FORMULATION AND INVITRO CHARACTERIZATION OF

NORFLOXACIN MUCOADHESIVE TABLET WITH NATURAL GUMS

Dissertation submitted to the

Jawaharlal Nehru Technological University, Kakinada

In partial fulfillment

Of the requirements for award of the degree

of

Master of Pharmacy

By

BAGADHI RAJINI (18DA1SO301)

Under the guidance of

Mr.B.SANTOSH KUMAR, M.Pharm

Assistant Professor

SRI SIVANI COLLEGE OF PHARMACY

(Affiliated by JNTUK, Approved by AICTE & PCI, New Delhi)

NH- 16,Chilakapalem Jn., Etcherla (M), Srikakulam (Dt) – 532402, 2018-2020

 SRI SIVANI COLLEGE OF PHARMACY
(NH- 16, Chilakapalem Jn., Etcherla (M), Srikakulam (Dt) – 532402

CERTIFICATE

This is to certify that the dissertation entitled FORMULATION AND INVITRO

CHARACTERIZATION OF NORFLOXACIN MUCOADHESIVE TABLET WITH
NATURAL GUMS. The bonafide Research work of BAGADHI RAJINI (18DA1S0301),
in partial fulfillment of the requirement of the award of the degree of Mater of Pharmacy in
PHARMACEUTICS under my supervision. The project report has not been previously
submitted for other degree.

Date :

Place: Chilakapalem

PRINCIPAL

Dr.RAJ KIRAN ,M.Pharm, Ph.D,

Sri Sivani College of Pharmacy,

Chilakapalem Jn., Srikakulam (Dt),

Andhra Pradesh-532402
 SRI SIVANI COLLEGE OF PHARMACY
NH- 16,Chilakapalem Jn., Etcherla (M), Srikakulam (Dt) – 532402

CERTIFICATE

This is to certify that the dissertation entitled FORMULATION AND INVITRO

CHARACTERIZATION OF NORFLOXACIN MUCOADHESIVE TABLET WITH
NATURAL GUMS is the bonafide Research work of BAGADHI RAJINI (18DA1S0301) in
partial fulfillment for the requirement of the award of the degree of Master of Pharmacy and is
based on the result of experiments carried out by her under my supervision”. The thesis has
not been previously submitted for other degree.

Date:

Place: Chilakapalem.

Signature of the Guide

B.SANTOSH KUMAR M.Pharm,

Assistant Professor

Sri Sivani College of Pharmacy,

Chilakapalem Jn., Srikakulam (Dt),
Andhra Pradesh-532402.
 SRI SIVANI COLLEGE OF PHARMACY
(NH- 16,Chilakapalem Jn., Etcherla (M), Srikakulam (Dt) – 532402

I hereby declare that the work described in this thesis, FORMULATION AND INVITRO
CHARACTERIZATION OF NORFLOXACIN MUCOADHESIVE TABLET WITH
NATURAL GUMS entitled, which is being submitted by me in partial fulfillment for the
award of Master of Pharmacy in the Department of Pharmaceutics, Sri Sivani College of
pharmacy to the Jawaharlal Technological University Kakinada, is the result of investigations
carried out by me under the Guidance of Mr.B.Santosh Kumar, Asst Professor. The work is
original and has not been submitted for any Degree/Diploma of this or any other university.

Date:

Place: Chilakapalem

BAGADHI RAJINI

(18DA1S0301)
 SRI SIVANI COLLEGE OF PHARMACY

(NH- 16, Chilakapalem Jn., Etcherla (M), Srikakulam (Dt) – 532402

EVALUATION CERTIFICATE

This is to certify that the dissertation work entitled FORMULATION AND INVITRO
CHARACTERIZATION OF NORFLOXACIN MUCOADHESIVE TABLET WITH
NATURAL GUMS is the bona fide Research work of BAGADHI RAJINI (18DA1S0301) in
partial fulfillment of the requirement for the award of degree of Bachelor of Pharmacy and is
based on the result of experiments carried out by her under the guidance of Mr.B.SANTOSH
KUMAR,M.Pharm ,Sri Sivani college of pharmacy ,NH-16, ChilakapalemJn.,Srikakulam
(Dt), Andhra Pradesh.

Examination Centre: Sri Sivani College of Pharmacy

Place: Chilakapalem

Date:

Internal Examiner External Examiner

 ACKNOWLEDGEMENT

It is a great time for me to acknowledge those without whom this work would not have
been fruitful.

I would like to thank to our beloved Principal DR.RAJ KIRAN ,M.Pharm.,Ph.D., Sri
Sivani College of Pharmacy for providing facilities and for the valuable encouragement
throughout the preparation of this work.

I consider myself lucky to work under the guidance of Mr.B.SANTOSH KUMAR

M.Pharm., Assistant Professor, Dept. of Pharmaceutics, Sri Sivani College of Pharmacy, for his
continuous guidance, constructive criticism and support have always propelled me to perform
better without his help this dissertation would not be as it is.

It is great pleasure and honor for me to owe gratitude to MANAGEMENT of Sri Sivani
College of Pharmacy for providing all the facilities enabling me to do project of this magnitude.

I would like to extent my deepest gratitude to D.PRIYA DARSHINI M.pharm (Ph.D),

S.K.SAHOO M.pharm (Ph.D), CH.KISHORE KUMAR M.pharm (Ph.D), G. SOWNDARYA
M.Pharm., P.SANTHOSH KUMAR Librarian., SATISH Lab tech. for their affectionate
encouragement and valuable suggestions.

I would like to thank to all my Teaching and Non Teaching staff members of Department
of Pharmacy, Sri Sivani College of Pharmacy who encouraged to complete this work.

I feel proud to express my hearty gratitude to all other my classmates who supported me
directly or indirectly. Last but not least I wish to express my deepest sense to respect and love to
Parents for their constant support and encouragement throughout.

Thanking to one and all

BAGADHI RAJINI

(18DA1S0301)
 DEDICATED TO

MY BELOVED PARENTS
 1
INTRODUCTION

CHAPTER1
INTRODUCTION
Oral route is the most convenient and commonly used route of drug administration.More than
50%of the drug delivery systems available in the market are oral drug delivery systems.These
systems have the obvious advantages i.e.ease of administrationand patient acceptance.The fact
that absorption and residence of the drug in particular sections of the gastrointestinal may be
correlatedand must be taken into account while developing oral drug dosage forms,Especially
show release formulation.Hence,attempts are made to work out such in which drug releases
slowly in a specific section of gastrorintestinal tract e.g. in stomach,smallintestine or colon.The
basic goal of any drug delivery system is to provide a therAupeutic amount of drug to the proper
Site in systemic circulation. Conventional drug theraupy results in the fluctuations of drug
concentration in systemic circulation, causing either toxic effect or no theraupeutic action . in
recent years scientific and technological advancements have been made in the research and
development of rate controlled oral drug delivery systems by overcoming physiological
adversities, short gastric residence time, less therapeutic index.
1.1 CONCEPT:
Solid medicaments may be administered orally as powders ,pills,cachets,capsules or
tablets.These dosage forms contain a quantity of drug which is given as a single unit and they are
known collectivey as a solid unit dosage forms,even in the case of sustained action preparations
which ,technically,contain the equivalent of several normal doses of drug .The stringent
formulation requirements of modern medicaments ,the many advantages of tablet and capsule
medicatiom,coupled with expanding health services and the commitment need for large –scale
economic manufacture,have led to asteady decline in the prescribing of powders and pills.
Tablets and capsules,on the other hand,currently account for well over third of the total number
and cost of medicines produced all over the world.Tablet is defined as a compressed solid dosage
form containing medicaments with or without excipients.According to the Indian pharmacopoeia
pharmaceutical tablets are solid,flat or biconvex dishes,unit dosage form,prepared by
compressing a drugs or a mixture of drugs,with or without diluents.They vary in shape and differ
greatly in size and weight,depending on amount of medicinal substances and the intended mode
of administration.It is the most popular dosage form and 70%of the totalmedicines are dispensed
 2
INTRODUCTION

in the form of tablet.All medicaments are available in the tablet form except where it is difficult
to formulate or administer.
1.2ORAL ROUTE AS THE MOST CONVENIENT ROUTE .
Oral ingestion has been the most convenient and commonly employed route of drug delivery.
Indeed, for sustained release systems, the oral route of administration has by far received the
most attention with respect to research on physiological and drug constraints as well as design
and testing of products. This is because there is more flexibility in dosage form design for the
oral route than there is for the parentral route.
The reason that the oral route achieved such popularity may be in part attributed to its ease of
administration as well as the traditional belief that by oral administration the drug is well
absorbed as the food stuffs that are ingested daily. In fact, the development of pharmaceutical
product for oral delivery, irrespective of its physical form involves varying extent of
optimization of dosage form characteristics within the inherent constraints of GI physiology.
Therefore the fundamental understanding of various disciplines, including GI physiology,
pharmacokinetics, pharmacodynamics and formulation design are essential to achieve a systemic
approach to the successful development of an oral pharmaceutical dosage form. The more
sophisticated a delivery system, the greater is the complexity of these various disciplines
involved in the design and optimization of the system. In any case, the scientific framework
required for the successful development of an oral drug delivery system consists of a basic
understanding of the following three aspects:
1. Physicochemical, pharmacokinetic and pharmacodynamics characteristics of the drug.
2. The anatomic and the physiologic characteristics of the GIT.
3. Physicochemical characteristics and drug delivery mode of the dosage form to be designed.
1.3 ADVANTAGES OF TABLET DOSAGE FORM ARE:
1.They are unit dosage form and offer the greatest capabilities of oral dosage form for the
greatest dose precision and the least content variability.
2.Cost is lowest of all oral dosage form.
3.Lighter and compact.
4.Easiest and cheapest to package and strip.
5.Easy to swallowing with least tendency for hang up.
6.Sustain release product is possible by enteric coating.
 3
INTRODUCTION

