from the skin by moisture, temperature, and physical movements
(Shin et al., 2003).
Mucousl membranes of human organism are relatively permeable and allow fast drug
absorption (Jasti, Li, Cleary, 2003). They are characterized by an epithelial layer whose
surface is covered by mucus. The mucus contains glycoproteins, lipids, inorganic salts
and 95% water by mass, making it a highly hydrated system. Mucin is the most important
glycoprotein of mucus and is responsible for its structure. The main functions of mucus
are protecting and lubricating the epithelium and other additional functions depending on
the epithelium covered. Mucus thickness can vary from 50-450 μm in the stomach to less
than 1 μm in the oral cavity (Smart, 2005). The mucous site most used for drug
administration and absorption is gastrointestinal (Junginger, Thanou, Verhoef, 2002), but
other routes, including nasal, ocular, buccal, vaginal, rectal, oral, and periodontal have
also been studied (Bruschi et. al. 2008, Bruschi, 2007; Hägerström, 2003; Woodley,
2001).
Bioadhesive systems applied to mucous membrane are frequently defined as

mucoadhesive, but the terms are interchangeable (Leung, Robinson, 1990). It is feasible
to design a bio(muco)adhesive system in different dosage forms, since the properties of
adhesion largely depend on the features of the material used in its preparation
(Evangelista, 2006). Therefore, several conventional drug delivery systems already in use
can become bioadhesive after redesign by including bioadhesive substances in their
formulation.
This approach to confer Bioadhesion properties has been widely applied in the
development of a number of drug delivery systems. Solid micro- and nano-particulate
systems based on chitosan and derivatives have been the focus of several studies (Bravo-
Osuna et al., 2007; Wittaya-Areekul, Kruenate, Prahsarn, 2006): microemulsions are
thermodynamically stable and isotropic liquid systems, which allow the incorporation of
bioadhesive molecules, such as polycarbophil (Vyas et al., 2006); colloidal dispersions of
bioadhesive polymers frequently used in preparations for oral hygiene (Kockisch et al.,
2001); semi-solid systems, as liquid crystalline mesophases (Bruschi et al., 2007, 2008)

and hydrogels (Bruschi et al., 2007; Huang et al., 2000), which can increase the contact
time between preparation and mucous membrane after they undergo in situ gelation.
There are a number of materials used for developing such systems. The most studied
materials are the polymers derived from polyacrylic acid, such as polycarbophil and
carbomers, polymers derived from cellulose, such as hydroxyethylcellulose and
carboxymethylcellulose, alginates, chitosan and derivatives and more recently, lectins and
their derivatives (Grabovac, Guggi, Bernkop- Schnürch, 2005; Smart, 2005).
Although studies on the mechanisms involved in mucoadhesion and the development

of novel mucoadhesive systems and polymers have evolved over the last twenty years,
mucoadhesion is not yet fully understood. Quantitative and qualitative techniques are still
treated separately. The aim of this study was to systematically review the mechanisms
and theories involving mucoadhesion, as well as to describe the methods and polymers
most used in mucoadhesive systems for drug delivery.
1.2. MECHANISMS OF MUCOADHESION
The mechanism of adhesion of certain macromolecules to the surface of a mucous

tissue is not well understood yet. The mucoadhesive must spread over the substrate to
initiate close contact and increase surface contact, promoting the diffusion of its chains
within the mucus. Attraction and repulsion forces arise and, for a mucoadhesive to be
successful, the attraction forces must dominate. Each step can be facilitated by the nature
of the dosage form and how it is administered. For example, a partially hydrated polymer
can be adsorbed by the substrate because of the attraction by the surface water (Lee, Park,
Robinson et al., 2000).
Thus, the mechanism of mucoadhesion is generally divided in two steps, the contact
stage and the consolidation stage (Figure 1). The first stage is characterized by the contact
between the mucoadhesive and the mucous membrane, with spreading and swelling of the
formulation, initiating its deep contact with the mucus layer (Hägerstrom, 2003). In some
cases, such as for ocular or vaginal formulations, the delivery system is mechanically
attached over the membrane. In other cases, the deposition is promoted by the
aerodynamics of the organ to which the system is administered, such as for the nasal
route. On the other hand, in the gastrointestinal tract direct formulation attachment over
the mucous membrane is not feasible. Peristaltic motions can contribute to this contact,

but there is little evidence in the literature showing appropriate adhesion. Additionally, an
undesirable adhesion in the esophagus can occur. In these cases, mucoadhesion can be
explained by peristalsis, the motion of organic fluids in the organ cavity, or by Brownian
motion. If the particle approaches the mucous surface, it will come into contact with
repulsive forces (osmotic pressure, electrostatic repulsion, etc.) and attractive forces (van
der Waals forces and electrostatic attraction). Therefore, the particle must overcome this
repulsive barrier (Smart, 2005).
In the consolidation step (Figure 1), the mucoadhesive materials are activated by the
presence of moisture. Moisture plasticizes the system, allowing the mucoadhesive
molecules to break free and to link up by weak van der Waals and hydrogen bonds
(Smart, 2005). Essentially, there are two theories explaining the consolidation step: the
diffusion theory and the dehydration theory. According to diffusion theory, the
mucoadhesive molecules and the glycoproteins of the mucus mutually interact by means
of interpenetration of their chains and the building of secondary bonds (Smart, 2005). For
this to take place the mucoadhesive device has features favoring both chemical and
mechanical interactions. For example, molecules with hydrogen bonds building groups (–
OH, –COOH), with an anionic surface charge, high molecular weight, flexible chains and
surface-active properties, which induct its spread throughout the mucus layer, can present
mucoadhesive properties (Mathiowitz, Chickering, Lehr, 1999).
FIGURE 1 – The two steps of the mucoadhesion process.

According to dehydration theory, materials that are able to readily gelify in an

aqueous environment, when placed in contact with the mucus can cause its dehydration
due to the difference of osmotic pressure. The difference in concentration gradient draws
the water into the formulation until the osmotic balance is reached. This process leads to
the mixture of formulation and mucus and can thus increase contact time with the mucous
membrane. Therefore, it is the water motion that leads to the consolidation of the
adhesive bond, and not the interpenetration of macromolecular chains. However, the
dehydration theory is not applicable for solid formulations or highly hydrated forms
(Smart, 2005).
FIGURE 2 – Dehydration theory of mucoadhesion
1.3. MUCOADHESION THEORIES
Although the chemical and physical basis of mucoadhesion are not yet well
understood, there are six classical theories adapted from studies on the performance of
several materials and polymer-polymer adhesion which explain the phenomenon
(Hägerström, 2003; Huang et al., 2000; Smart, 2005).
 Electronic theory:
Electronic theory is based on the premise that both mucoadhesive and biological
materials possess opposing electrical charges. Thus, when both materials come into
contact, they transfer electrons leading to the building of a double electronic layer at the
interface, where the attractive forces within this electronic double layer determines the
mucoadhesive strength (Mathiowitz, Chickering, Lehr, 1999).
 Adsorption theory:

According to the adsorption theory, the mucoadhesive device adheres to the mucus by
secondary chemical interactions, such as in van der Waals and hydrogen bonds,
electrostatic attraction or hydrophobic interactions. For example, hydrogen bonds are the
prevalent interfacial for ces in polymers containing carboxyl groups (Hägerström, 2003;
Huang et al., 2000; Lee, Park, Robinson, 2000; Smart, 2005). Such forces have been
considered the most important in the adhesive interaction phenomenon (Smart, 2005)
because, although they are individually weak, a great number of interactions can result in
an intense global adhesion (Mathiowitz, Chickering, Lehr, 1999).
 Wetting theory:
The wetting theory applies to liquid systems which present affinity to the surface in
order to spread over it. This affinity can be found by using measuring techniques such as
the contact angle. The general rule states that the lower the contact angle then the greater
the affinity (Figure 3). The contact angle should be equal or close to zero to provide
adequate spreadability (Mathiowitz, Chickering, Lehr, 1999).
FIGURE 3 – Schematic diagram showing influence of contact angle between device

and mucous membrane on bioadhesion.
The spreadability coefficient, SAB, can be calculated from the difference between
the surface energies γB and γA and the interfacial energy γAB, as indicated in equation (1)
(Smart, 2005).

The greater the individual surface energy of mucus and device in relation to the
interfacial energy, the greater the adhesion work, WA, i.e. the greater the energy needed to
separate the two phases (Smart, 2005).
 Diffusion theory:
Diffusion theory describes the interpenetration of both polymer and mucin chains to a
sufficient depth to create a semi-permanent adhesive bond (Figure 4). It is believed that
the adhesion force increases with the degree of penetration of the polymer chains
(Mathiowitz, Chickering, Lehr, 1999). This penetration rate depends on the diffusion
coefficient, flexibility and nature of the mucoadhesive chains, mobility and contact time
(Hägerström, 2003; Huang et al., 2000; Lee, Park, Robinson, 2000; Smart, 2005).
According to the literature, the depth of interpenetration required to produce an efficient
bioadhesive bond lies in the range 0.2-0.5 μm. This interpenetration depth of polymer and
mucin chains can be estimated by equation 3:
where t is the contact time, and Db is the diffusion coefficient of the mucoadhesive
material in the mucus. The adhesion strength for a polymer is reached when the depth of
penetration is approximately equivalent to the polymer chain size (Mathiowitz
Chickering, Lehr, 1999).
In order for diffusion to occur, it is important that the components involved have good
mutual solubility, that is, both the bioadhesive and the mucus have similar chemical
structures. The greater the structural similarity, the better the mucoadhesive bond
(Mathiowitz Chickering, Lehr, 1999).

FIGURE 4 – Secondary interactions resulting from interdiffusion of polymer chains

of bioadhesive device and of mucus.
 Fracture theory:
This is perhaps the most-used theory in studies on the mechanical measurement of
mucoadhesion (Mathiowitz Chickering, Lehr, 1999). It analyses the force required to
separate two surfaces after adhesion is established (Hägerström, 2003; Smart, 2005). This
force, sm, is frequently calculated in tests of resistance to rupture by the ratio of the
maximal detachment force, Fm, and the total surface area, A0, involved in the adhesive
interaction (equation 4):
In a single component uniform system, the fracture force, sj, which is equivalent to
the maximal rupture tensile strength, sm, is proportional to the fracture energy (gc), for
Young’s module (E) and to the critical breaking length (c) for the fracture site, as
described in equation 5:
Fracture energy (gc) can be obtained from the reversible adhesion work, Wr (energy
required to produce new fractured surfaces), and the irreversible adhesion work, Wi (work
of plastic deformation provoked by the removal of a proof tip until the disruption of the
adhesive bond), and both values are expressed as units of fracture surface (Af).

The elastic module of the system (E) is related to the stress (s) and to the shear (e) by
Hooke’s law:
In equation 7, the stress is the ratio between force (F) and area (A0), and shear is
given by the ratio between the variation of system thickness (Dl) and the original
thickness (l0).
A criticism of this analysis is that the system under investigation must have known
physical dimensions and should be constituted by a single and uniform material. In virtue
of this, the relationship obtained cannot be applied to analyze the fracture site of a
multiple component bioadhesive. In this case, the equation should be expanded to
accommodate elastic dimensions and modules for each component. Besides, it must be
considered that a failure of adhesion will occur at the bioadhesive interface. However, it
has been demonstrated that the rupture rarely occurs at the surface, but near it
(Mathiowitz Chickering; Lehr, 1999) or at the weakest point, which can be the interface
itself, the mucus layer or the hydrated region of the mucus, as illustrated in Figure 5
(Smart, 2005).
Since the fracture theory is concerned only with the force required to separate the
parts, it does not take into account the interpenetration or diffusion of polymer chains.
Consequently, it is appropriate for use in the calculations for rigid or semi-rigid
bioadhesive materials, in which the polymer chains do not penetrate into the mucus layer
(Mathiowitz Chickering, Lehr, 1999).

FIGURE 5 – Regions where the mucoadhesive bond rupture can occur.
 Mechanical theory:
Mechanical theory considers adhesion to be due to the filling of the irregularities on a
rough surface by a mucoadhesive liquid. Moreover, such roughness increases the
interfacial area available to interactions thereby aiding dissipating energy and can be
considered the most important phenomenon of the process (Peppas, Sahlin, 1996; Smart,
2005).
It is unlikely that the mucoadhesion process is the same for all cases and therefore it
cannot be described by a single theory. In fact, all theories are relevant to identify the
important process variables (Lee, Park, Robinson, 2000).
The mechanisms governing mucoadhesion are also determined by the intrinsic

properties of the formulation and by the environment in which it is applied (Lee, Park,
Robinson, 2000). Intrinsic factors of the polymer are related to its molecular weight,
concentration and chain flexibility. For linear polymers, mucoadhesion increases with
molecular weight, but the same relationship does not hold for non-linear polymers. It has
been shown that more concentrated mucoadhesive dispersions are retained on the mucous
membrane for longer periods, as in the case of systems formed by in situ gelification.
After application, such systems spread easily, since they present rheological properties of
a liquid, but gelify as they come into contact the absorption site, thus preventing their
rapid removal. Chain flexibility is critical to consolidate the interpenetration between
formulation and mucus (Lee, Park, Robinson, 2000).

Environment-related factors include pH, initial contact time, swelling and

physiological variations. The pH can influence the formation of ionizable groups in
polymers as well as the formation of charges on the mucus surface. Contact time between
mucoadhesive and mucus layer determines the extent of chain interpenetration. Super-
hydration of the system can lead to build up of mucilage without adhesion. The thickness
of the mucus layer can vary from 50 to 450 μm in the stomach (Smart, 2005) to less than
1μm in the oral cavity. Other physiological variations can also occur with diseases (Lee,
Park, Robinson, 2000).
None of these mechanisms or theories alone can explain the mucoadhesion which
occurs in an array of different situations. However, the understanding of these
mechanisms in each instance can help toward the development of new mucoadhesive
products (Smart, 2005).
1.4. MUCOADHESIVE MATERIALS
The first study presenting the use of a mucoadhesive material was conducted by
Nagai, and proposed an improved treatment for stomatitis by using adhesive tablets.
Additionally, an increase in the systemic bioavailability of insulin was observed in the
form of bioadhesive powder after nasal administration in dogs (Nagai et al.,1984; Nagai,
1985). Thereafter, bioadhesive materials have been used as absorption promoters for
several administration routes. Earlier experiments were also done with known polymers
available on the market, such as polyacrylic acids. Currently, the latest research is seeking
to develop materials that direct the formulation more specifically to the action site and
that can offer other functions besides mucoadhesion such as control over permeation
within epithelial tissues, and inactivation of enzymes which can compromise release
system action (Hägerström, 2003).
 First generation mucoadhesive materials:

These materials are natural or synthetic hydrophilic molecules containing numerous
organic functions that generate hydrogen bonds such as carboxyl, hydroxyl and amino
groups, which do not adhere specifically onto several surfaces. The very first use of
mucoadhesive was as denture fixers and the most known examples are carbomers,
chitosans, alginates and cellulose derivatives. They can be incorporated into solid

formulations, such as tablets, transdermal adhesives and microparticles, and into

semisolid formulations including gels, ointments, pastes and suppositories (Smart, 2005).
These polymers can be subdivided into three classes: cationic, anionic and nonionic.
Cationic molecules can interact with the mucus surface, since it is negatively charged
at physiological pH. Mucoadhesion of cationic polymers such as chitosan, occurs because
of the electrostatic interactions of their amino groups with the sialic groups of mucin in
the mucus layer. Chitosan is a semi-synthetic polymer obtained by the deacetylation of
chitin and has been extensively investigated as a drug delivery mucoadhesive systems
(Woodley, 2001). Studies have demonstrated that chitosan can promote the absorption of
hydrophilic molecules by the structural reorganization of the proteins associated to the
intercellular junctions (Bravo-Osuna et al., 2007). The presence of chitosan at the surface
of nanoparticles clearly increased their intestinal mucoadhesive behavior in rats (Bravo-
Osuna et al., 2007). Bocataj et al. (2003) demonstrated in their studies that chitosan
showed higher mucoadhesion than carboxymethylcellulose and polycarbophil.
In contrast, synthetic polymers derived from polyacrylic acid (carbomers) are

negatively charged but are also mucoadhesive. In this case, mucoadhesion results from
physical-chemical processes, such as hydrophobic interactions, hydrogen and van der
Waals bonds, which are controlled by pH and ionic composition (Woodley, 2001).
Polyacrylic acid hydrogels have been extensively studied as mucoadhesive systems. Their
chains are flexible and have non-abrasive characteristics when in the partially hydrated
state, which decreases the tissue damage caused by friction when they come into contact
(Huang et al., 2000). The majority of polyacrylic acid derivatives are not water soluble,
such as polycarbophil, but form viscous gels when hydrated (Woodley, 2001). Other
examples of anionic polymers are carboxymethylcellulose and alginates. The alginates,
negatively charged polysaccharides, are widely used in the production of microparticles
and are frequently reported as polyanionic mucoadhesive polymers (Wittaya-Areekul,
Kruenate, Prahsarn, 2006).
Nonionic polymers, including hydroxypropylmethylcellulose, hydroxyethylcellulose

and methylcellulose, present weaker mucoadhesion force compared to anionic polymers
(Mortazavi, Moghimi, 2003).

There is a new class of substances being identified as bioadhesive. This class consists
of ester groups of fatty acids, such as glyceryl monooleate and glyceryl monolinoleate,
able to build liquid crystals which in turn can act as controlled release systems. These
fatty acids build lyotropic liquid crystalline mesophases in the presence of water at body
temperature. Liquid crystals can be considered structures of micelles ordered in a
molecular arrangement characterized by alternate hydrophobic and hydrophilic regions.
Different liquid-crystalline forms including lamellar, hexagonal, and cubic can be built as
the surfactant concentration increases (Malmsten, 2002). Cubic phase favors the
controlled release of drugs, since it has a structure made up of tridimensional curved
lipidbilayers, separated by congruent water channels. This structure has the appearance of
highly viscous transparent gel. Due to this relatively high viscosity, it is difficult to ad-
minister on any mucous membrane. In order to circumvent the administration problems, a
less viscous mesophase, e.g., the lamellar phase, can be used. In these instances this phase
is considered a precursor of the cubic phase. In the case of lyotropic mesophases, the
precursor absorbs water in situ and spontaneously builds the cubic phase (Bruschi et al.,
2007; Nielsen, Schubert, Hansen, 1998).
Some hydrogels do not build liquid crystals but are able to gelify in situ after
exposure to an external stimulus. These are the so-called environmental sensitive
polymers and are classified as thermosensitive, e.g. poloxamers and carbomers (Bruschi
et al., 2007; Park et al., 2001), pH sensitive, e.g. polyacrylic acid, presenting increased
viscosity at higher pH values, glucose sensitive, e.g. polymers linked to concavalin A,
electric signal sensitive e.g. polymethacrylic acid, light sensitive, like hyaluronic acid
(Qiu, Park, 2001) or ionic concentration sensitive, such as gellan gum (Hagerstrom et al.,
2000). All these stimuli are found in the organism, making these polymers of great
potential for use in the design of controlled release systems (Qiu, Park, 2001).
Mucoadhesion for gels formed by both liquid crystals and by environmental sensitive
polymers can be explained by their rheological properties. These properties decrease the
mucociliar clearance and increase the contact time of the formulation with the mucous
membrane (Bruschi et al., 2007; Nielsen, Schubert, Hansen, 1998).
 Second generation mucoadhesive materials:

Studies on novel mucoadhesive systems involve the use of multifunctional materials.
An ideal polymer should exhibit the ability to incorporate both hydrophilic and lipophilic

drugs, show mucoadhesive properties in its solid and liquid forms, inhibit local enzymes
or promote absorption, be specific for a particular cellular area or site, stimulate
endocytosis and finally to have a broad safety range (Lee, Park, Robinson, 2000).
These novel multifunctional mucoadhesive systems are classified as second

generation polymers (Lee, Park, Robinson, 2000). They are an alternative to non-specific
bioadhesives (Smart, 2005) because they bind or adhere to specific chemical structures on
the cell or mucus surface. Good examples of these molecules are lectins, invasins,
fimbrial proteins (Woodley, 2001), antibodies (Chowdary, Rao, 2004), and those obtained
by the addition of thiol groups to known molecules (Bravo-Osuna et al., 2007).
Lectins are immunogenic vegetal glycoproteins that specifically recognize sugar

molecules. They are able to non-covalently bind to glycosilated components of the
cellular membrane but not of the mucus, and adhesion can therefore be called
cytoadhesion. Through the transmission of a cellular signal, this specific bond can result
not only in bioadhesion but also in cellular internalization by different lysosomal and
non-lysosomal mechanisms (Lehr, 2000). The most commonly found lectins are those
isolated from Abrus precatroius, Agaricus bisporus, Anguilla anguilla, Arachis
hypogaea, Pandeiraea simplicifolia, and Bauhinia purpurea (Chowdary, Rao, 2004).
Bacterial invasins are proteins from the membrane of Yersinia pseudotuberculosis that
stimulate fagocytosis at cellular membrane through linkage with integrin receptors
(Chowdary, Rao, 2004; Lehr, 2000; Woodley, 2001).
Bacterial fimbrial proteins are able to adhere to the epithelial surface of erythrocytes.
This adhesion is related to the pathogenicity of the bacteria. Bacterial adhesive factors can
be an efficient mechanism of improving adhesion of mucoadhesive agents used in release
systems (Chowdary, Rao, 2004).
Antibodies can be produced against selected molecules present on the mucus surface.
Due to their high specificity, antibodies can be a rational choice as polymeric ligand in
the development of site-specific mucoadhesives. This strategy can be useful for instance,
in drugs targeting tumor tissues (Chowdary, Rao, 2004).
Thiolated polymers are obtained by the addition of conjugated sulfidryl groups

(Grabovac, Guggi, Bernkop- Schnürch, 2005). Bravo-Osuna et al. (2007) showed that

thiolated chitosan increased mucoadhesive properties due to formation of disulfide

bridges with cystein domains of glycoproteins of the mucus. Additionally, these products
promoted mucus permeation by a mechanism of glutathione regeneration. Finally, they
possess antiprotease activity due to their binding ability with divalent cations, such as
zinc and magnesium, which are co-factors for many proteases. All these characteristics
make thiolated chitosan a promising material for administering peptides and proteins in
mucous membrane (Bravo-Osuna et al., 2007). Another study, carried out by Grabovac,
Guggi, and Bernkop-Schnürch (2005) established a ranking of the most studied polymers,
showing that both thiolated chitosan and polycarbophil are the most mucoadhesive.
Currently, the addition of elements of sensitization and recognition continue being

used for the design of polymers with more intelligent mechanisms of mucoadhesion. By
binding functional groups within polymer chains, hydrogels can be made more sensitive
to surrounding environmental conditions like temperature, moisture, pH, electrical fields
and ionic forces (Peppas, Huang, 2004).
1.5. METHODS OF ANALYZING MUCOADHESION
No technology has still been developed specifically to analyze mucoadhesion. Most of

the tests available were adapted from other preexisting techniques but are useful and
necessary for selecting the promising candidates as mucoadhesives as well as in
elucidating their mechanisms of action.
 In vitro and ex vivo tests
In vitro/ex vivo tests are important in the development of a controlled release

bioadhesive system because they contribute to studies of permeation, release, com-
patibility, mechanical and physical stability, superficial interaction between formulation
and mucous membrane and strength of the bioadhesive bond. These tests can simulate a
number of administration routes including oral, buccal, periodontal, nasal,
gastrointestinal, vaginal and rectal. The in vitro and ex vivo tests most prevalent in the
literature are reported below.