7. Objectionable odour and bitter taste can be masked by coating technique.

8. Suitable for large scale production.
9. Greatest chemical and microbial stability over all oral dosage form.
10. product identification is easy and rapid requiring no additional steps when employing an
embossed and /or monogrammed punch face.
1.4 DISADVANTAGES OF TABLET DOSAGE FORM ARE :
1.Difficult to swallow in case of children and unconscious patients.
2.Some drugs resist compression into dense compacts,to owing to amorphous nature, low density
character.
3.Drug with poor wetting,slow dissolution properties,optimum absorption high in GIT may be
difficult to formulate or manufacture as a tablet that will still provide adequate or full drug
bioavailability.
4.Bitter testing drugs,drugs with an objectionable odour or drugs that are sensitive to oxygen
may require encapsulation or coating .In such cases,capsule may offer the best and lowest cost.
1.5 GENERAL PROPERTIES OF TABLET DOSAGE FORMS:
1.A tablet should have elegant product identity while free of defects like chips, cracks
,discolouration and contamination.
2.Should have sufficient strength to withstand mechanical shock during its production,
packaging, shipping and dispensing.
3.Should have the chemical and physical stability to maintain its physical attributes over time.
4.The tablet must be able to release the medicinal agents in a predictable and reproducible
manner.
5.Must have a chemical stability over time so as not to follow alteration of the medicinal agent.
1.6 GRANULATION TECHNOLOGY ON LARGE SCALE BY VARIOUS
TECHNIQUES.
1.6.1 DIRECT COMPRESSION:
Processing steps are :
Rawmaterial –weighing -screening –mixing-compression
Direct compression consists ofcompressing tablets directly from powdered materials without
modifying physical nature of materials.this method is applicable forcrystalline chemicals having
good compressable characteristics and flow properties such as : potassium salt(chlorate, chloride,
 4
INTRODUCTION

bromide),sodium chloride, Ammonium chloride, Methenamine etc. If necessary ,direct

compression vehicles can be used which are having good flow and compressible characteristics
.commonly used directly compression diluents are: MCC(microcrystallinecellulose (avicel),spray
dried lactose, starch- (star x 1500,embdex,cellutab),sugar(sugartab, nutab),dicalcium phosphate
dehydrate(Ditab),mannitol for chewable tablet.
ADVANTAGES:
1.Low labour input.
2.A dry process
3.Fewest processing steps.
DISADVANTAGES:
1.Stratification may occour due to differences in particle size and bulk density which results poor
content uniformity.
2.a large dose drug may cause problem in direct compression.it requires diluents.The tablet
becomes lage in size which is difficult to swallow and also costly.
3.During handling of dry materials static charge may form which may present uniform
distribution of drug.
4.Direct compression diluents may interact with the drug .For example,amine drud with lactose
produce discolouration of tablet.
1.6.2 DRYGRANULATION:
Processing steps are:
Rawmaterials –weighing –screening –mixing –slugging –milling -screening-mixing-
compression.
When tablet ingredients are to moisture and/or unable to withstand elevated temperature during
drying and when the tablet ingredient have insufficient cohesive properties, slugging may be
used to form granules. This method is refer to as dry granulation. This technique is used in
preparation of aspirin ,aspirin combination, acetophenetidine, thiaminehydrochloride, ascorbic
acid, magnesiumhydroxide.
Table 1.1 Comparative processing chart of Different granulation techniques:

Processing step Wet Dry Direct

Raw material X X X
 5
INTRODUCTION

Weigh X X X
Screen X X X
Mix _ X _
Compress(slug) _ X _
Wet mass X _ _
Mill X _ _
Dry X _ _
Mill X X _
Mix X X _
Compress X X X

Compression granulation involves the compaction of the components of a tablet by means of flat
punch. These compact masses are called slug and the process is called slugging. slugs are then
milled or screened to produce a granular form. and large scale operation compression granulation
can be performed on a specially designed machine called roller compacter.

1.6.3 WETGRANULATION:
Processing steps are:
Rawmaterials- weighing- screening- wetmassing- sieving/milling- drying-screening- mixing-
compression.
The most widely used and most general method of tablet preparation is the wet granulation
method. The active ingredient ,diluents and disintegrants are mixed or blended well, For
largescale production twin shell-blender,double cone blender,plantory mixer,sigmablade
mixer,ribbon mixer etc.are commonly used.solutiond of the binding agent are added to the mixed
powder with stirring.the powder mass is wetted with the binding solution until the mass has the
constituency of damp snow.If the granulation is over wetted the granules will be hard,if not
sufficientluy,the resulting granules will be too soft, breaking down during lubrication.The
wetmass is forced through a 6 or 8 mesh(Mesh no.is the number of wires passing through an
inch)screen or several mills can be used.moist materials from wet milling steps is placed on large
trays and placed in drying chambers with a circulating air current and thermostable heat
controller.commonly used dryers are tray dryer ,fluidized bed dryer.After drying,the granulation
 6
INTRODUCTION

is reduced in particle size by passing smaller mesh screen.The screen size depends on the
diameter of the punch as follows:
Tablet up to 3/16 in diameter---------------------20 mesh.
Tablet upto 7/32 into5/16 in diameter-------------------16mesh.
Tablet upto 11/32 into 13/32 in diameter--------------------14mesh.
Tablet upto 7/16 in and more---------------------------16 mesh.
After drying granulation,the lubricants or glidants is added as fine powder to promote flow of
granules .these granules then compressed to get tablet.
1.7 THE GOAL IN DESIGNING SUSTAINED OR CONTROLLED DELIVERY
SYSTEM .
Over the past 30 years, as the expense and complications involved in marketing new drug entities
have increased, with concomitant recognition of the therapeutic advantages of novel drug
delivery, greater attention has been focused on development of sustained or controlled release
drug delivery system. There are several reasons for the attractiveness of these dosage forms. It is
generally recognized that for many disease states, a substantial number of therapeutically
effective compounds already exists. The effectiveness of these drugs however is often limited by
side effects or the necessity to administer the compound in a clinical setting.
The major goal set in designing sustained or controlled delivery is to:
· Reduce the frequency of dosing.
· Increase effectiveness of the drug by localization at the site of action.
· Reducing the dose required.
· Providing the uniform drug delivery.
So, the controlled release dosage form is a dosage form that release one or more drugs
continuously in a predetermined pattern for a fixed period of time, either systemically or to a
specified target organ.
In the past, many of the terms used to refer therapeutic systems of controlled and sustained
release have been used in an inconsistent and confusing manner. Sustained release, sustained
action, prolonged action, controlled release (drug release with zero order kinetics) and repository
dosage forms are terms used to identify drug delivery systems that are designed to achieve
prolonged therapeutic effects by continuously releasing medication over an extended period of
time after administration of a single dose. In general, the goal of a sustained release dosage form
 7
INTRODUCTION

is to maintain therapeutic blood or tissue levels of drug for an extended period this is usually
accomplished by attempting to obtain zero-order release from the dosage form; zero-order
release constitutes drug release from the dosage form. Sustained release systems generally do not
attain this type of release and provides drug is a slow first order fashion. In recent year sustained
release dosage forms continue to draw attention in the search for improved patient compliance
and decreased incidence of adverse drug reactions.
Sustained release, sustained action, prolonged action controlled release, extended action, timed
release, depot and repository dosage forms are terms used to identify drug delivery system that
are designed to achieve or prolonged therapeutic effect by continuously releasing medication
over an extended period of time after administration of a single dose.
According to Flynn, controlled release has been defined as “the use of whatever means
possible, be it chemical or mechanical, to regulate a drug access rate to the body’s central
compartment, or in some cases, directly to the involved tissues”.
Controlled drug delivery system is produced when a polymer whether natural or synthetic is
properly mixed with the active ingredient so that the drug is released in a predetermined manner.

Controlled release also denotes systems which can provide some control whether this is of a
temporal or spatial nature of both for drug release in the body. The system attempts to control
drug concentration in the target tissue or cells.

Oral controlled release systems continue to be most popular ones among all the drug delivery
systems, as it offers several advantages over the conventional systems like

 Improve patient compliance and convenience due to less frequent dosing of drug.
 Reduction in fluctuation of steady state plasma level.
 Maximum utilization of drug enabling reduction in total amount of dose administered.
 Constant drug delivery.
 According to the United States of Pharmacopoeia, the term “Modified Release Dosage
Forms” is used to denote the dosage forms for which the drug release characteristics of
time course and/or location are chosen to accomplish therapeutic objectives not offered
by the conventional dosage forms.
 8
INTRODUCTION

1.8 MODIFIED-RELEASE DRUG DELIVERY SYSTEMS MAY BE DIVIDED

CONVENIENTLY IN TO FOUR CATAGORIES

1.· Delayed release.

2.· Sustained release.

3.· Site-specific targeting.

4.· Receptor targeting.

1. Delayed release dosage forms:

These systems are those that use repetitive, intermittent dosing of a drug form one or more
immediate release units incorporated into a single dosage form. In these dosage forms the drug is
released after some time of administration. However, it may release a portion of drug just after
the administration. It includes enteric coated dosage forms and repeat action tablets or capsules.

2. Sustained release dosage forms:

These systems include any drug delivery system that achieves slow release of drug over an
extended period of time. These dosage forms releases a sufficient amount of drug initially to
produce the desired pharmacological effect. The remaining amount of drug is released
periodically over an extended period to maintain the pharmacological effect which is produced
initially. These dosage forms deliver the drug at a predetermined time but not a predetermined
rate.

i) Controlled Release

These systems also provide a slow release of drug over an extended period of time and
also can provide some control, whether this is of a temporal or spatial nature, or both, of drugs
release in the body, or in other words, the system is successful at maintaining constant drug level
in the target tissue or cells (figure:1.1).
 9
INTRODUCTION

ii) Extended Release

It is defined as the one that allow at least a twofold reduction in the dosing frequency as
compared to that of conventional dosage form and releases the drug slowly than normal manner.