 Techniques utilizing gut sac of rats

The everted gut sac technique is an example of an ex vivo method. It has been used
since 1954 to study intestinal intestinal transport. Santos et al. (1999) applied this method
on mucoadhesion assays. It is easy to reproduce and can be performed in almost all
laboratories. Figure 6 schematically represents the technique. A segment of intestinal
tissue is removed from the rat, everted, and one of its ends sutured and filled with saline.
The sacs are introduced into tubes containing the system under analysis at known
concentrations, stirred, incubated and then removed. The percent adhesion rate of the
release system onto the sac is determined by subtracting the residual mass from the initial
mass (Santos et al., 1999).
FIGURE 6 – Everted gut sac procedure.
 Tests measuring mucoadhesive strength
Most in vitro/ex vivo methodologies found in the literature are based on the evaluation
of mucoadhesive strength, that is, the force required to break the binding between the
model membrane and the mucoadhesive. Depending on the direction in which the
mucoadhesive is separated from the substrate, is it possible to obtain the detachment,
shear, and rupture tensile strengths (Hägerström, 2003), as indicated in Figure 7.

FIGURE 7 – Different forces evaluated in mucoadhesion tests
The force most frequently evaluated in such tests is rupture tensile strength
(Bromberg et al., 2004; Bruschi et al., 2007; Hägerström, 2003). Generally, the
equipment used is a texture analyzer (Figure 8) or a universal testing machine. In this test,
the force required to remove the formulation from a model membrane is measured, which
can be a disc composed of mucin (Bruschi et al., 2007), a piece of animal mucous
membrane, generally porcine nasal mucus (Hägerström, 2003) or intestinal mucus from
rats (Bromberg et al., 2004). Based on results, a force-distance curve can be plotted which
yields the force required to detach the mucin disc from the surface with the formulation
(Bruschi et al., 2007), the tensile work (area under the curve during the detachment
process), the peak force and the deformation to failure (Hägerström, 2003). This method
is more frequently used to analyze solid systems like microspheres (Chowdary, Rao,
2004), although there are also studies on semi-solid materials (Bromberg et al., 2004;
Bruschi et al., 2007)

FIGURE 8 – Bioadhesion test using the texture analyzer.
In addition to rupture tensile strength, the texture analyzer can also, as inferred by its
name, evaluate the texture of the formulations and assess other mechanical properties of
the system. A mobile arm containing an analytical probe forces down into a sample held
in a flask placed on the equipment’s platform. Speed rate, time and depth are preset. From
the resulting force-time and force-distance plots, it is possible to calculate the hardness
(force required to reach a given deformation), compressibility (work required to deform
the product during the compression), and adhesiveness (work required to overcome the
attraction forces between the surfaces of sample and probe). Using this technique, it is
possible to perform a previous evaluation of the material’s adhesive capacity, evidencing
mucoadhesion properties (Bruschi, 2006).
Mucoadhesion strength can also be measured in terms of shear strength. This test
measures the force required to separate two parallel glass slides covered with the polymer
and with a mucus film (Bruschi, Freitas, 2005; Chowdary, Rao, 2004). This can also be

done using Wilhemy’s model (Figure 9), in which a glass plate is suspended by a
microforce balance and immersed in a sample of mucus under controlled temperature.
The force required to pull the plate out of the sample is then measured under constant
experimental conditions (Ahuja, Khar, Ali, 1997). Although measures taken by this
method are reproducible, the technique involves no biological tissue and therefore does
not provide a realistic simulation of biological conditions (Wong, Yuen, Peh, 1999).
FIGURE 9 – Apparatus to determine mucoadhesion in vitro, using Wilhemy’s

technique
Wilhemy’s plate technique, or the microforce balance technique, can also be modified
in order to measure the specific adhesion force of microparticles (Chowdary, Rao, 2004;
Hägerström, 2003). This involves the use of a microtensiometer and a microforce balance
(Figure 10) and is specific, yielding both contact angle and surface tension. The mucous
membrane is placed in a small mobile chamber with both pH and physiological
temperature controlled. A unique microsphere is attached by a thread to the stationary
microbalance. The chamber with the mucous

FIGURE 10 – Microbalance method for measuring mucoadhesion.
membrane is raised until it comes into contact with the microsphere and, after contact
time, is lowered back to the initial position (Mathiowitz, Chickering, Lehr, 1999).
1.6. Tests analyzing molecular interactions involved in mucoadhesion
The general problem arising from methods that show the adhesion force and from the
rheological methods is that the mucoadhesive response is seen macroscopically while the
interactions occur at a microscopic level.
The use of low frequency dielectric spectroscopy represents an attempt to study gel-
mucus interactions near the molecular level. It evaluates the possible physicochemical
interactions between molecules and glycoproteins of the mucus at the interface, which is
considered the step preceding the formation of bonds during the mucoadhesion process.
This technique involves the study of material response to the application of an electrical
field. A sinusoidal voltage is applied throughout the sample and the response is measured
in function of the frequency. From the responses, the impedance or permittivity of the
sample is obtained and the property of charges changing in the system can be determined
(Hägerström, 2003). This technique can provide information about the compatibility
between mucus and mucoadhesive system by means of the evaluation of the movement of

the charged particles. This compatibility is achieved according to the ease with which the
particle crosses the barrier between the gel and mucous membrane. The dielectric
measures reveal information about the gel and the mucous membrane separately, and
about the interface between them (Hägerström, Edsman, Strømme, 2003).
Since the mucoadhesion process can be a consequence of interactions between the

mucus layer and the mucoadhesive polymer, it is highly dependent upon the molecular
structure, including its charge. It is also well known that glycoproteins molecules, which
form the mucus structure, are negative at physiological pH. By means of zeta potential, it
is possible to understand the polymer-mucin electrostatic interactions (Takeuchi et al.,
2005). The zeta potential of dispersion is defined as the potential between the liquid
superficial layer surrounding the dispersed particle and the remaining solution volume. It
is a measure of the net surface charge of particles in a dispersed system (Bocataj et al.,
2003). In this test, the mucin particles are suspended in an appropriate buffer and mixed
with a solution of the polymer. If the addition of the polymer changes the zeta potential
value of the mucin particles, this can suggest greater affinity between polymer and mucin
particles (Takeuchi et al., 2005).
Another technique being applied to evaluate molecular interactions is the optical

biosensor, or resonant mirror biosensor technique. Sigurdsson, Loftsson and Lehr (2006)
used this technique to measure the interaction between glycoproteins of the mucus and
different polymers. It allows the monitoring of any interaction between two unknown
molecules in real time, since one of them can be immobilized with covalent or non-
covalent on the system surface while the other remains in solution at the surface. The
molecules in solution, when binding to the immobilized molecules, alter the refraction
index of the medium and this change is detected by the screening of a laser beam. The
results of this study suggested the need for a clearer definition of mucoadhesion, because
they called into question the polymers that are swelling dependent and undergo in situ
gelification, because they do not seem to interact with glycoproteins, although they are
called mucoadhesives (Sigurdsson, Loftsson, Lehr, 2006).
Another test using the same principle, the Biacore test, was applied for the analysis of
mucoadhesion by Takeuchi et al. (2005). This test is based on the passage of a mucin

suspension through a sensor containing the immobilized polymer. When a mucin particle
binds to the polymer at the sensor, both the solute concentration and the refraction index
on this surface undergo changes, where the interaction is quantitatively evaluated and
reproduced on a diagram. The sensor is a chip with a glass surface covered in a fine gold
layer, where functional groups are introduced and the polymer is attached (Takeuchi et
al., 2005).
 Imaging methods
Optical microscopes offer insufficient resolution for studying effects at a molecular
level. For such investigations, a resolution at micro- or nanometric level is needed.
Electronic microscopy gives a larger view, but the environmental conditions in which the
sample must be submitted are far from the physiological conditions. For instance, the
samples are analyzed in a vacuum chamber and generally are covered with a metallic film
to avoid changes caused by the electronic rays (Mathiowitz, Chickering, Lehr, 1999).
Atomic force microscopy (AFM) is a relatively new technique that overcomes such
restrictions, because it can be used under any environmental conditions, in air, liquids or
9
vacuum. It enlarges more than 10 -fold, which enables visualization of isolated atoms and
offers a tridimensional image of the surface. The equipment (Figure 12, left side) has a
support combined with a probe perpendicularly attached to it. This tip moves toward a
plane parallel to the sample, acquiring its topographic characteristics and the tip position
is recorded by an optic deflection system: a laser beam is reflected onto the support and
its position is then further reflected by a mirror reaching a photodiode sensor. A force-
distance curve is plotted to measure the forces between this tip and the surface of interest
(Mathiowitz, Chickering, Lehr, 1999). This curve is then used in bioadhesion studies.
This entails coating the tip in adhesive material, which is generally spherical in shape
(Figure 12, right side) and then the interaction with the surface, in this case the mucous
membrane, can be measured (Cleary, Bromberg, Magner, 2004).