In these dosage forms the drug is released over an extended period of time to obtain a
prolonged therapeutic effect. USP used the term to describe a formulation that does not release
active substance immediately after oral dosing and that also allow a reduction in dosing
frequency.

3. Site-specific or timed release dosage forms:

It refers to targeting of drug directly to a certain biological location.

This is a type of dosage form which releases the drug at or near the intended physiological site of
action. Extended release characteristics may also be incorporated in the targeted release dosage
form.

4. Receptor targeting:

These systems refer to targeting of drug directly to a certain biological location. In this case the
target is the particular receptor for a drug within an organ or tissue.
 10
INTRODUCTION

Site specific targeting and receptor targeting systems satisfy the spatial of drug delivery and are
also considered to be controlled drug delivery systems.

1.9 DESIGN AND FORMULATION OF ORAL SUATAINED RELEASE DRUG

DELIVERY SYSTEM.

The oral route of administration is the most preferred route due to flexibility in dosage form,
design and patient compliance. But here one has to take into consideration, the various pH that
the dosage form would encounter during its transit, the gastrointestinal motility, the enzyme
system and its influence on the drug and the dosage form.

Fig 1.2: A Hypothetical plasma concentration-time profile conventional multiple dosing

and single doses of sustained and controlled delivery formulation

The majority of oral sustained release systems rely on dissolution, diffusion or a combination of
both mechanisms, to generate slow release of drug to the gastrointestinal milieu. Theoretically
and desirably a sustained release delivery device, should release the drug by a zero-order process
which would result in a blood level time profile similar to that after intravenous constant rate
infusion (as shown in figure 1.2) .
Advantages of Sustained Release Drug delivery.
1. decreased local and systemic side effects:
 Reduced gastrointestinal irritation.
2. Better drug utilization:
 11
INTRODUCTION

 Minimum drug accumulation on chronic dosing.

3. Improved efficiency in the treatment:
 More uniform blood concentration.
 Reduction in fluctuation in drug level and hence more uniform pharmacological response.
4. Improved patient compliance:
 Less frequent dosing.
 Reduced night-time dosing.
5. Economy
 Although the initial unit cost of sustained release products is usually greater than that of
the conventional dosage form because of the special nature of these products, the average
cost of treatment over an extended time period may be less.

Disadvantages of sustained release drug delivery.

1. Dose dumping:
 Dose dumping may occur with faulty formulations.
2. Need for additional patient education:
 Patients may need substantial additional information as to the proper use of sustained
release products e.g. “Do not crush or chew the dosage unit. Tablet residue may appear in
the stools”. In some instances, patients must be started on an immediate release product
and then switched over to the sustained release products.
3. Possible reduction in systemic availability:
 Reduced systemic availability has been shown for some sustained release formulations of
Theophylline, Procainamide and Vitamin combinations.
1.10 CRITERIA TO BE MET BY DRUG PROPOSED TO BE FORMULATED IN

CONTROLLED RELEASE DOSAGE FORMS

a. Desirable half life: The half-life of a drug is an index of its residence time in the body.
The dosage form may contain a prohibitively large quantity of the drug if the drug has a
short half-life (less than 2hrs). On the other hand, drug with elimination half-life of eight
hours or more are sufficiently sustained in the body, when administered in conventional
dosage form, and controlled release drug delivery system is generally not necessary in
 12
INTRODUCTION

such cases. Ideally, the drug should have half-life of three to 4 hrs.

b. High therapeutic index: Drugs with low therapeutic index are unsuitable for
incorporation in controlled release formulations. If the system fails in the body, dose
dumping may occur, leading to fatalities e.g. Digitoxin. 13

c. Small dose: If the dose of a drug in the conventional dosage form is high, its suitability
as a candidate for controlled release is seriously undetermined. This is chiefly because the
size of a unit dose controlled release formulation would become too big, to administer
without difficulty.12

d. Desirable absorption and solubility characteristics: Absorption of poorly water

soluble drug is often dissolution rate limited. Incorporating such compounds into
controlled release formulations is therefore unrealistic and may reduce overall absorption
efficiency.5

e. Desirable absorption window: certain drugs when administered orally are absorbed
only from a part of gastrointestinal tract. This part is referred to as the ‘absorption
window’. Drugs exhibiting an absorption window like fluorouracil, thiazide diuretics, if
formulated as controlled release dosage form are unsuitable.

f. First pass clearance: As discussed earlier in the disadvantages of controlled drug

delivery system, delivery of the drug to the body in desired concentrations is seriously
hampered in case of drugs undergoing extensive hepatic first pass metabolism, when
administered in controlled release forms.5

1.11 CLASSIFICATION OF ORAL SUSTAINED /CONTROLLED RELEASE

SYSTEMS.

1. Diffusion controlled system.

a. Reservoir type.
 13
INTRODUCTION

b. Matrix type
2. Dissolution controlled system.
a. Reservoir type.
b. Matrix type.

3. Methods using Ion-exchange.

4. Methods using osmotic pressure.

5. PH independent formulations.

6. Altered density formulations.

1. Diffusion controlled System

Basically diffusion process shows the movement of drug molecules from a region of a higher
concentration to one of lower concentration. The flux of the drug J (in amount / area - time),
across a membrane in the direction of decreasing concentration is given by Fick’s law. J= - D
dc/dx
. Where, D = diffusion coefficient in area/ time.
dc/dx = change of concentration 'c' with distance 'x'

In common form, when a water insoluble membrane encloses a core of drug, it must diffuse
through the membrane.

The drug release rate dm/ dt is given by

dm/ dt= ADKΔ C/L

Where,

A = Area.

K = Partition coefficient of drug between the membrane and drug core.

 14
INTRODUCTION

L = Diffusion path length (i.e. thickness of coat).

ΔC = Concentration difference across the membrane.

a. Reservoir Type: In this system, a water insoluble polymeric material encases a core of
drug. Drug will partition into the membrane and exchange with the fluid surrounding the
particle or tablet. Additional drug will enter the polymer, diffuse to the periphery and
exchange with the surrounding media.
Matrix Type: A solid drug is dispersed in an insoluble matrix and the rate of release of
drug is dependent on the rate of drug diffusion and not on the rate of solid dissolution.

Higuchi has derived the appropriate equation for drug release for this system:

Q = Dε/ T [2 A –εCs] Cst ½

Where,

Q = Weight in gm of drug released per unit area of surface at time t.

D = Diffusion coefficient of drug in the release medium.
ε = Porosity of the matrix.
Cs = Solubility of drug in release medium.
T= Tortuosity of the matrix.
A = Concentration of drug in the tablet, as mg/ ml.
A third possible diffusional mechanism is the system where a partially soluble
membrane encloses a drug core. Dissolution of part of membrane allows for diffusion of
the constrained drug through pores in the polymer coat.
The release rate can be given by following equation
Release rate = AD / L = [C1- C2]
Where,
A = Area.
D = Diffusion coefficient.
 15
INTRODUCTION

C1 = Drug concentration in the core.

C2 = Drug concentration in the surrounding medium.
L = Diffusion path length.
Thus diffusion controlled products are based on two approaches the first approach entails
placement of the drug in an insoluble matrix of some sort. The eluting medium penetrates the
matrix and drug diffuses out of the matrix to the surrounding pool for ultimate absorption. The
second approach involves enclosing the drug particle with a polymer coat. In this case the
portion of the drug which has dissolved in the polymer coat diffuses through an unstirred film of
liquid into the surrounding fluid.
2. Dissolution controlled Systems
A drug with a slow dissolution rate is inherently sustained and for those drugs with high water
solubility, one can decrease dissolution through appropriate salt or derivative formation. These
systems are most commonly employed in the production of enteric coated dosage forms.
To protect the stomach from the effects of drugs such as Aspirin, a coating that dissolves in
natural or alkaline media is used. This inhibits release of drug from the device until it reaches the
higher pH of the intestine. In most cases, enteric coated dosage forms are not truly sustaining in
nature, but serve as a useful function in directing release of the drug to a special site. The same
approach can be employed for compounds that are degraded by the harsh conditions found in the
gastric region.
a. Reservoir Type: Drug is coated with a given thickness coating, which is slowly
dissolved in the contents of gastrointestinal tract. By alternating layers of drug with the
rate controlling coats as shown in figure, a pulsed delivery can be achieved. If the outer
layer is quickly releasing bolus dose of the drug, initial levels of the drug in the body can
be quickly established with pulsed intervals. Although this is not a true sustained release
system, the biological effects can be similar. An alternative method is to administer the
drug as group of beads that have coating of different thickness. This is shown in figure.
Since the beads have different coating thickness, their release occurs in a progressive
manner. Those with the thinnest layers will provide the initial dose. The maintenance of
drug levels at late times will be achieved from those with thicker coating. This is the
principle of the spansule capsule. Cellulose nitrate phthalate was synthesized and used as
an enteric coating agent for acetyl salicylic acid tablets.
 16
INTRODUCTION

b. Matrix Type: The more common type of dissolution sustained dosage form as shown in
figure. It can be either a drug impregnated sphere or a drug impregnated tablet, which
will be subjected to slow erosion.
Two types of dissolution-controlled pulsed delivery systems
 Single bead type device with alternating drug and rate controlling layer.
 Beads containing drug with differing thickness of dissolving coats.
Amongst sustained release formulations, hydrophilic matrix technology is the most widely used
drug delivery system due to following advantages:
 Provide desired release profiles for a wide therapeutic drug category, dose and solubility.
 Simple and cost effective manufacturing using existing tableting unit operation
equipment.
 Robust formulation.
 Broad regulatory and patient acceptance.
 Ease of drug release modulation through level and choice of polymeric systems and
function coatings. A hydrophilic matrix tablet consists of mixture of drug, polymer and
excipients (filler/diluent as well as other excipients) prepared by common tableting
equipment. Drug release is controlled by hydrophilic (water swellable) polymer in the
matrix. Formulators often choose from a range of hydrophilic polymers, as stand alone or
in combination with different polymers for release rate control. Majority of commercially
successful hydrophilic matrix tablets are based on HPMC (hydroxy propyl methyl
cellulose) due to wide range of chemistries and viscosity ranges to modulate release
profiles of different dose / solubility characteristics of active pharmaceutical ingredient.
3. Methods using lon Exchange

It is based on the formation of drug resin complex formed when a ionic solution is kept in
contact with ionic resins. The drug from these complexes gets exchanged in gastrointestinal tract
and released with excess of Na+ and Cl- present in gastrointestinal tract.