FIGURE 11 – Constituents of AFM and the adaptations made for measuring

the adhesive force between polymer and mucus surface. Adapted from Cleary,
Bromberg and Magner, (2004), Mathiowitz, Chickering and Lehr (1999).
Besides AFM, there are other techniques using photographic images, such as
fluorescence microscopy and confocal laser scanning microscopy (CSLM). Results
achieved in ex vivo tests like the non-everted gut sac test (Keely et al., 2005), can be
better visualized with this technique. Using radioisotopes or radioactive markers, it is
possible to trace the polymer or the substance to be incorporated into the release system,
where their location is visualized on the specific microscope, after the excision of the
membrane. Takeuchi et al. (2005) used CSLM to analyze liposomes formulated with a
fluorescent tracer and administered by the oral route in rats. The intestines were removed
at an appropriate time after administration and the retention of the formulation was
verified through the images achieved on the confocal microscope.
In the specific case of bioadhesive microspheres, the greater difficulty in their

development is the sensitive quantification of the bioadhesive interactions under
physiological conditions. Several techniques are being developed to measure the adhesion
of great volumes in this kind of sample and others to offer more qualitative data. The
previously described microforce balance methodology was an attempt to circumvent this
difficulty. In parallel, another technology was developed, Electromagnetic Force-
transduction (EFT). In addition to information about bioadhesive forces, this technology
also offers the simultaneous video image of the interactions, with high resolution and
under physiological conditions. Figure 13 schematically illustrates the technique. The
mucous membrane is mounted in a compartment under physiological conditions and the

microsphere is positioned directly below the magnetic probe. The compartment is slowly
moved down, in an opposite direction to the probe, and the video camera is used to detect
sphere movement. According to the movement, the control system increases the magnetic
current and the resulting magnetic force (Fm) pulls the sphere to its initial position,
separating it from the tissue. After the experiment, the magnetic current is converted into
force and the computer calculates the parameters of adhesion. The mucous membrane to
be analyzed can be attained after an experiment using an everted gut sac (Mathiowitz,
Chickering, Lehr, 1999).
FIGURE 12 - Elements of EFT. Adapted from Mathiowitz, Chickering and

Lehr (1999).
An alternative technique which also uses a video camera is the flow-channel

method. A fine glass channel is filled with an aqueous bovine submaxillary mucin
solution maintained at 37 ºC and humid air is passed through the channel. A particle of
the bioadhesive polymer is placed in the mucin gel and both the static and dynamic
behaviors are monitored by the camera at frequent time intervals (Ahuja, Khar, Ali,
1997).
 Falling Liquid Film Method
Nielsen, Schubert and Hansen (1998) used a method proposed by Rango Rao and Buri
(1989) in which the chosen mucous membrane is placed in a stainless steel cylindrical
tube, which has been longitudinally cut. This support is placed inclined in a cylindrical

cell with a temperature controlled at 37 ºC. An isotonic solution is pumped through the
mucous membrane and collected in a beaker (Figure 14). Subsequently, in the case of
particulate systems, the amount remaining on the mucous membrane can be counted with
the aid of a coulter counter (Chowdary, Rao, 2004). For semi-solid systems, the non
adhered mucoadhesive can be quantified by high performance liquid chromatography
(Nielsen, Schubert, Hansen, 1998). In this later case, porcine stomach, intestinal and
buccal mucus were tested, and also jejunum from rabbits. The validation of this method
showed that the type of mucus used does not influence the results. The release systems
tested were precursors of liquid crystals constituted by monoglycerides. This
methodology allows the visualization of formation of liquid-crystalline mesophase on the
mucous membrane after the flowing of the fluids and through analysis by means of
polarized light microscopy (Nielsen, Schubert, Hansen, 1998).
FIGURE 13 – Schematic representation of in vitro model used by Nielsen, Schubert

and Hansen (1998), adapted from Rango Rao and Buri (1989).
 In vivo tests
There is scant information available on the in vivo behavior of mucoadhesive
formulations, especially in humans. Säkkinen et al. (2006) applied gamma scintigraphy to
analyze mucoadhesion in vivo of chitosan within the gastrointestinal tract. Gamma

scintigraphy allows the immediate visualization of all the formulation transit, with low
exposure of the subjects to radiation. The study emphasized the importance of in vivo
studies, because although chitosan exhibits an outstanding mucoadhesion capacity in
vitro, the retention time at the absorption site in the human gastrointestinal tract was
relatively short and not sufficiently reproducible (Säkkinen et al., 2006). The
gastrointestinal transit time in animals can also be evaluated in a non-invasive way, in
which the release systems can be formulated with opaque radioisotopes and signals can
be followed by X-rays, without affecting normal gastrointestinal motility (Chowdary,
Rao, 2004).
The number of methodologies applied to analyze mucoadhesion is constantly

growing, although the use of different methods may sometimes lead to incoherence
among results due to the heterogeneity of parameters and conditions used (Sigurdsso,
Loftsson, Lehr, 2006). Ahuja et al. (1997) examined various studies that used the tension
resistance method and each had employed different models of mucous membrane and
equipment. Despite the large body of evidence obtained to date, further investigations
aimed at standardizing the methodologies are warranted.
Studies on mucoadhesive systems have focused on a broad array of aspects. It is a

growth area whose goal is the development of new devices and more “intelligent”
polymers, as well as the creation of new methodologies that can better elucidate the
mucoadhesion phenomenon. With the great influx of new molecules stemming from drug
research, mucoadhesive systems may play an increasing role in the development of new
pharmaceuticals.

2. REVIEW OF LITERATURE
Literature survey was carried out on the proposed topic with the facility of internet
and helinet and referring scientific journal. The survey reveals that, no work has undertaken
on the proposed topic and some related research work are coated below.
Vishnu M. Patel et. al., Designed buccal patches containing propranolol

hydrochloride were prepared using solvent casting method, by eudragit L-100 carbopol-934
and PVP K-30 polymers, and evaluated for surface pH, folding endurance, swelling index,
ex-vivo mucoadhesive strength, in-vitro drug release. Results indicates that the high amount
of carbopol 934 and low amount of PVP K30 favour the ex-vivo mucoadhesive strength, but
low amount of carbopol 934 and high amount of PVP K30 favour the dissolution rate and
swelling index of the patches.
Thimmasetty J et. al., Prepared mucoadhesive buccal patches of carvedilol using the
polymer such as HPMC, carbapol-934, eudragit RL 100 and ethyl cellulose. The formulated
patches were evaluated for different parameters and in-vitro release studies were conducted
for carvedilol loaded patches. Good results were obtained both in-vitro and in-vivo condition
for carvedilol patches. The results can be extrapolated to the human beings as the structure
and the permeability of buccal membrane of the rabbits is similar to that of human being.
Raghvendra Rao NG et. al., Buccal films of montelukast were prepared using
mucoadhesive polymers like HPMC (K4M), HPMC (50cps), HPMC (5cps), Eudragit RL-100
and PVP K-30 by solvent casting technique, films were characterized for number of
parameters and bursting strength, in-vitro drug release study. All formulations follow zero-
order kinetics as (r2) values are higher than that of first-order release kinetics. Mechanism of
drug release pattern was confirmed by Higuchi plots.
Giradkar KP et. al., Deigned the polymeric films of tizanidine composed different
proportions of NaCMC and CP 934 by solvent casting method, glycerol was used as
plasticizer. Films were evaluated for different parameters It was concluded that NaCMC and
CP-934(60:40) showed moderate drug release for 8 hrs. Increase in CP934 concentration
resulted in decreasing the swelling index and surface pH. The mucoadhesive strength and in-
vitro residence time is slightly increased beyond 30%concentration of Carbopol 934.
Shafiullah D. et. al. Formulated mucoadhesive chlorhexidine buccal films formulated

films were evaluated for compatibility, drug content, antibacterial activity against Escherichia

coli and in-vitro release studies. In-vitro release studies for films should a higher rate of drug
release for HPMC films compared to chitosan films.
El-Samaligy MS et.al, Prepared buccal adhesive discs of diclofenac sodium using

carbopol-941P, polycerbophil PEO and evaluated for release pattern, swelling index capacity
mucoadhesive performance. The buccoadhesive discs of diclofenac sodium can be a good
way to bypass the extensive hepatic first pass metabolism and is expected to be less irritant to
gastric mucosa.
Vamshi Vishnu et. al., Prepared mucoadhesive buccal patches of carvedilol using
two different polymers such as HPMC E-15 and HPCJF and were tested for in-vitro drug
permeation studies, buccal absorption test, in-vitro drug release studies, moisture absorption
studies and in-vitro bioadhesion studies and bioavailability studies in healthy pigs. Good
results were obtained both in-vitro and in-vivo for films of HPMC E15 LV. In healthy pigs
showed a significant improvement in bioavailability up to 2.29 times from patches, when
compared to oral route. Hence the development of bioadhesive buccal formulation of
carvedilol may be decreased dose and side effects may be reduced.
Sahni J. et. al., Designed buccoadhesive drug delivery system of insulin by solvent
casting techniques and were characterized for different parameters and skin permeation
studies. The results suggested that sodium deoxycholate 5% (w/v) was the best permeation
enhancer among evaluated. The optimized patches were also satisfactory in surface pH and
bioadhesive strength. It is concluded that the system is success as compared to conventional
formulation with respect to invasiveness and the first pass metabolism.
Fatma A. et. al., Mucoadhesive patches of cetylpyridinium chloride prepared by

using PVA, HEC and chitosan. Swelling and bioadhesive strength determined for both plain
and medicated patches. The results showed increase in swelling after addition of the water-
soluble drug to the plain formulation. A decrease in the residence time was observed for PVA
and chitosan containing formulation. Higher drug release was obtained from PVA patches
compared to HEC. A decrease release was observed for chitosan after the addition of water-
soluble additives, (PVP) and gelatin.
Ananta Choudhury et. al., Designed a sustained release films of ciprofloxacin

hydrochloride using different concentration of HPMC and PVA and evaluated for different
parameters also in-vitro and ex-vivo drug release study, and release kinetic behavior. From

the results concluded that all the prepared films having desire flexibility and mucoadhesive
properties, good in-vitro and ex-vivo drug release performance. It was also concluded that in
respect to mucoadhesion time, mucoadhesion strength study and in-vitro drug release study
the performance of films composed of HPMC gives better results as compare to the films
composed of PVA.
Goudanavar PS et. al., Developed mucoadhesive buccal films of glibenclamide with

HPC, PVP, and EC polymer combination, by solvent casting technique and evaluated for
number of parameters. The results revealed that the release of drug is depended on the
polymer type as well as on their concentration. Film containing HPC alone released the
maximum drug. Incorporation of PVP or EC reduced the release rate of Glibenclamide from
the buccal films.
Satishbabu BK et. al., Prepared bilaminated buccoadhesive film of atenolol, by

solvent casting technique. The mucoadhesive layer was composed of mixture of drug and
sodium alginate with or without carbopol-934P and backing layer was made of EC, and films
were evaluated for different parameters. The results show that bilaminated films were flexible
and having suitable toughness. Also, sodium alginate was easily laminated on ethyl cellulose.
The study concludes that the addition of carbopol-934P increases the viscosity and swelling
of films, thereby control the release of drug and improves the mucoadhesive properties.
Upendra Kulkarni et. al., Prepared mucoadhesive buccal films of felodipine by

using PVP and PVA polymers glycerin and propylene glycol used as plasticizers, films were
evaluated percentage of swelling and drug content uniformity, stability study revealed,
decrease in drug content in various patches. The results shows that prepared films have
satisfactory characteristics regarding to integrity, flexibility, dispersion of the drug and
quality control parameters.
Nappinnai M. et. al., Formulated buccal films of nitrendipine by using different

polymers like HPMC K100, HPC, NaCMC, Sodium alginate, PVA, PVP K-30 and carbopol-
934 were used. The films were evaluated for different parameters and ex-vivo permeation.
From results, it was concluded that buccal films of HPMC and NaCMC showed moderate
drug release and satisfactory film characteristics, selected as best formulation.
Manish et. al., Developed mucoadhesive buccal films of famotidine using HPMC,
NaCMC and PVA by solvent casting method. The films were evaluated for their physical

characteristics. Good results were obtained both in-vitro and in-vivo conditions for
famotidine films. The results can be extrapolated to the human beings as the structure and
permeability of buccal membrane of rabbits is similar to that of human beings. Hence the
development of bioadhesive buccal formulations for famotidine may be a promising one as
the dose of famotidine may be decreased and hence side effects may be reduced.
Satyabrata Bhanja et. al., Developed mucoadhesive buccal patches of methotrexate

by using of mixture sodium alginate alone or in combination with, NaCMC, PVP, carbopol-
934 and EC, and evaluated for different parameters. The release kinetic fits Higuchi, Peppas
equation while through ex-vivo it was zero-order and the mechanism of drug release was
diffusion controlled. The value more than one, so release was non Fickinian means not
depends upon the concentration gradients.
Viram et. al., Formulated buccal films of carvedilol by using polymers like Eudragit
RL-100, PVP, HPMC, NaCMC and Carbopol 934 in various combinations by solvent casting
technique, using plasticizer propylene glycol with and without penetration enhancers like
DMSO, Tween-60 and castor oil. In ex-vivo diffusion studies formulation were consisting
DMSO which increase the drug permeability up to 15% given as the best formulation.
Shah Divyen et. al., Formulated mucoadhesive buccal films of lycopen using water
soluble polymers by solvent casting technique, propylene glycol used as plasticizer. Films
were evaluated for thickness, tensile strength, bending strength, film swelling and erosion
properties, ex-vivo mucoadhesion time. It was concluded that formulation contains lower
drug dose, sufficient for therapeutic effect, non-irritant, high mucoadhesion force and time
required to dissolve is also high compare to other formulation.
Attama AA et. al., Formulated novel buccoadhesive patches of hydrochlorothiazide

using EC and HPMC by solvent casting method. The patches were evaluated for different
parameters. The result of the study indicated that 1:2 ratios of EC and HPMC gave the
highest buccoadhesive strength. The area swelling ratio indicated that the patches did not
swell up to two times their initial areas, with the batch containing 3:2 ratios of EC and HPMC
possessing the highest area swelling ratio. Higuchi analysis of the release mechanism
indicated that the release of HCTZ from the patches formulated with 1:1 and 2:1 ratios of EC
and HPMC predominantly occurred by a diffusion process.

Dharani S. et. al., Design and evaluated mucoadhesive buccal patches of ondensetron
HCL by solvent casting technique using HPMC-E15 as mucoadhesive polymer. The patches
were evaluated for weight variation, thickness, surface pH, moisture absorption, in-vitro
residence time, mechanical properties, in-vitro release, ex-vivo permeation studies and drug
content uniformity and got the better results and obey first order kinetics.
Pavankumar GV et. al., Prepared buccal films of salbutamol sulphate using different
polymers in various proportions and combinations. The physicochemical parameters in order
to study the effect of polymer and its concentration to achieve controlled drug release. The
results of drug release studies indicated the first order controlled release kinetics in all
formulations for up to 8 hrs. It was also observed that as the lower permeability coefficient,
the greater was the drug release, and concluded that the polymers and their combination
influenced film properties as well as release characteristics.
Deshmane SV et. al., Design and characterization of carbopol-HPMC- EC based

buccal Compact containing propranolol HCl, and evaluated the effect of formulation
variables on release properties and bioadhesive strength in development of three layered
buccal compact containing highly water-soluble drug propranolol hydrochloride by using
polymer ratio (carbopol 934P: HPMC 4KM) and core layer polymer ratio (HPMC 4KM:
sodium alginate) as two independent formulation variables. Results shows the decrease in
PRPH release was observed with an increase in both the formulation variables and as the
carbopol: HPMC ratio increases the bioadhesive strength also increases.
Koland et. al., Formulated and evaluated fast dissolving films of ondensetron
hydrochloride for sublingual administration by PVA, PVP, Carbopol- 934 in different ratios,
propylene glycol or PEG 400 as plasticizers and mannitol as sweeteners. Films evaluated for
different parameters and bioadhesive strength. Concluded that use of water soluble
sweeteners especially mannitol increases taste, also increases in drug release and drug
permeation.
Vishnu M. Patel et. al., Designed mucoadhesive buccal patches containing

propranolol hydrochloride using solvent casting method, by eudragit L-100, carbopol-934
and PVP K-30 polymers. Patches were evaluated for different parameters and ex-vivo
mucoadhesive strength, in-vitro buccal permeation. Results indicates that the high amount of
carbopol 934 and low amount of PVP K30 favour the ex-vivo mucoadhesive strength of the

patches but low amount of carbopol 934 and high amount of PVP K30 favour the dissolution
rate and swelling index of the patches.
Biswajit Basu et. al., Formulated mucoadhesive buccal patches of pimozide by using
HPMC (15 and 47cps) carbopol 934, PVA, and PVP. The patches were evaluated for
different parameters. The data of in vitro release from patches were fits into Hixon-Crowell,
Higuchi and Korsmeyer-Peppas models. In-vivo studies in rabbits showed 85.97% of drug
absorption from HPMC (15cps) patch in 60 min.
Patel RS et. al., Prepared buccal patches of salbutamol sulphate for the controlled
delivery to avoid first pass hepatic metabolism and evaluated for the physicochemical,
mechanical, drug release characteristics. It is concluded that the combination of polymers
PVA, chitosan and PVP showed good mucoadhesive and swelling characteristics. Medicated
patches maintained a satisfactory residence in the buccal cavity and demonstrated non-
Fickian release of the drug over a relatively long period (5 hrs).
Mona Semalty et. al., Formulated mucoadhesive buccal films of glipizide by solvent
casting techniques using HPMC, NaCMC, Carbopol-934P and Eudragit RL-100. The films
were evaluated for different parameters. From the results it was concluded that films
containing 5 mg glipizide in 4.9 HPMC% (w/v) and 1.5% (w/v) NaCMC shows satisfactory
swelling, an optimum residence time and drug release.
Dheeraj Baviskar et. al., Developed mucoadhesive buccal patch of aceclofenac

using Gelatine, Poly NaCMC and PVA polymer, and evaluated for various parameters, also
evaluated for volume entrapment efficiency %, measurement of % elongation at break, in-
vitro mucoadhesive time, in-vitro release and stability study. Results indicate that all the
patches, pH near to (7.0). Hence it is expected to be non-irritant to buccal mucosa.
Wong CF et. al., Prepared controlled release buccal patches of metoprolol using
eudragit incorporating HPMC, NaCMC and carbopol and were evaluated for various physical
properties and drug release kinetics. Insoluble, flexible, organic solvent-free, controlled
release patches could be fabricated using Eudragit NE 40D as the base matrix. The drug
release as well as the adhesive properties of the patches could be modified by incorporating
bioadhesive polymers. For the above purposes, Cekol 700 appeared to be the most suitable
since it provided both satisfactory bioadhesion and a predictable rate of drug release.

Shidhaye et. al., Prepared mucoadhesive bilayered buccal patches of sumatriptan

succinate using chitosan as the base matrix by solvent casting method. The patches were
evaluated for different parameters. It can be concluded that buccal route can be one of the
alternatives available for administration of sumatriptan succinate. The results showed that
mucoadhesive bilayered buccal patch containing 3.5% w/v chitosan, 1% PVP K-30 and 3%
DMSO produced buccal patches having good mucoadhesive strength, 98% drug release over
2 hrs and 12% permeation of the drug through buccal mucosa without causing any tissue
damage.
Kapil KP et. al., Formulated mucoadhesive patches of timolol maleate, which were designed
to prolong the residence time and thus to improve the bioavailability of the drug and its half
life. (HPMC) polymer which is having good mucoadhesive property therefore various
formulations were developed by using release rate controlling and gel forming polymers like
HPMC-K 100M, Eudragit RL100 and Ethyl cellulose by solvent casting method.

NEED FOR STUDY
Over the last few decades pharmaceutical scientists throughout the world are trying to
explore transdermal and transmucosal routes as an alternative to injections. Among the
various transmucosal sites available, mucosa of the buccal cavity was found to be the most
convenient and easily accessible site for the delivery of therapeutic agents for both local and
systemic delivery as retentive dosage forms, because it has expanse of smooth muscle which
is relatively immobile, abundant vascularization, rapid recovery time after exposure to stress.
The buccal route of administration has a number of advantages including bypassing

the gastrointestinal tract and hepatic first pass effect and prolonged residence time of the
dosage form at the site of absorption. Due to an increased residence time one can expect
enhanced absorption as well the therapeutic efficacy of the drug. As the dosage form is
adhered to buccal cavity, drug can be protected from degradation in the acidic environment of
the GIT. Within the oral mucosal cavity, the buccal region offers more advantages than other
modes of administration for systemic purposes.
The zolmitriptan is a serotonin (5-HT1) agonist used for the treatment of migraine
with or without aura. The absolute oral bioavailability is about 40 to 50%. The half-life of
zolmitriptan is 2.5 to 3 hrs and it undergoes hepatic metabolism. Zolmitriptan an anti
migraine agent requires to elicit its action rapidly and continuously So, in order to improve
the bioavailability and efficacy, it can be prepared as buccal patches.

AIM: Main aim of present work was to prepare and evaluate zolmitriptan buccal patches.
OBJECTIVES:
Main objectives include:
1. To design buccal films of zolmitritan by using HPMC, SOD CMC, CARBOPOL

934P, EUDRAGIT and PVP to improve the bioavailabilty of drug.
2. To formulate above buccal films with combination of polymers to maintain good film
properties.
3. To know the effect of polymers on film properties and drug release.
4. To know the possible interactions between drug and excipients.
5. To conduct stability studies according to ICH gfuidelines.
PLAN OF WORK:
1. Literature review.
2. Procurement of desired raw materials.
3. Preformulation studies on API and polymers.
4. Formulation development of buccal films of zolmitriptan using various concentrations

of polymers such as HPMC E5, sodium CMC carbopol 934p and Eudragit.
5. Selection of the optimized formulation.
6. Evaluation of physical parameters of prepared films such as,

 Weight Variation
 Thickness
 Tensile strength
 Percent elongation
 Folding endurance
 Disintegration time
 Content uniformity
 Invitro dissolution studies and
 Stability studies.

MATERIALS AND METHODS

4.1. Materials:
Following materials were procured and used in the present study.
Table: 1. List of Material used in the formulation development.
Materials Source
Zolmitriptan Suven life sciences, Hyderabad
Carbopol 934p Suven life sciences, Hyderabad
HPMC E5 Suven life sciences, Hyderabad
Eudragit Rs 100 Dr. Reddys Labs, Hyderabad
Na CMC Dr. Reddys Labs, Hyderabad
PVP Dr. Reddys Labs, Hyderabad
Methanol ISP, Hyderabad
PEG-400 ISP, Hyderabad
Potassium Dihydrogen Phosphate ISP, Hyderabad
Sodium hydroxide ISP, Hyderabad
4.2. Equipments:
Table: 2. List of equipments used in the study.
Equipments Manufacturers
Electronic Balance Shimadzu, Japan
Dissolution Apparatus Tab-machines, Mumbai
UV-Visible Spectrophotometer Elico Pvt. Ltd. Hyderabad
Magnetic stirrers Remi equipments
Screw gauge Micro
Hot air oven Tempo instrument and equipment
pH meter Systronic, Ahmedabad
Sonicator Sidilu ultrasonic
Tensile strength tester Hounsfield universal testing machine, japan
% Elongation tester Hounsfield universal testing machine, japan

4.3 DRUG PROFILE
Zolmitriptan:
Trade Names: Zomig, Zomigon, AscoTop and Zomigoro.
Chemical name: (S)-4-({3-[2-(Dimethylamino)ethyl]-1H-indol-5-yl}methyl)-1,3-oxazolidin-

2-one
Structure:
Molecular formula: C16H21N3O2
Molecular weight: 287.357 g/mol
Category: It is a selective serotonin receptor agonist of the 1B and 1D subtypes
Description: It is a white powder.
Solubility: It is partially soluble in water.
Bioavailability: 40% oral.
Metabolism: Hepatic.
Administration: Orally or Intranasally (as a single spray into 1 nostril).
Storage Conditions: It is stored at 20–25°C; and protect from light and moisture.
Medicinal Uses: It is used for the acute treatment of migraines with or without aura in adults.
Contraindications: Zolmitriptan should not be given to patients with ischemic heart disease.
It increase blood pressure, it should not be given to patients with uncontrolled hypertension.