Anion Exchangers: Resin+ - Drug - + Cl- goes to Resin+ - Cl- + Drug-

Cation Exchangers: Resin- - Drug+ + Na+ goes to Resin- - Na+ + Drug+

These systems generally utilize resin compounds of water insoluble cross linked polymer. They
contain salt forming functional group in repeating positions on the polymer chain. The rate of
 17
INTRODUCTION

drug diffusion out of the resin is sustained by the area of diffusion, diffusional path length and
rigidity of the resin which is function of the amount of cross linking agent used to prepare resins.
The release rate can be further sustained by coating the drug resin complex by
microencapsulation process.
4. Methods Using Osmotic Pressure
A semi permeable membrane is placed around a tablet, particle or drug solution that allows
transport of water into the tablet with eventual pumping of drug solution out of the tablet through
a small delivery aperture in tablet coating.
Characterization: Drug surrounded by semi permeable membrane and release governed by
osmotic pressure.
Two types of osmotically controlled systems are
 Type A contains an osmotic core with drug.
 Type B contains the drug in flexible bag with osmotic core surrounding.
5. PH – Independent Formulations
The gastrointestinal tract present some unusual features for the oral route of drug administration
with relatively brief transit time through the gastrointestinal tract, which constraint the length of
prolongation, further the chemical environment throughout the length of gastrointestinal tract is
constraint on dosage form design. Since most drugs are either weak acids or weak bases, the
release from sustained release formulations is P H dependent. However, buffers such as salts of
amino acids, citric acid, phthalic acid phosphoric acid or tartaric acid can be added to the
formulation, to help to maintain a constant P H thereby rendering PH independent drug release. A
buffered sustained release formulation is prepared by mixing a basic or acidic drug with one or
more buffering agent, granulating with appropriate pharmaceutical excipients and coating with
gastrointestinal fluid permeable film forming polymer. When gastrointestinal fluid permeates
through the membrane, the buffering agents adjust the fluid inside to suitable constant P H thereby
rendering a constant rate of drug release e.g. propoxyphene in a buffered sustained release
formulation, which significantly increase reproducibility.
6. Altered Density Formulations
It is reasonable to expect that unless a delivery system remains in the vicinity of the absorption
site until most; if not all of it would have limited utility. To this end, several approaches have
 18
INTRODUCTION

been developed to prolong the residence time of drug delivery system in the gastrointestinal
tract.
a.High Density Approach: In this approach the density of the pellets must exceed that of normal
stomach content and should be at least 1- 4gm/cm3, therefore these pellets would remain in
stomach for a longer period of time. In preparing such formulations drug can be coated on heavy
core like titanium dioxide of iron powder.

b.Low Density Approach: In this approach the density of the pellets should be lower than that
of normal stomach content. e.g., Globular shells which have an apparent density lower than that
of gastric fluid can be used as a carrier of drug for sustained release purpose.

1.12 MATRIX SYSTEM USED FOR CONTROLLED RELEASE OF DRUG

Matrix Systems .

Historically, the most popular drug delivery system is the matrix system because of its
low cost and ease of fabrication. Methods of altering the kinetics of drug release from the
inherent first order behavior especially to achieve a constant rate of drug release from matrix
devices have involved several factors.

1.Hydrophilic matrix system

Drug delivery technologists usually tend to consider all hydrophilic delivery systems,
as hydrogels. Hydrogels are hydrophilic macromolecular networks that after swelling maintain
their shape due to permanent links. The very high water content and special surface
properties of swollen form give them the ability to simulate natural tissues. The most widely
used polymers for drug delivery control, particularly in oral applications are swellable
polymers. Carboxy methyl cellulose sodium, hydroxyl methyl cellulose, polyethylene oxide,
polyvinyl pyrolidone and natural gums can be used as matrix materials. The matrix may be
tableted by direct compression of the blend of active ingredient and certain hydrophilic
carriers or from a wet granulation containing the drug and hydrophilic matrix material. On
immersion in water the hydrophilic matrix quickly forms a gel layer around the tablet. Drug
release is controlled by the gel diffusional barrier and /or tablet erosion.

2.Matrix System: In these systems, the drug is dispersed throughout the three
 19
INTRODUCTION

dimensional structure of the hydrogel. Release occurs due to diffusion of the drug through the
water filled pores.

Figure 1.3: Hydrogel formation in reservoir systems

1.13 MATERIALS USED AS RETARDANTS IN MATRIX TABLET FORMULATIONS

There are different classes of materials used as release retardants in matrix tablet formulations.
They are:

A. Insoluble inert polymers

Tablets prepared from these materials are designed to be ingested intact and not break apart in GI
tract. Ingested tablets contain unreleased drug in the core. For example Polyethylene, poly vinyl
chloride, Ethyl cellulose, Methyl acrylate-methacrylate copolymer.

B. Insoluble, Erodable Polymers

These form materials that control release through both pore diffusion and erosion. Release
characteristics are therefore more sensitive to digest fluid composition than to the totally
insoluble polymer matrix. Total release of drug from wax-lipid matrices is not possible, since a
certain fraction of the dose is coated with impermeable wax films. For example Carnauba wax in
combination with stearic acid, ceto stearyl alcohol, Castor wax & Triglycerides

C. Hydrophilic polymers

This group represents non-digestible materials that form gels in situ. Drug release is controlled
by penetration of water through a gel layer produced by hydration of the polymer and diffusion
of drug through the swollen, hydrated matrix, in addition to erosion of the gelled layer. The
 20
INTRODUCTION

extent to which diffusion or erosion controls release depends on the polymer selected for
formulation as well as on the drug : polymer ratio. For example, methyl cellulose, hydroxyl ethyl
cellulose, hydroxylpropyl methylcellulose, Eudragit, Sodium alginate.

D. Non-cellulose natural or semi-synthetic polymers

Agar-agar; carob gum; alginates; molasses; polysaccharides of mannose and galactose; chitosan
and modified starches.

E. Polymers of acrylic acid

Carbopol 934, the most used variety.

F. Mucoadhesive polymers

Polycarbophil, sodium carboxymethyl cellulose, tragacanth, pectin.

G. Natural gums

Xantham gum, Guar gum, Karaya gum.

1.14 Mechanism of Drug Release from Matrix System

Now a day’s many types of commercial sustained release formulations are available,
none works by a single drug release mechanism. The release of drug from controlled
system is by dissolution or diffusion or a combination of the two mechanisms.

a. Diffusion- controlled systems:

In diffusion- controlled sustained release systems the transport by diffusion of dissolve

drugs in pores filled with gastric or intestinal juice or in a solid (normally polymer) phase is the
release-controlling process. Depending on the part of the release unit in which the drug
diffusion takes place, diffusion controlled release systems are divided into matrix systems
(also referred to as monolithic systems) and reservoir systems. The release unit can be a tablet
or a nearly spherical particle of about 1 mm in diameter (a granule or a millisphere). In both
cases the release unit should stay more or less intact during the course of release profile. In
matrix system diffusion occurs in pores located within the bulk of release unit.
 21
INTRODUCTION

Figure 1.4: Diffusion controlled systems

b. Dissolution Controlled system

A drug with slow dissolution rate will demonstrate sustaining properties, since the
release of the drug will be limited by the rate of dissolution. In principle, it would possible to
prepare sustained release products by decreasing the dissolution rate of drugs that are highly
water-soluble. This can be done by, preparing an appropriate salt or derivative. Coating the drug
with a slowly dissolving material - encapsulation dissolution control. Incorporating the drug into
a tablet with a slowly dissolving carrier - matrix dissolution control (a major disadvantage is
that the drug release rate continuously decreases with time). The dissolution process can be
considered diffusion-layer controlled, where the rate of diffusion from the solid surface to the
bulk solution through an unstirred liquid film is the determining step. The dissolution process at
steady-state is described by the

Noyes-Whitney equation:

dc/dt = kD. A. (CS- C) = D/ h. A. (CS- C)  (11)

c. Erosion-Controlled Systems:

In erosion-controlled extended-release systems the rate of drug release is

controlled by the erosion of a matrix in which the drug is dispersed. The matrix is normally a
tablet, i.e. the matrix is formed by a tabletting operation, and the system can thus be described
as a single-unit system. The erosion in its simplest form can be described as a continuous
liberation of matrix material (both drug and excipients) from the surface of the tablet, i.e
surface erosion. The consequences will be a continuous reduction in tablet weight during the
course of the release process (Fig 1.6).
 22
INTRODUCTION

Figure 1.6: Schematic illustration of the mechanism of drug release from an erosion
tablet.