4.4. POLYMER PROFILE
4.4.1 CARBOXYMETHYL CELLULOSE SODIUM:
Non proprietary names:
B.P: Carmellose sodium
U.S.P: Carboxymethylcellulose sodium
Eur ph: Carboxymethylcellulosum natricum
Synonym: Akucell; Blanose; Cekol; cellulosegum; CMCsodium; courlose; E466; Nymcel;

SCMC; sodiumcarboxymethylcellulose; sodium cellulose glycolate; sodium CMC;
TyloseCB.
Chemical name: Cellulose, carboxymethyl ether, sodium salt.
Structural formula:
Fig. 14 structural formula of Carboxymethylcellulose sodium
Molecular weight: 90,000-7,00,000.
Category: Coating agent, stabilizing agent, suspending agent. Tablet binder: viscosity
enhancer, tablet and capsule disintegrant.
Description: It is odorless, white to almost white colored, granular powder.
Solubility: Practically insoluble in acetone, ethanol, ether and toluene. Easily dispersed in
water at all temperatures
Viscosity: The viscosity of polymer ranges from 50 to 200% of the declared value.

Stability: It is a stable material although it is hygroscopic. Under high humidity conditions it

absorbs large quantity of water.
Applications in Pharmaceutical Formulation or Technology: Carboxymethylcellulose

sodium is widely used in oral and topical pharmaceutical formulations, primarily for its
viscosity-increasing properties. Viscous aqueous solutions are used to suspend powders
intended for either topical application or oral and parenteral administration.(1,2)
Carboxymethylcellulose sodium may also be used as a tablet binder and disintegrant,(3–6)
and to stabilize emulsions.
Storage conditions: The powder should be stored in a well-closed container in a cool and
dry place.
Safety: It is generally regarded as nontoxic and nonirritant material although excessive

consumption may have a laxative effect. Hypersensitivity and anaphylactic reactions may
occur if used in parenteral formulations such as vaccines and penicillin’s.
4.4.2 HYDROXYPROPYL METHYLCELLULOSE
1. Nonproprietary Names:
 BP: Hypromellose
 JP: Hypromellose
 PhEur: Hypromellose
 USP: Hypromellose
2. Synonyms: Benecel MHPC; E464; hydroxypropyl methylcellulose; HPMC;

hypromellosum; Methocel; methylcellulose propylene glycol ether; methyl
hydroxypropylcellulose; Metolose; MHPC; Pharmacoat; Tylopur; Tylose MO.
3. Chemical Name and CAS Registry Number:
Cellulose hydroxypropyl methyl ether [9004-65-3]
4. Empirical Formula and Molecular Weight:
The PhEur 6.3 describes hypromellose as a 39 artly-methylated and O-(2-

hydroxypropylated) cellulose. It is available in several grades that vary in viscosity and extent

of substitution. Grades may be distinguished by appending a number indicative of the

apparent viscosity, in mPa s, of a 2% w/w aqueous solution at 208C. Hypromellose defined in
the USP 32 specifies the substitution type by appending a four-digit number to the
nonproprietary name: e.g. hypromellose 1828. The first two digits refer to the approximate
percentage content of the methoxy group (OCH3). The second two digits refer to the
approximate percentage content of the hydroxypropoxy group (OCH2CH(OH)CH3),
Molecular weight is approximately 10 000–1 500 000.
Chemical structure:
Figure.15 Structural formula of hydroxypropyl methylcellulose
Description: Hypromellose is an odorless and tasteless, white or creamy-white fibrous or

granular powder
Typical Properties
Acidity/alkalinity pH = 5.0–8.0 for a 2% w/w aqueous solution.
Ash = 41.5%
Auto ignition temperature= 3608C
Density (bulk) = 0.341 g/cm3
Density (tapped) = 0.557 g/cm3
Density (true) = 1.326 g/cm3
Melting point = Browns at 190–2008C; chars at 225–2308C.
Glass transition temperature is 170–1808C.

Solubility: Soluble in cold water, forming a viscous colloidal solution; practically insoluble
in hot water, chloroform, ethanol (95%), and ether, but soluble in mixtures of ethanol and
dichloromethane, mixtures of methanol and dichloromethane, and mixtures of water and
alcohol. Certain grades of hypromellose are soluble in aqueous acetone solutions, mixtures of
dichloromethane and propan-2-ol, and other organic solvents. Some grades are swellable in
ethanol.
Stability and Storage Conditions: Hypromellose powder is a stable material, although it is

hygroscopic after drying. Solutions are stable at pH 3–11. Hypromellose undergoes a
reversible sol–gel transformation upon heating and cooling, respectively. The gelation
temperature is 50–908C, depending upon the grade and concentration of material. For
temperatures below the gelation temperature, viscosity of the solution decreases as
temperature is increased. Beyond the gelation temperature, viscosity increases as temperature
is increased.
Applications: Suspending agent, Viscosity modifier, Film and Matrix forming

material, Tablet binder and adhesive ointment ingredient.
Table: 3. Different HPMC grades (Methocel) and their properties (Colorcon, Asia ltd)
Viscosity Molecular Weight of various Grades of

HPMC (Methocel)
A E K F
3 7000
5 10000
15 16000 17000 16000 17000
50 18000 20000 19000 19000
100 26000 28000 27000 27000
400 41000 44000 42000 43000
1500 63000 68000 65000 66000
4000 86000 92000 88000 90000
10000 104000 113000 108000 109000
15000 120000 131000 125000 127000
100000 208000 225000 215000 218000

TABLE: 4 HPMC grades and their molecular units
Grade No. of Molecular Units

A 186
E 201
K 192
F 195
Characteristics:
1. Hydration
After administration, hydrophilic matrix tablet made with HPMC moistens and
hydrates to form a gel layer which defines the drug release pattern. The most important aspect
of this matrix system is homogeneity of HPMC particles in the tablets. The selection of
HPMC grades affects the initial swelling of hydration and gel strength. In the first stage,
usually within 30-60 minutes after administration, the polymer particles on the tablet surface
become partially hydrated. Sometimes tablet’s disintegration or excess dissociation of the
active ingredients is observed in this period. In the second stage, the gel layer is completed
with a uniform distribution of the active ingredients (Wan et al., 1993).
2. Swelling Characteristics
A hydrogel such as HPMC has an ability to swell in water while retaining a significant
fraction of water within due to presence of hydrophilic groups. The driving force for swelling
arises from the water polymer thermodynamic mixing contributing of the overall free energy
that is coupled with an elastic polymer. In ionic hydrogel, the swelling process is due to the
previous two contributions as well as the ionic interaction between changed polymer and free
ions render the polymers more hydrophilic and thus lead to very high water uptake. Both the
viscosity and particle size affect the swelling properties. Higher viscosity type shows a
greater swelling volume, and small particle size results in a smaller swelling volume (Victoria
et al., 1999).
3. Gel Strength
The hydrogel strength of HPMC is strongly related to both the hydroxyl propyl content
and its viscosity. The initial quick gel formation over the surface of the matrix tablet reduces

excess dissolution of the drug at first stage and the higher gel strength influences the drug
release. Higher polymer content results in a great amount of gel formation (Wan et al., 1993).
4. Effect of Viscosity
Drug release profile is strongly influenced by the viscosity of the gel layer, which forms
on the tablet surface as a result of hydration of the constituent polymers (Alderman et al.,
1984). The viscosity of cellulose derivatives increases with concentration and the higher
molecular weight grades are more viscous. Sung et al., 1996 studied the influence of HPMC
on odinazolam mesylate and observed faster drug release rate for the lowest viscosity grade
i.e., K100 LV formulation. The K4M formulation exhibited a slightly greater drug release
rate than K15M, K100M formulations. The lack of differences in drug release profiles for
K15M and K100M formulations suggest the existence of a limiting HPMC viscosity i.e., for
the system studied, the release rate no longer decreased when the viscosity grade was
increased above 15000cps
5. Release Mechanisms:
Drug release from HPMC matrix tablets is controlled by the hydration of HPMC, which
forms a gelatinous barrier layer at the surface of the matrix, through which the included drug
diffuses out. In addition, the resistance of such gel layer to erosion is controlled by viscosity
grade HPMC. Water-soluble drugs generally released primarily by diffusion; while poorly
water-soluble drugs are released predominantly by erosion mechanism (Victoria et al., 1999).
Generally the drug release from an HPMc matrix tablet involves water penetration to matrix,
hydration and swelling of the polymer, diffusion of the dissolved drug and erosion of the gel
layer (Wan et al., 1993).
4.4.3 EUDRAGIT
Non-proprietary Names:
Ph. Eur. Methacrylic Acid - Methyl Methacrylate Copolymer (1:1)
Methacrylic Acid - Methyl Methacrylate Copolymer (1:2)
USP/NF Methacrylic Acid Copolymer, Type A – NF *
Methacrylic Acid and Methyl Methacrylate Copolymer (1:1) – NF **
Methacrylic Acid Copolymer, Type B – NF *

Methacrylic Acid and Methyl Methacrylate Copolymer (1:2) – NF **
JPE Methacrylic Acid Copolymer L; Methacrylic Acid Copolymer S

Chemical structure:
Anionic copolymers based on methacrylic acid and methyl methacrylate. The ratio of
the free carboxyl groups to the ester groups is approx. 1:1 in EUDRAGIT® L 100 and
approx. 1:2 in EUDRAGIT® S 100.
The monomers are randomly distributed along the copolymer chain. Based on SEC
method the weight average molar mass (Mw) of EUDRAGIT® L 100 and EUDRAGIT® S
100 is approximately 125,000 g/mol.
Structural formula:
Fig: 16 Structural formula of eudragit
Description:
White powders with a faint characteristic odour.
Solubility:
1 g of EUDRAGIT® L 100 or EUDRAGIT® S 100 dissolves in 7 g methanol,

ethanol, in aqueous isopropyl alcohol and acetone (containing approx. 3 % water), as well as
in 1 N sodium hydroxide to give clear to cloudy solutions.
EUDRAGIT® L 100 and EUDRAGIT® S 100 are practically insoluble in ethyl acetate,
methylene chloride, petroleum ether and water.

Test solution:
A 12.5 % solution of the dry substance is used for the Test solution: a quantity of
EUDRAGIT® L 100 or EUDRAGIT® S 100 corresponding to 12.5 g dry substance is
dissolved in a mixture of 84.9 g isopropyl alcohol and 2.6 g water.
Particle size:
At least 95 % less than 0.25 mm
The particle size is determined according to Ph. Eur. 2.1.4 or USP <811>.
Film formation:
When the Test solution is poured onto a glass plate, a clear film forms upon
evaporation of the solvent
Dry substance / Residue on evaporation
At least 95.0 %
The test is performed according to Ph. Eur. 2.2.32 method d. 1 g powder is dried in an
oven for 6 hrs at 110 °C.
Viscosity / Apparent viscosity:
EUDRAGIT® L 100: 60 - 120 mPa . s
EUDRAGIT® S 100: 50 - 200 mPa . s
The viscosity of the Test solution is determined by means of a Brookfield viscometer

(Spindle 1 / 30 rpm / 20 °C).
The test is performed according to Ph. Eur. 2.2.10 or USP <912> method I.
Viscosity / Kinematic viscosity
JPE: EUDRAGIT®L 100: 10 - 24 mm2/ s
EUDRAGIT® S 100: 22 - 52 mm2/ s
The test is performed according to the JPE monograph.