1.15 MUCOADHESION AND MUCOADHESIVE DRUG DELIVERY SYSTEM:

Mucoadhesion can be defined as the state in which two materials adhere to each other for
extended periods of time with the help of interfacial forces and when one of these materials is
biological in nature, the phenomenon is known as bioadhesion. Longer and Robinson defined the
term bioadhesion as the “attachment of a synthetic or natural macromolecule to mucus and/or
epithelial surface” . The theory of mucoadhesion was introduced in the controlled drug delivery
field in the early phase of the 1980s. This phenomenon has a potential to optimise controlled
drug delivery, in both localized drug delivery by spatial placement within gastrointestinal tract
(GIT) as well as systemic delivery by keeping the formulation in intimate contact with tissue or
cells at absorption site as in the case of nasal and vaginal delivery. Further mucoadhesion has
became an area of interest for the administration of various unstable bioactives including high
molecular weight molecules (proteins and oligonucleotides) via different routes of administration
viz. ocular , nasal, vaginal and buccal which are generally difficult to administer by oral route .
Mucoadhesion phenomenon has shown numerous path-breaking advantages including (i)
prolonged residence time enhances absorption, which results in an increase in the therapeutic
efficacy of the drug, (ii) enormous blood supply and good blood flow rates cause rapid
absorption of the drug, (iii) prevention of first pass metabolism results in increase in drug
bioavailability, (iv) avoidance of drug degradation due to acidic environment in gastrointestinal
tract, (v) ease of drug administration therefore improved patient compliance, and (vi) faster onset
of action due to mucosal surface .. Finally the scientists concluded that these mucoadhesive
systems could serve as promising delivery systems [9]. Bioadhesive/mucoadhesive polymers are
continuously being explored for various drug delivery applications. . Mucoadhesive polymers
 23
INTRODUCTION

have also been investigated in ocular, nasal and buccal delivery of bioactives. Along with
polymers having special characteristics like thermosensitive, pH sensitive, enzyme or chemical
sensitive polymers, mucoadhesive polymers are extensively being investigated for promising
biomedical application which may soon be translated into potential clinical applications
1.16 Mechanistic approaches/theories of mucoadhesion
Since mucoadhesion is being studied for longer duration since the 1980s, a significant
knowledge has been procured. Till date a number of different mechanisms taking place at the
formulation–mucus interface and the properties affecting these mechanisms have been
investigated by scientists. Although mucoadhesion simply defined as the attachment of drug
loaded carrier to the biological membrane, it is a complex . phenomenon and to explain the
included mechanism numerous theories have been proposed. These theories involve wetting,
fracture, electronic interlocking, diffusion, adsorption, and interpenetration of polymers but the
most widely accepted theories include surface energy thermodynamics and
interpenetration/diffusion theories of mucoadhesion.
The different theories involved in mucoadhesion are described below
. 1.16.1 Wetting theory is primarily applied to liquid or low viscosity mucoadhesive systems.
This theory describes the ability of a mucoadhesive polymer to spread on biological surfaces thus
it gives an account of “spreadability” of active drug delivery system. According to this, the
adhesive component when comes in contact with mucosa penetrates surface deformations, get
hardens and attaches to the surfaces due to change in surface and interfacial energies. The
contact angle goniometry techniques are used to determine the affinity of a liquid for a surface to
measure the contact angle of the liquid on the surface based on the principle that the lower the
contact angle, the greater the affinity of the liquid to the solid surface. This process defines the
energy required to counteract the surface tension at the interface between the two surfaces
allowing for a good mucoadhesive spreading and exposure of the biological substrate [21]. Thus,
the contact angle (θ), which is easy to determine experimentally, is related to interfacial tension
(γ), of the mucosa surface and mucoadhesive system as described in
Eqs. (1) and (2): γSG ¼ γSL þ γLG ð1Þ S ¼ γSG–ð Þ γSL−γLG ð2Þ
where γLG, γSL, and γSG are surface tension at liquid–gas, solid–liquid
 24
INTRODUCTION

and solid–gas interface, respectively . Bioadhesive systems reveal structure and functional
groups havingaffinity to mucosal surface and hence show improved miscibility; that results in a
greater degree of polymer spreadability across the mucosalsurface.
1.16.2. Adsorption theory
Based on the adsorption theory, Ahuja et al. established two types ofchemical bonds for adhesive
interactions i.e. hydrogen bond and van derWaals' forces. After an initial contact amongst inter-
surfaces; themucoadhesive substance adheres due to the surface forces acting between the
molecules of two surfaces. According to the chemisorptions theory, interaction across the
interface occurs as a result of strong covalent bonding .
1.16.3 Electronic theory
Different surfaces have different structural properties and electronicstructures. This theory is
transfer between polymbased on electronic differences in structure; it describes that bonding
occurs due to electron eric system and the mucus membrane epithelium. As a result of this a
bilayer of electronic charges formed at the mucus and mucoadhesive systeminterface as shown in
. Ultimately this is responsible for the formation of attractive force amongst the two surfaces via
electronic double layer .
1.16.4 Fracture theory
According to this theory, the adhesive bonds between systems arerelated to the force required to
separate both surfaces fromone another.This “fracture theory” relates the force for polymer
detachment from the mucus to the strength of their adhesive bond. The work fracture has been
found to be greater when the polymer network strands are longer or the degree of cross-linking
within system is reduced. This theory allows the determination of fracture strength (σ) following
the separation of two surfaces via its relationship to Young's modulus ofelasticity (E), the
fracture energy (ɛ) and the critical crack length(L) through following equation

1.16.5 Diffusion interlocking theory

This theory proposes the time-dependent diffusion of mucoadhesive polymer chains into the
glycoprotein chain network of the mucus layer. This is a two-way diffusion process with
penetration rate being dependentupon the diffusion coefficients of both interacting
polymers.Although there are many factors involved in such processes, the basic properties that
 25
INTRODUCTION

significantly influence this diffusion are molecular weight, cross-linking density, chain
mobility/flexibility, expansion capacity of both networks and temperature (as important
environmental factor). Although it is recognised that long chain polymer may diffuse,
interpenetrate and ultimately enmesh to a greater extent with mucus surface, yet to get sufficient
interpenetration and molecular entanglement it is documented that a critical chain length of
atleast 100 kDa is required.The time (t) for maximum adhesion between two substrates during
interpenetration has been supported by experimental evidence in recent studies including FTIR
and rheological techniques, and may be determined using the depth of interpenetration (L), and
the diffusion coefficient (Db) t ¼ L2=Db: ð4Þ
1.16.5 Mechanical theory
The mechanical theory considers adhesion due to the filling of irregularities on a rough surface
by amucoadhesive liquid. Additionally, such irregularity increases the interfacial area available
for interactions and can be considered the most important phenomenon of the process.
1.17 Factors affecting of Mucoadhesion.
The adhesive bond between a bio-adhesive system and mucin gel can be investigated in term of
contribution of the following factors
 Molecular weight- The molecular weight of the polymer increases with the
mucoadhesivness of polymers.

 Chain length- With the increase in the chain length of the polymers there is an increase
in the mucoadhesive property of the polymer.

 Spatial arrangement- spatial conformation of a molecule is also important factor. The

helical conformation of dextran may shield many adhesively active groups, primarily
responsible for adhesion, unlike PEG polymers, which have a linear conformation.[12]
Flexibility- Flexible polymer chains helps in the better penetration and entanglement of the
polymer chains with that of mucosal layer thereby improving the bio-adhesive property.
The flexibility of the polymer chains is generally affected by the cross-linking reactions and
the hydration of the polymer network. Higher the cross-linking density, lower is the
flexibility of the polymer chains.
 26
INTRODUCTION

1.18 Mucoadhesive polymers

are water-soluble and water insoluble polymers. Mucoadhesive polymers that adhere to the
mucin-epithelial surface can be conveniently divided into three broad classes.[8]
 Polymers that become sticky when placed in water and owe their mucoadhesion to
stickiness.
 Polymers that adhere through nonspecific, non-covalent interactions those are primarily
electrostatic in nature (although hydrogen and hydrophobic bonding may be significant).
Polymers that bind to specific receptor site on tile sel
 Hydration of polymer- In addition to the reduced flexibility of the polymer chains, cross-
linking results in the reduced diffusion of water into the cross-linked polymer matrix.
Hence highly cross-linked polymeric matrix limits the interpenetration of polymer and
mucin chains amongst themselves which in turn results in the decrease in the
mucoadhesive strength.

 Hydrogen bonding- In general, stronger the hydrogen bonding stronger is the adhesion.
The functional groups responsible for such kind of interaction include hydroxyl,
carboxyl and amino groups.
 Charge and degree of ionization of polymer- The presence of charged functional groups
in the polymer chain has a marked effect on the strength of the bio-adhesion. Anionic
poly-electrolytes have been found to form stronger adhesion when compared with
neutral polymers.
 Polymer concentration- In general, polymer concentration in the range of 1-2.5% weight
may exhibit sufficient mucoadhesive property for biomedical applications.

An ideal mucoadhesive polymer has the following characteristic:

1.They should be nontoxic and should be non-absorbable from the gastrointestinal tract.

2. It should be nonirritant to the mucous membrane.

3.It should preferably form a strong non-covalent bond with the mucin-epithelial cell surfaces.
 27
INTRODUCTION

4.It should adhere quickly to most tissue and should possess some site-specificity.

5.It should allow daily incorporation to the drug and offer no hindrance to its release.

6.The polymer must not decompose on storage or during the shelf life of sthe dosage form

1.19 CLASSIFICATION OF MUCOADHESIVE POLYMERS

1. Origin based

(a) Synthetic polymers: Synthetic polymers are human-made polymers. They can be classified
into four main categories: thermoplastics, thermosets, elastomers, and synthetic fibers.
Examples: Polyhydroxyethy methylacrylate, poly vinyl pyrrolidone, poly vinyl alcohol, cellulose
derivatives, poly acrylic acid polymers,
(b) Natural polymers: Natural polymers occur in nature and its can be extracted. These are
basically polysaccharides. They are water soluble and water insoluble. some of the Natural
polymers are discussed below-

1.20 NATURAL POLYMERS: In recent years, there has been a tremendous development in
natural products which are needed to be used for a variety of purposes. Nature has provided us a
wide variety of materials to help improve and sustain the health of all living things. A Polymer is
a large macromolecule composed of many repeated subunits. Polymers are of two types,
Synthetic and Natural polymers. Natural polymers occur widely in nature and can be extracted.
These are basically polysaccharides. They are water soluble and water insoluble. Natural
polymers have been used as pharmaceutical excipients. They are biocompatible without any side
effect, Various Natural polymers for example Guar gum, Okara gum, Locust bean gum, Pectin,
Amylose, Chitosan, Alginate, Xanthan gum, are used in various pharmaceutical formulations.
They serve as a potential candidate for novel drug delivery system (NDDS). Synthetic polymers
are human made polymers, for examples of synthetic polymers include Polythene, Polyester,
epoxy, etc. Natural polymers offers various advantages such as non-toxicity, less cost, easy
availability and chemically inert. This review provides insight into the natural polymers used for
the formulation of mucoadhesive drug delivery systems
Advantages of Natural polymers
1. All natural polymer should be Biodegradable
 28
INTRODUCTION

2. They are Biocompatible as well as non-toxic.

3. They must be Economic.

4. Safe and devoid of side effects.

5. Easy availability is also one of the advantages of natural polymer.

Disadvantages of Natural polymers

1. Microbial contamination.

2. Batch to batch variation.

3. The Uncontrolled rate of hydration.

4. Slow Process.

5. Heavy metal contamination. .

1.21.Mucoadhesion evaluation methods
To develop a new mucoadhesive drug delivery system the evaluation of its mucoadhesive
property is quite important. Mucoadhesive polymers can be characterised by testing their
adhesion strength by in vitro and in vivo tests. These tests are necessary for screening many
candidates for mucoadhesive systems and to study their mechanisms .In vitro tests were initially
considered to monitor potential mucoadhesives with a view to conduct in vivo testing, if
successful. Currently, more stress is being placed on elucidating the mechanisms of
mucoadhesion as an evaluation of mucoadhesive properties for the design of innovative
mucoadhesives. The most commonly employed in vitro tests are tensile strength test, shear
strength test, peel strength test, in vitro retention time, mucoadhesive force measurement and
rheological methods. The various methods have been developed and reported are as follows.
1.21.1. Tensile strength test
Many of the tensile strength testing machines were investigated for the measurement of
mucoadhesive strengths in which sample of an aqueous dispersion of a mucoadhesive polymer
was placed between two discs of POM (polyoxymerhylene). The upper disc is generally made up
of movable part whereas the lower disc is fixed on stationary frame of machine. Then tensile
force could be applied and maximum force required in detaching next to fracture and adhesion
 29
INTRODUCTION

work can be determined via force displacement curve. Tensile strength is the strength required to
detach the mucoadhesive cups perpendicularly from freshly excised bovine buccalmucosa . In
this test stress is uniformly distributed all over the mucoadhesive joint. In a study, the large
intestine mucus membrane of pig was attached to upper movable disc. Polymers were used in
different concentrations (carbopol EX-55, carbopol 934P, HPMC/Mythical K4M and sod.
alginate). After determining the maximum force and work to detach, it was concluded that the
tensile strength was dependent on the concentration as well as the type of polymer used
Hagerstromand Edsman reported a newtechnique for the measurement of tensile strength based
on determination of mucoadhesive properties of polymer gels using freshly excised porcine nasal
mucosa and a texture analyser. Model polymers like sodium CMC, PAA and sodium hyaluronate
and a cross-linked polymer PAA were used and found that there was no dependence of the
results on the contact time in the interval 2–20 min whereas the tensile work originated is more
applicable than the fracture strength for the interpretation of mucoadhesive properties .
1.21.2 Shear strength test
The shear strength of the adhesive cups and the force necessary for parallel detachment from
freshly excised bovine buccal mucosa were determined by Metia and Bandyopadhyay using
particularly designed apparatus . The mucoadhesive cup was fixed to a movable plastic strip by
synthetic polymer. The other side of the cup was pressed over excised bovine buccalmucosa for
30 s applying constant pressure. After 5 min, the weight required to detach the adhesive cup from
the mucosa was recorded using following formula. Force of adhesion ðNÞ ¼ Weight ðgÞ=1000
_ 9:81. Bond strength N=m2¼ Force of adhesion ðNÞ=Surface area of cup m2
1.21.3 Peel strength test
Peel strength is the amount of force or energy required for tangential detachment of
mucoadhesive formulation (cups) from freshly excised bovine buccal mucosa The test has shown
limited use for mucoadhesive formulations. However, for the patches it is of great value. The
stress in this test is mainly focused at the edge of adhesive system.
The tensile strength and shear strength tests have been used to determine mechanical property of
the developed mucoadhesive formulations, while peel strength test determines resistance towards
the peeling force. From the literature it is clear that the most commonly
used mucoadhesive evaluation method is the tensile strength test.
1.21.4 In vitro retention time
 30
INTRODUCTION

The in vitro retention time is one of the most important physical parameters for the evaluation of
amucoadhesive cup. Amucoadhesive cup was pressed over the excised bovine buccal mucosa for
30 s after previously being secured on a glass slab and was immersed in a beaker containing
500ml of isotonic phosphate buffer (pH 6.6) at 37 ± 0.2 °C. A stirrer was fitted at a distance of
5cm from the assembly and rotated at 25 rpm and the time for complete erosion or detachment of
the formulation from the mucosa was recorded .
1.21.5 Ex vivo mucoadhesion time
A mucoadhesive patchwas used to studymucoadhesive time. Phosphate buffer pH 6.6 (800 ml)
was used as disintegrationmedium maintained at 37 °C. Porcine check mucosa, 3 cm long, was
attached to the surface of a glass slab which was vertically attached to the apparatus. The patch
was then hydrated from one surface using 15 μl phosphate buffer and then itwas brought into
contactwith themucosal membrane . The apparatuswas allowed tomove up and down to immerse
the patch completely in the buffer solution. The time required for complete detachment of the
patch from the mucosal surface was recorded

1.21.6. Mucoadhesive force determination

A tensile tester (Rheometric Scientific Inc., UK)was used to measure themucoadhesive force of
the adhesive polymeric systems using a plastic (PVC) plate. Polymeric films and plastic plates
were cut with the predetermined area (1 cm2, thickness of 0.8mm) and the film was wetted with
water and positioned over the surface of the plastic plate. It was kept in contact with the plate
under the force of finger tip for 2 min before the measurement. The peak force required to detach
the film from the plastic plate was measured .
1.21.7.In vivo mucoadhesion study
In the literature there is shortage of in vivo study reports, which might be due to cost, time and
ethical concerns. The in vivo performance of amucoadhesive formulation not only depends on
themechanisms taking place at the interface, but also on the properties of the whole
mucoadhesive composite such as the dosage form, the mucosa and the interface linking them.
Wistar rats were used for in vivo study. Rats were fasted for 24 h and then divided into eleven
groups at random. Each group consisted of six rats. Five groups of rats were administered orally
with hundred particles of mucoadhesive microspheres. After administration, the ratswere kept
fasted until theywere sacrificed by cervical displacement after 2 h. The remaining six groups
 31
INTRODUCTION

were administered with hundred particles of microspheres (ACVms or ACV-ad-ms) and

sacrificed after 2 h, 4 h, and 6 h. The stomachs and small intestine mucosa were removed.
Themicrospheres that remained in the GIT were counted, and the percentage of remaining
microspheres was calculated.
 LITERATURE REVIEW

CHAPTER-2

2.1 LITERATURE REVIEW:

2.1.1 A LITERATURE REVIEW ON MUCOADHESIVE TABLETS: 1.Rahamatullah

Shaikh, Thakur Raghu Raj Singh,et.al, Mucoadhesion is commonly defined as the adhesion
between two materials, at least one of which is a mucosal surface. Over the past few decades,
mucosal drug delivery has received a great deal of attention.Mucoadhesive dosage forms may be
designed to enable prolonged retention at the site of application, providing a controlled rate of
drug release for improved therapeutic outcome. Application of dosage forms to mucosal surfaces
may be of benefit to drug molecules not amenable to the oral route, such as those that undergo
acid degradation or extensive first-pass metabolism. The mucoadhesive ability of a dosage form
is dependentupon a variety of factors, including the nature of the mucosal tissue and the
physicochemical properties of the polymeric formulation. This review article aims to provide an
overview of the various aspects of mucoadhesion, mucoadhesive materials, factors affecting
mucoadhesion, evaluating methods, and finally various mucoadhesive drug delivery systems
(buccal, nasal, ocular, gastro, vaginal, and rectal).

2. Goswami Dhruba Sankar, Goyal Sandeep ,et.al, Famotidine is a histamine H2-receptor

antagonist. It is widely prescribed in active duodenal ulcers, gastric ulcers, Zollinger-Ellison
syndrome, gastroesophageal reflux disease, and erosive esophagitis. The effective treatment of
erosive esophagitis requires administration of 20 mg of Famotidine 4 times a day. a conventional
dose of 20 mg can inhibit gastric acid secretion up to 5 hours but not up to 10 hours. An
alternative dose of 40 mg leads to plasma fluctuations; thus a sustained release dosage form of
famotidine is desirable. The short biological half-life of drug (2.5-4 hours) also favors
development of a sustained release formulation. The present study aims to reduce the dosing
frequency by using single and combinations of synthetic and natural polymers for preparation of
mucoadhesive tablets. Various approaches to combine synthetic (HPMC-K4M, SCMC and
sodium alginate) and natural (tragacanth and acacia) hydrophilic polymers have been made to
prepare total eight formulations. Further, these formulations were subjected to different
evaluation studies like friability, content uniformity, surface pH, wash-off and dissolution tests.
All the tests were performed using standard methods. Results for in vitro drug release and wash-
off studies suggest that the formulation (FHT) containing HPMC-K4M and tragacanth has shown
better mucoadhesive property. Other studies have shown satisfactory results in all eight
formulations. Thus, the present investigation suggests the combination of HPMC-K4M and
tragacanth, as hydrophilic polymers for preparation of famotidine mucoadhesive tablets.