Refractive index nD 20: 1.390 - 1.395
The refractive index of the Test solution is determined according to Ph. Eur. 2.2.6.
Relative density 20d20: 0.831 - 0.852
The relative density of the Test solution is determined according to Ph. Eur. 2.2.5.
Detection in dosage forms
The dosage forms are extracted using the solvents listed under "Solubility,” if
necessary after crushing. Insoluble substances are isolated by filtration or centrifugation. The
clear filtrate is boiled down and the residue identified by IR spectroscopy.
Storage:
 Store at controlled room temperatures (USP, General Notices)
 Protect against moisture. Any storage between 8 °C and 25 °C fulfils this requirement.
Stability:
Minimum stability dates are given on the product labels and batch-related Certificates
of Analysis. Storage Stability data are available upon request.

4.5. METHODS
4.5.1 ANALYTICAL METHODS
4.5.1.1 Preparation of Standard Solution for Standard Graph.
100mg of zolmitriptan was accurately weighed and taken into a 100ml volumetric
flask, to this 6.8 pH phosphate buffer was added to dissolve the drug and volume was made
up to 100ml and mixed which is called as stock -I solution. 10 ml of the above solution is
diluted to 100 ml with the same buffer solution, which is called as Stock-II solution. From
this stock-II solution serial dilutions were made to obtain solutions of the drug in the
concentrations ranging from 2, 4, 6, 8, and 10μg/ml.
The volumetric solutions were scanned in a UV- Visible spectrophotometer to

determine the λ max (222 nm) of the drug. The absorbance of the volumetric solutions was
recorded at λ max of the drug and plotted graphically to give the standard graph of
zolmitriptan.
4.5.2 PREFORMULATION STUDIES:
The following preformulation studies were carried out for zolmitriptan.
1. Solubility
2. Determination of pH
3. Moisture Content
4. Melting point
5. Sieve analysis
6. Drug – Polymer compatibility studies.
1. Solubility:
The solubility of drug is important for its release from dosage form and
absorption. The solubility of a drug may be expressed in number of ways. Solubility
of Zolmitriptan was determined in different solvents.

Table: 5 Solubility chart.
2. Determination of pH:
pH of the drug solution (1%) with water was determined by using pH meter. The glass
electrode of the pH meter was immersed in drug solution and pH was recorded.
3. Moisture content :
The moisture content of drug was determined by Sartorius moisture determining

apparatus. 5 gm of Zolmitriptan was transferred to an aluminium plate and moisture content
was determined at 1030C
4. Melting point
Melting point of the drug was determined by using melting point apparatus.
5. Drug – Polymer compatability studies:
Zolmitriptan was mixed with different proportions with all excipients to be used in our
formulation in different ratios and kept at 40ºc for four weeks. The physical properties
(colour change) were monitored regularly. The change in colour in any mixture was basis for
discarding from study.
4.5.3 FORMULATION DEVELOPMENT
4.5.3.2 Technology Used: Solvent casting method.
The key ingredients to be included in the formulations are:
1. Drug: Zolmitriptan

2. Hydrophilic Polymers: HPMC E5, Sodium CMC, Carbopol 934p, Eudragit RS-100
and PVP.
3. Placisizer: PEG-400
4. Solvent: Methanol
4.5.4 FORMULATION OF BUCCAL FILMS OF ZOLMITRIPTAN
4.5.4.1 Preparation of buccal films of Zolmitriptan with HPMC E5:
Required amount of HPMC E5 and PVP were accurately weighed and dissolved in
one portion of methanol and the solution was kept aside for 30 min for swelling of polymer.
Then 35 mg of drug was dispersed slowly to another portion of solvent. Finally the second
portion was added to first portion very slowly under continuous stirring. To this final solution
required quantity of PEG-400 was added and mixed thoroughly to maintain plasticity of the
film.
Table: 6 Composition of film formulated with HPMC E5:
S.No Ingredients Quantity for 50.24 cm2 film

Z1 Z2 Z3
1. Zolmitriptan (mg) 35 35 35
2. HPMC E5 100 200 300
3. PVP 25 25 25
4. PEG-400 15 15 15
5. Methanol q.s q.s q.s
4.5.4.2 Preparation of buccal films of Zolmitriptan with Sodium CMC:
Required amount of Sodium CMC and PVP were accurately weighed and dissolved in
one portion of methanol and the solution was kept aside for 30 min for swelling of polymer.
Then 35 mg of drug was dispersed slowly to another portion of solvent. Finally the second
portion was added to first portion very slowly under continuous stirring. To this final solution
required quantity of PEG-400 was added and mixed thoroughly to maintain plasticity of the
film.

Table: 7 Composition of film formulated with Sodium CMC:

Z4 Z5 Z6
2. Sodium CMC 100 200 300
3. PVP 25 25 25
4. PEG-400 15 15 15
4.5.4.3 Preparation of buccal films of Zolmitriptan with Carbopol 934p
Required amount of Carbopol 934p and PVP were accurately weighed and dissolved
in one portion of methanol and the solution was kept aside for 30 min for swelling of
polymer. Then 35 mg of drug was dispersed slowly to another portion of solvent. Finally the
second portion was added to first portion very slowly under continuous stirring. To this final
solution required quantity of PEG-400 was added and mixed thoroughly to maintain plasticity
of the film.
Table: 8 Composition of film formulated with Carbopol 934p

Z7 Z8 Z9
2. Carbopol 934p 100 200 300
3. PVP 25 25 25
4. Triethanolamine 5 5 5
5. PEG-400 15 15 15
Preparation of buccal films of Zolmitriptan with Eudragit RS-100
Required amount of Eudragit RS-100 and PVP were accurately weighed and
dissolved in one portion of methanol and the solution was kept aside for 30 min for swelling
of polymer. Then 35 mg of drug was dispersed slowly to another portion of solvent. Finally

the second portion was added to first portion very slowly under continuous stirring. To this
final solution required quantity of PEG-400 was added and mixed thoroughly to maintain
plasticity of the film.
Table: 9 Composition of film formulated with Eudragit RS-100

Z10 Z11 Z12
2. Eudragit RS-100 100 200 300
3. PVP 25 25 25
4. PEG-400 15 15 15
4.5.5 Evaluation of films:
Zolmitriptan buccal films were evaluated for:
1) Physical appearance
2) Surface texture
3) Weight variation
4) Thickness
5) Tensile strength
6) Percent elongation
7) Folding endurance
8) Content uniformity
9) Invitro dissolution studies
Physical appearance:
This test was performed simply by visual inspection of films for their colour and
transparency.
Surface texture:
This test was evaluated by just touching the surface of the film.
Weight Variation Test:
To study weight variation, one square inch film was cut at five different places in the
cast film. The weight of each film strip was taken and the weight variation was calculated.

Thickness:
The thickness of the film was determined using a Screw gauge at different positions
of the film, and the average thickness was calculated.
Tensile strength:
Tensile strength of the film was determined with digital tensile tester, which consists
of two load cell grips. The lower one is fixed and upper one is movable. The test film of
specific size 3 inch x 10 mm was fixed between these two cell grips and force was gradually
applied till the film breaks.
Percent elongation:
Percent elongation of the film was determined with Hounsfield universal testing
machine, which consists of two load cell grips. The lower one is fixed and upper one is
movable. The test film of specific size 3 inch x 10 mm was fixed between these two cell grips
and force was gradually applied till the film breaks. Readings were taken from the
instrument.
Folding endurance:
Folding endurance was measured by manually for the prepared films. A strip of film
(4.5 X2.5 cm) was cut evenly and repeatedly folded at the same place till it broke. The
number of times the film could be folded at the same place without breaking gave the exact
value of folding endurance.
Content Uniformity:
A film of size 2 cm diameter was cut and placed in a beaker. 10 ml of phosphate

buffer solution (pH 6.8) was placed. The contents were stirred in magnetic stirrer to dissolve
the film. The contents were transferred to a volumetric flask (10 ml). The absorbance of the
solution was measured against corresponding blank solution at 222 nm. A blank solution was
prepared in a similar manner by using a blank polymer film. The experiment was carried out
in triplicate and average value was calculated.
Dissolution Studies:
The release rate of Zolmitriptan from fast dissolving film was determined using USP
Dissolution Test Apparatus (Type II). The dissolution test was performed using 500 ml of

Phosphate buffer solution (pH 6.8), at 37 ± 0.5°C with the paddle speed of 50 rpm. Aliquot (5
ml) of the solution was collected from the dissolution apparatus at time interval of 1hr and
were replaced with same amount of fresh dissolution medium. Absorbance of the filtrates was
measured at 222 nm. Aliquots were withdrawn from a zone midway between the surface of
dissolution medium and the top of rotating paddle not less than 1 cm apart from the vessel
wall. Cumulative percentage drug release was calculated using an equation obtained from a
standard curve. Drug Release studies were performed in triplicate.

5. RESULTS AND DISCUSSIONS
5.1 Standard Graph of Zolmitriptan in pH 6.8 Phosphate Buffer:
Standard graph of Zolmitriptan drug in pH 6.8 Phosphate buffer medium was plotted by
preparing the concentrations from 2 - 10 µg/ml and absorbance was checked at 222 nm. An
excellent correlation coefficient (R=0.999) was observed.
Tale: 10. Zolmitriptan Standard Graph Parameters:
Concentration Absorbance
(mcg/ml)
0 0
2 0.24
4 0.438
6 0.649
8 0.876
10 1.108
1.2
0.8
Absorbance
0.6 y = 0.1105x + 0.0026

R² = 0.9998
0.4
0.2
0
0 2 4 6 8 10 12
Concentration (mcg/ml)
Fig: 17 Standard Graph of Zolmitriptan in pH 6.8 Phosphate Buffer.

5.2 PRE-FORMULATION STUDIES
The following preformulation studies were preformed for Zolmitriptan.
1. Solubility:
Zolmitriptan slightly solubilized in water.
2. Determination of pH:
Zolmitriptan 1% (W/V) solution in water showed pH of 6.3-6.8
3. Moisture content:
Moisture content of Zolmitriptan sample was found to be 0.28%.
4. Melting point:
Melting point of the Zolmitriptan was found to be 139-141°C
5. Drug - excipients compatability studies:

Zolmitriptan was mixed with different proportions with all excipients to be
used in our formulation in different ratios and kept at 40ºc for four weeks. The
physical properties (colour change) were monitored regularly. The change in colour in
any mixture was basis for discarding from study.