3. Remeth Jacky Diasa, Sfurti Shamling Sakhare,et.al, The purpose of this study was to
design and optimize an oral controlled release acyclovir mucoadhesive tablet, in term of its drug
release and mucoadhesive strength. A 32 full factorial
design was employed to study the effect of independent variables like Carbopol-934P and
swelling index, ex-vivo mucoadhesive strength and in-vitro drug release. Tablets were prepared
 LITERATURE REVIEW

by direct compression and evaluated for mucoadhesive strength and in-vitro dissolution
parameters. In all the nine formulations studied, the exponent (n) varied between 0.5266 and
relaxation, resulting in a controlled and complete drug release up to 12 h. Both these polymers
force of detachment against sheep gastric mucosa. Besides unraveling the effect of the two with
excellent mucoadhesive strength and controlled drug release. It can be concluded that by
formulating mucoadhesive tablets of acyclovir, its complete release can be ensured prior to
absorption window and hence the problem of incomplete drug release and erratic absorption
could be solved by increasing the retention of drug in GIT for a longer duration.
4.Anup Kumar Roy, Vinod kumar sm,et.al, The main aim of this work was to formulate and
study mucoadhesive buccal tablets of Valsartan using various suitable bioadhesive polymers
such as CP 934, HPMC K4M, and Na CMC. A backing layer of ethyl cellulose was used which
is impermeable in nature. Six formulations of Valsartan were prepared by direct compression
method. The prepared tablets were characterized by swelling studies, % matrix erosion, surface
pH, bioadhesive properties, In-vitro drug dissolution and In-vitro diffusion studies. It was found
that swelling index was proportional to CP and Na CMC content. As the Na CMC content
increases the swelling index also increased. The surface pH of all formulations was found to be
satisfactory,and values were in between the range of 5-7 pH, hence no irritation to buccal cavity
is assumed. Tablets containing CP: HPMC in the ratio 1:3 has shown maximum percentage of
In-vitro drug release as well as In-vivo diffusion through buccal mucosa. The drug release was
found to be zero order release. The formulation F3 was considered as the optimized formulation
based on satisfactory bioadhesive strength, In-vitro dissolution drug release of 59.69 ± 0.95%,
In-vitro drug diffusion of 43.66 ± 0.68% for 8 h.
5.Katta. Manogna, P. Nagaveni,et.al,Mucoadhesive drug delivery systems interact with the
mucus layer covering the mucosal epithelial surface, and mucin molecules increase the residence
time of the dosage form at the site of absorption. Bioadhesion may be defined as the state in
which two materials, at least one of which is of a biological nature, are held together for extend
periods of time by interfacial forces Mucosal layer represents potential sites for the attachment of
any bioadhesive systems because mucosal layer lines number of the body including the gastro
intestinal tract, the urogenital tract, vaginal tract, the eye, ear, and nose. The mucoadhesive
Bilayer tablets consisting of two various types of drug molecules and they show on set of actions
at their particular sites. This review describes the
structure of mucosal layer, mechanism of action of mucoadhesion, and preparation techniques of
bilayer tablets and evaluation parameters of tablets.
6.Murali Krishna.B, Praveen Kumar Uppala,et.al, The present study involves formulation
and evaluation of buccal tablets of Linagliptin, an antidiabetic drug belonging to class of drugs
that inhibit the enzyme, dipeptidyl peptidase-4
(DPP-4) and has high first pass metabolism. Buccal drug delivery has been considered an
alternative to the oral dosing for compound subjected to degradation in the gastrointestinal tract
or to first pass metabolism. Here in an attempt has been
 LITERATURE REVIEW

made to develop mucoadhesive buccal tablets comprising of drug, mucoadhesive layers and drug
free backing layer of ethyl cellulose to release the drug for extended period of time while
reducing the dosing frequency, dose related side effects and improving the bioavailability of
drug. Tablets of Linagliptin
were prepared by direct compression using mucoadhesive polymers Carbopol 934-P and HPMC
K4M, Hydroxy ethyl cellulose. Buccal tablets were evaluated by different parameters such as
thickness, hardness, and weight uniformity, content
uniformity, swelling index, surface pH, in vitro drug release, in vitro drug permeation and FTIR
studies. All the formulations followed Fickian release mechanism. The overall results indicated
that the polymers API and Carbopol 934 in the ratio of 1: 6 showed satisfactory mucoadhesive
properties. The optimized formulation also showed satisfactory surface pH and physical
parameters, effective in vitro permeation, satisfactory stability in human saliva.
7.Yuri Ikeuchi-Takahashi, Naoko Watanabe,et.al, Context: Nonsteroidal anti-inflammatory
drugs (NSAIDs) are administered for pain relief from oral mucositis. However, the systemic
administration of NSAIDs is limited due to the side effects of thrombocytopenia.Objective: To
avoid systemic side effects, a matrix type mucoadhesive tablet as a topical application
preparation to treat oral aphtha was developed. Methods: A mixture of hard fat with a low irritant
property and mucoadhesive polymers was used as the matrix base, and indomethacin was used as
a model drug. Results: Among the water-soluble polymers, carbopol and xanthan gum increased
the adhesive force of tablets prepared by the suspending method, but the tensile strength was not
increased. Tablets containing ethylcellulose10 or 45 (EC10, EC45) from a water-insoluble
polymer increased the adhesive force and tensile strength. Tablets prepared by the dissolve-
drying method containing EC45 showed a 1.8-fold increase of adhesiveness to the eggshell
membrane compared with hard fat tablets, and showed a sustained release of the drug (17%) over
an 8 h period. The drug release was increased to 28% by a modification to the dissolve-drying
method using EC10.
Conclusions: Since this matrix type tablet has long-acting properties, adhesiveness and low
irritating properties, its potential as a newly designed preparation to treat oral aphtha is
suggested.
8. Swati Mittal,et.al, Drug delivery via buccal route using mucoadhesive dosage forms offers a
novel route that can improve bioavailability of many drugs. Pantoprazole sodium is a proton
pump inhibitor indicated for erosive esophagitis associated with gastroesophageal reflux disease
(GERD). It is completely absorbed after oral administration, has short half life and low
bioavailability because of first pass metabolism. It is a suitable candidate for administration via
buccal route. Materials and methods: Various synthetic and natural bioadhesive polymers were
studied for suitability as mucoadhesive buccal delivery. Bilayer mucoadhesive buccal tablets
were prepared by direct compression. The tablets were evaluated for in vitro drug dissolution and
ex vivo mucoadhesion. Results: Hydroxyl propyl methyl cellulose and sodium alginate were
found to be most suitable mucoadhesive polymers. Drug release and ex vivo mucoadhesion was
observed for 8 hours.
 LITERATURE REVIEW

9.Shakir Mansuri , Prashant Kesharwani,et.al, Mucoadhesion, the state in which two

materials, amongst which one is biological in nature, adhere to each otherfor extended periods of
time with the help of interfacial forces, provides an attractive strategy to overcome the hurdles of
conventional drug delivery systems including first pass metabolism, and localized delivery of
biomolecules including proteins, peptides and oligonucleotides. Mucoadhesion provides great
opportunities for the delivery of a variety of compounds via different routes of administration
viz. ocular, nasal, vaginal and buccal. In addition mucoadhesion also makes it possible to obtain
prolonged, local or systemic drug action. In this review we discussed about potential applications
of mucoadhesion and mucoadhesive polymers in drug delivery along with the mechanism of
mucoadhesion and the methods for evaluation of mucoadhesive drug delivery systems.
10.Deepak Sharma, Mankaran Singh,et.al, Mucoadhesion is a field of current interest in the
design of drug delivery systems. Mucoadhesion is commonly defined as the adhesion between
two materials, at least one of which is a mucosal surface. Mucoadhesive drug delivery system
may be designed to enable prolonged residence time of the dosage form at the site of application
or absorption and facilitate an intimate contact of the dosage form with the underline absorption
surface. Extending the residence time of a dosage form at a particular site and controlling the
release of drug from the dosage form are useful especially for achieving controlled plasma level
of the drug as well as improving bioavailability. Application of these dosage forms to mucosal
surfaces may be of benefit to drug molecules not amenable to the oral route, such as those that
undergo acid degradation or extensive first-pass metabolism. The present review describes
mucoadhesion, mucoadhesive polymers and use of these polymers in designing different types of
mucoadhesive gastrointestinal, nasal, ocular, vaginal and rectal drug delivery systems. The
research on mucoadhesives, however, is still in its early stage, and further advances need to be
made for the successful translation of the concept into practical application in controlled drug
delivery.
11.Luana Perioli , Valeria Ambrogi,et.al, The aim of this work was the realization of new
formulations for vaginal application to improve the pharmacological effect of benzydamine,
displaying both anti-inflammatory and antiseptic activities. For
this reasons, this drug was formulated in solid dispersions, by using the mucoadhesive polymers
HPMC and/or Carbopol®, then compressed. Tablets were characterized by studies of friability,
hardness, hydration,DSC, mucoadhesion and in vitro release. Kinetics, responsible for drug
delivery, was investigated as
well.Tablets prepared by using only HPMC showed the best results in terms of swelling and
mucoadhesion(time and force) together with prolonged and complete drug release, by diffusive
mechanism, through gelled layer. Despite the good mucoadhesive properties, Carbopol® does
not represent a good excipient
because, after the contact with water, it generates a spongy gel layer, not homogeneous, stif,
brittle and with breaking tendency when highly swelled. This kind of gel does not guarantee a
linear drug release and could provoke discomfort because of fragment release. HPMC
 LITERATURE REVIEW

mucoadhesive tablets could be a proper delivery system for benzydamine administration

representing a good alternative to traditional dosage forms for vaginal topical therapy.
12. K.L. Deepthi, V. Mercy Pourna Chandra,et.al,
The main aim of present study is gastroretentive delivery systems of Norfloxacin was
successfully developed in the form of hydro dynamically balanced tablets to improve the local
action and its bioavailability, which reduces the wastage of drug and ultimately improves the
solubility for drugs that are less soluble in high pH environment. Norfloxacin can be developed
to increase gastric residence time and thereby increasing its bioavailability. Norfloxacin floating
tablets were prepared by using HPMCK4M, HPMC K15M, Carbopol 934P polymers with
excipients-sodium bicarbonate and lactose. The prepared formulation can be used to perform in-
vivo studies in animals. The floating tablets were evaluated by various physicochemical
parameters like hardness, friability, thickness, weight variation and content uniformity.