Table: 11. Different combinations of API and Excipients for Drug-Excipient

compatibility study. (Exposed conditions 40ºc)
Initial
Formula code D:E observation Week1 Week2 Week3 Week4
White
Drug alone ---- crystalline NC NC NC NC
powder
Drug+HPMC White
1:5 NC NC NC NC
E5 powder
Drug + Sodium White
1:5 NC NC NC NC
CMC powder
Drug+ Carbopol White
1:5 NC NC NC NC
934p powder
Drug+ Eudragit White
1:5 NC NC NC NC
RS-100 powder
All physical
White
mixture with ---- NC NC NC NC
powder
drug
Physical
White
mixture without ---- NC NC NC NC
powder
drug
D: E- Drug: Excipient, NC - No color change

5.3 FORMULATION STUDIES:
Buccal films of Zolmitriptan were prepared by casting method. The films of

Zolmitriptan were prepared with an objective to release the drug in controlled manner. PEG-
400 (15%) was used as a plasticizer and to enhance tensile strength of the film.
5.4 EVALUATION OF ZOLMITRIPTAN BUCCAL FILMS:
Table: 12. Physical evaluation parameters of all formulations
Formulation Thickness Weight variation Drug
code (mm) (mg) content
Z1 0.314±0.5 14.56±0.15 98.64
Z2 0.328±0.5 22.36±0.54 98.13
Z3 0.344±0.5 30.67±0.97 99.75
Z4 0.373±0.5 13.49±0.82 99.25
Z5 0.335±0.5 22.55±0.38 99.66
Z6 0.351±0.5 31.28±0.47 99.31
Z7 0.357±0.5 15.63±0.36 99.27
Z8 0.312±0.5 22.29±0.24 99.08
Z9 0.326±0.5 31.18±0.46 98.73
Z10 0.342±0.5 14.75±0.31 99.48
Z11 0.372±0.5 23.66±0.49 98.21
Z12 0.357±0.5 31.08±0.92 99.36
Physical parameters of all formulations were within the limits.

Table: 13. Mechanical properties of all formulations
Formulation Tensile % Folding

code strength Elongation Endurance
(kN/cm2)
Z1 1.452 24.85 52
Z2 1.634 30.42 85
Z3 1.846 38.94 102
Z4 1.566 25.14 63
Z5 1.749 32.97 95
Z6 1.963 41.08 126
Z7 1.483 25.37 66
Z8 1.647 33.48 83
Z9 1.791 45.21 120
Z10 1.548 28.43 61
Z11 1.746 36.91 96
Z12 1.961 47.62 138

2.5
Tensile strength
Tensile strength (kN/cm2)

2
1.5
0.5
0
Z1 Z2 Z3 Z4 Z5 Z6 Z7 Z8 Z9 Z10 Z11 Z12
Formulation code
Fig: 18 Graphical representations for Tensile Strength of all formulations
60
% Elongation
50
40
% Elongation
30
20
10
0
Z1 Z2 Z3 Z4 Z5 Z6 Z7 Z8 Z9 Z10 Z11 Z12
Formulation code
Fig: 19 Graphical representations for Percent Elongation of all formulations

160
Folding Endurance
140
120
Folding endurance
100
80
60
40
20
0
Z1 Z2 Z3 Z4 Z5 Z6 Z7 Z8 Z9 Z10 Z11 Z12
Formulation code
Fig: 20 Graphical representations for Folding Endurance of all formulations
From the above graphical representations it was observed that as the polymer concentration
increases in the formulations tensile strength, and folding endurance of the film increases but
percent elongation property decreases. All these mechanical properties of the films depends
on the type of polymer and their respective concentration in the formulations.
INVITRO DRUG RELEASE STUDIES:
Table: 14. % Cumulative drug release of formulations Z1, Z2, & Z3
Time % Cumulative drug release

(Hrs) Z1 Z2 Z3
0 0 0 0
1 31.92 24.67 18.67
2 56.68 51.37 38.94
3 79.34 74.61 55.19
4 99.48 96.37 71.49
6 99.67
8

120
100
80
% CDR
60 Z1
Z2
40 Z3
20
0
0 1 2 3 4 5 6 7 8 9
Time in hrs
Fig 21: % Cumulative drug release profile of formulations Z1, Z2, & Z3
From the above graphical representation it is clearly observed that as the polymer
concentration increases percent cumulative drug release from the formulation decreases. Z1,
Z2, & Z3 formulations were prepared with HPMC E5, due to low viscosity of this polymer it
was failed to release total drug up to 8 hrs.
Table: 15. % Cumulative drug release of formulations Z4, Z5, & Z6

(Hrs) Z4 Z5 Z6
0 0 0 0
1 15.46 12.08 10.67
2 28.47 23.31 20.86
3 40.35 34.67 31.18
4 51.48 46.42 43.28
6 70.18 65.38 62.49
8 88.39 84.67 78.54

100
90
80
70
60
% CDR
50 Z4
40 Z5
30 Z6
20
10
0
0 2 4 6 8 10
Time in hrs
Z5, & Z6 formulations were prepared with Sodium CMC, due to high viscosity of this
polymer it was failed to release total drug within 8 hrs.
Table: 16. % Cumulative Drug Release of formulations Z7, Z8, & Z9

(Hrs) Z7 Z8 Z9
0 0 0 0
1 14.08 12.47 10.69
2 28.66 23.53 20.76
3 40.39 35.67 32.09
4 51.28 46.11 41.94
6 73.16 68.34 64.49
8 94.37 91.51 86.34

100
90
80
70
60
% CDR
50 Z7
40 Z8
30 Z9
20
10
0
0 2 4 6 8 10
Time in hrs
Z8, & Z9 formulations were prepared with carbopol 934p, due to high viscosity of this
polymer it was failed to release total drug within 8 hrs.
Table: 16. % Cumulative Drug Release of formulations Z10, Z11, & Z12

(Hrs) Z10 Z11 Z12
0 0 0 0
1 21.54 15.74 11.73
2 38.36 28.62 24.18
3 54.41 41.19 35.18
4 69.19 53.38 46.97
6 98.19 77.43 70.24
8 98.86 92.49

120
100
80
% CDR
60 Z10
Z11
40 Z12
20
0
0 2 4 6 8 10
Time in hrs
Z11, & Z12 formulations were prepared with Carbopol 934p. Formulation Z12 released
exactly 99% of drug at the end of 8hrs.
Stability studies:
From the stability studies, it can be said that the optimized formulation didnot show any
difference in drug content and % cumulative drug release after 2 months study.

FTIR STUDIES:
FIG: FTIR of Zolmitriptan pure drug.
FIG: FTIR of Zolmitriptan+HPMC

FIG: FTIR of Zolmitriptan+Sod CMC
FIG: FTIR of Zolmitriptan+Carbopol 934p

FIG: FTIR of Zolmitriptan optimized formulation.

6. SUMMARY & CONCLUSION
Zolmitriptan buccal films were successfully developed in the present work for
controlled drug delivery in buccal region to improve bioavailability by preventing first pass
metabolism. Buccal Films of Zolmitriptan were prepared by Solvent - Casting Method using
hydrophilic polymers HPMC Grade E, sodium CMC and carbopol 934p, Eudragit and PVP.
Based on four week drug – excipient compatability studies at 400c desired polymers
and other excipients were successfully incorporated in all formulations.
From the physical parameter evaluation studies it was found that the tensile strength,
folding endurance values increases with concentration of polymers proportionally, whereas
percent elongation decreases. Content uniformity studies showed that the drug is uniformly
distributed in film. Present study reveals that all the formulated films showed satisfactory
film properties.
Among all formulations, formulation Z11 releases the 99% of drug in calculated 8 hrs
but other formulations released more or less drug up to 8 hrs..
Finally it can be concluded that buccal film containing Zolmitriptan can be prepared by
casting method. It improves bioavailability of drug by releasing the drug slowly in buccal
cavity.

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DESIGN AND EVALUATION OF BUCCAL PATCHES OF

In Partial Fulfillment for the degree of

Ms. YARA NAGAMANI

Place: (Ms. YARA NAGAMANI)

Evaluation of Buccal Patches of Zolmitriptan” has been carried out in the

laboratories of Vaagdevi Institute of Pharmaceutical Sciences, Bollikunta, Warangal

Ms. Yara Nagamani under my guidance and supervision.

Prof. Y. MADHUSUDAN RAO

Evaluation of Buccal Patches of Zolmitriptan” has been carried out in the

laboratories of Vaagdevi Institute of Pharmaceutical Sciences, Bollikunta, Warangal

Ms. Yara Nagamani.

Dr. K. Rajitha Dr. M. Radhakishan

I owe my profound gratitude, indebtedness and heartfelt thanks to my guide

I am sincerely thankful to Dr. M. Radhakishan, Principal, Vaagdevi Institute

My special gratitude to Shri Ch. Devender Reddy,, Secretary and

I wish to convey my deep sense of gratitude to Dr. K. Rajitha, HOD,

(Ms. YARA NAGAMANI)

F. no. Title of the figure

1 The two steps of the mucoadhesion process.

Table no. Title of the table

Sl. No CONTENTS Page No.

4 Materials & Method 36

5 Results & Discussion 54

6 Summary & Conclusion 68

Department of Pharmaceutics- VIPS, Bollikunta Page 1

Bioadhesive systems applied to mucous membrane are frequently defined as

Department of Pharmaceutics- VIPS, Bollikunta Page 2

Although studies on the mechanisms involved in mucoadhesion and the development

1.2. MECHANISMS OF MUCOADHESION

The mechanism of adhesion of certain macromolecules to the surface of a mucous

Department of Pharmaceutics- VIPS, Bollikunta Page 3

FIGURE 1 – The two steps of the mucoadhesion process.

Department of Pharmaceutics- VIPS, Bollikunta Page 4

According to dehydration theory, materials that are able to readily gelify in an

FIGURE 2 – Dehydration theory of mucoadhesion

1.3. MUCOADHESION THEORIES

Department of Pharmaceutics- VIPS, Bollikunta Page 5

FIGURE 3 – Schematic diagram showing influence of contact angle between device

Department of Pharmaceutics- VIPS, Bollikunta Page 6

Department of Pharmaceutics- VIPS, Bollikunta Page 7

FIGURE 4 – Secondary interactions resulting from interdiffusion of polymer chains

Department of Pharmaceutics- VIPS, Bollikunta Page 8

Department of Pharmaceutics- VIPS, Bollikunta Page 9

FIGURE 5 – Regions where the mucoadhesive bond rupture can occur.

The mechanisms governing mucoadhesion are also determined by the intrinsic

Department of Pharmaceutics- VIPS, Bollikunta Page 10

Environment-related factors include pH, initial contact time, swelling and

1.4. MUCOADHESIVE MATERIALS

 First generation mucoadhesive materials:

Department of Pharmaceutics- VIPS, Bollikunta Page 11

formulations, such as tablets, transdermal adhesives and microparticles, and into

In contrast, synthetic polymers derived from polyacrylic acid (carbomers) are

Nonionic polymers, including hydroxypropylmethylcellulose, hydroxyethylcellulose

Department of Pharmaceutics- VIPS, Bollikunta Page 12

 Second generation mucoadhesive materials:

Department of Pharmaceutics- VIPS, Bollikunta Page 13

These novel multifunctional mucoadhesive systems are classified as second

Lectins are immunogenic vegetal glycoproteins that specifically recognize sugar

Thiolated polymers are obtained by the addition of conjugated sulfidryl groups

Department of Pharmaceutics- VIPS, Bollikunta Page 14

thiolated chitosan increased mucoadhesive properties due to formation of disulfide

Currently, the addition of elements of sensitization and recognition continue being

1.5. METHODS OF ANALYZING MUCOADHESION