2.1.2 A LIERATURE REVIEW ON MUCOADHESIVE POLYMERS:

13.Flavia Laffleur,et.al, Raising the concept of mucoadhesion in the 1980s, the use of
mucoadhesive polymers for buccal drug delivery has been the subject of interest. Buccal route is
one of the non-invasive routes comprising several advantages such as targeting the specific tissue
(I), bypassing the first-pass effect (II) as well as higher patient compliance (III) and higher
bioavailability (IV) have rendered administration route feasible for a variety of drugs. This
review highlights the use of mucoadhesive polymers in buccal drug delivery. An overview of the
oral mucosa’s anatomy, theories of mucoadhesion as well as mucoadhesive polymers is given
within this review. Furthermore, recent advantages in mucoadhesive polymers according to the
variety of drug delivery forms are presented.
14. Suhel Khan, Nayyar Parvez,et.al, In recent years, there has been a tremendous
development in natural products which are needed to be used for a variety of purposes. Nature
has provided us a wide variety of materials to help improve and sustain the health of all living
things. A Polymer is a large macromolecule composed of many repeated subunits. Polymers are
of two types, Synthetic and Natural polymers. Natural polymers occur widely in nature and can
be extracted. These are basically polysaccharides. They are water soluble and water insoluble.
Natural polymers have been used as pharmaceutical excipients. They are biocompatible without
any side effect, Various Natural polymers for example Guar gum, Okara gum, Locust bean gum,
Pectin, Amylose, Chitosan, Alginate, Xanthan gum, are used in various pharmaceutical
formulations. They serve as a potential candidate for novel drug delivery system (NDDS).
Synthetic polymers are human made polymers, for examples of synthetic polymers include
Polythene, Polyester, epoxy, etc. Natural polymers offers various advantages such as non-
toxicity, less cost, easy availability and chemically inert. This review provides insight into the
natural polymers used for the formulation of mucoadhesive drug delivery systems.
15.Nazila Salamat-Miller, Montakarn Chittchang,et.al, Buccal delivery of the desired drug
using mucoadhesive polymers has been the subject of interest since the early 1980s. Advantages
associated with buccal drug delivery have rendered this route of administration useful for a
 LITERATURE REVIEW

variety of drugs. This review highlights the use of mucoadhesive polymers in buccal drug
delivery. Starting with a review of the oral mucosa, mechanism of drug permeation, and
characteristics of the desired polymers, this article then proceeds to cover the theories behind the
adhesion of bioadhesive polymers to the mucosal epithelium. Additionally, we focus on the new
generation of mucoadhesive polymers such as thiolated polymers, followed by the recent
mucoadhesive formulations for buccal drug delivery.
16. HAKON H. SIGURDSSON, ELIN KNUDSEN,et.al, in this study the interactions between
a cationic polymer and an anionic cyclodextrin were investigated. The system has the potential
for use in a sustained release dosage forms for use on mucous membranes. As mucous
membranes are negatively charged the objective of this study was to investigate whether a drug
delivery system based on a cationic polymer and an anionic cyclodextrin would be more
mucoadhesive than a system containing a cationic polymer and a neutral cyclodextrin. For this
purpose the cationic polymer hexadimethrine bromide (HDMBr) and anionic sulfobutylether β-
cyclodextrin (SBEβCD) were utilized as well as the neutral hydroxypropyl β-cyclodextrin
(HPβCD). Triclosan was used as a model drug. The drug delivery system was formulated as a
solution or semi-solid and its adhesion to porcine buccal mucosa and cation exchange media was
measured. In addition the release of triclosan from the system was quantified. No difference was
observed between the two systems when they were applied to the mucosal surface. However, the
formulations showed improved adhesion, compared to the neutral cyclodextrin/drug delivery
system, when they could also reach the underlyingsurface of the excised tissue. The drug
delivery system was much better retained on the cation exchange media than the uncharged
system. Significant interactions were observed between the negatively charged cyclodextrin and
the positively charged polymer. The results indicate that the interactions could be used to obtain
a mucoadhesive sustained drug delivery system under certain circumstances. The positive charge
of HDMBr did not have the expected effect on the buccal mucosa and it can be concluded that
although a positive charge is likely to promote mucoadhesion, other attributes of polymers, such
as molecular weight and viscosity, may have equally beneficial effect.
17. Rakesh Kumar Meel,et.al, The present research work endeavor is directed towards
formulation, development and evaluation of sustained release matrix tablet of glipizide using
Sodium stearyl fumarate as a matrix forming agent. Which is used as a lubricant but due to its
both hydrophilic & hydrophobic properties, it can be used as a matrix forming agent. On the
basis of this we tried to develop a sustained release matrix tablet using different pH dependent
substances like tartaric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate,
trisodium hydrogen phosphate and glipizide as a model drug. Nine formulations (F1-F9) of
glipizide were prepared by wet granulation method. The formulations were evaluated for various
pre compression and post compression parameters also in vitro release studies were carried out in
7.4 pH phosphate buffer using the USP Type 2 apparatus as per USP monograph. F6, F7, F8, F9
formulations were prepared by using different pH dependent substance like tartaric acid, sodium
dihydrogen phosphate, disodium hydrogen phosphate and trisodium hydrogen phosphate
respectively. Optimized formulation F7 prepared by using sodium dihydrogen phosphate
 LITERATURE REVIEW

exhibited best sustained release pattern among all formulations. The dissolution data and drug
contain was found to be maximum in F7 formulation as 42.85%, 59.27%, 76.21% and 92.78% at
1 hour, 3 hour, 6 hour and 10 hour respectively.
18.Satish Patil1 and Gokul S,et.al, Lafutidine a newly developed histamine H2-receptor
antagonist having biological half-life of 1.92 ± 0.94 h due to its selective absorption from upper
part of gastrointestinal tract the development of mucoadhesive sustained release drug delivery
system is recommended in order to enhance the bioavailability. A mucoadhesive tablets was
developed using the natural polymer, sodium alginate, xanthan gum and karaya gum.
Mucoadhesion is a complex phenomenon which involves wetting, adsorption and
interpenetration of polymer chains. The prepared tablets of various formulations were evaluated
for a total mucoadhesion time, buoyancy lag time and percentage drug released. The formulation
with xanthan gum showed better results. Thus, it may be useful for prolonged drug release in
stomach to improve the bioavailability and reduced dosing frequency. Non-fickians release
transport was confirmed as the drug release mechanism from the optimized formulation by
Korsmeyer–Peppas. The optimized formulation (B3) showed a mucoadhesive strength 435 g. In
vivo study was performed using rabbits by X-ray imaging technique. Radiological evidences
suggest that, a formulated tablet was well adhered for 410 h in rabbit’s stomach. Optimized
lafutidine mucoadhesive tablets showed no significant change in physical appearance, drug
content, mucoadhesive properties and in vitro dissolution pattern after storage at 40 _C
temperature 75 ± 5% relative humidity for 3 months.
19.Francesco Cilurzo , Chiara G.M. Gennari ,et.al, The work aimed at studying a new
mucoadhesive prolonged release tablet containing 24 lg clobetasol-17 propionate (CP) suitable
for the management of oral lichen planus. Low swellable dosage forms were designed by
combining a mucoadhesive polymer, i.e. poly(sodium methacrylate, methylmethacrylate),
with hydroxypropylmethylcellulose and MgCl2. This formulation was selected to modify the
tablet erosion rate in order to obtain a release of CP over a 6-h period. A double-blind, controlled
study was performed using three groups of patient (n = 16) who received three applications-a-
day over 4 weeks of the developed CP tablets (group CP-T), placebo tablets (group CP-P) or
commercial CP ointment for cutaneous application (123 lg/application) extemporary mixed with
Orabase™ (group CP-O). At the end of the study, pain and ulceration resolved in 13/16 and
11/16 patients of group CP-T and group CP-O, respectively. In the group CP-O, a transient acute
hyperaemic candidosis (n = 2) and taste alteration (n = 4) were also observed. No changes in
clinical signs of patients in the group CP-P were evident. The application of mucoadhesive tablet
containing 24 lg CP 3 times a day appeared to be effective, avoiding the side effects
of the generally used treatment.
20.Raphaela Regina de Araújo Pereira,et.al, The vaginal mucosal cavity is a feasible, safe,
very attractive site for drug delivery and highly dynamic with
respect to absorption of drugs, their metabolism and their elimination. Compared with other
mucosal application sites, the vagina has the following advantages as, a fall in the incidence and
severity of gastrointestinal side effects, avoidance of the inconvenience caused by pain, tissue
 LITERATURE REVIEW

damage and risk of infections which are associated with parenteral routes, ease of self-insertion
and removal of the dosage form is possible. In addition, a prolonged contact of a delivery system
with the vaginal mucosa may be achieved more easily than at other absorption sites like rectum
or intestinal mucosa. Mucoadhesive systems provide intimate contact between a dosage form and
the vaginal mucosa, which may result in high concentration in a local area and hence high drug
flux through the vaginal mucosa. The efficacy of vaginal mucoadhesive drug delivery systems
(DDS) is affected by the biological environment and the properties of the polymer and the drug.
A 2.1.3LITERATURE REVIEW USING NATURAL POLYSACCHARIDES:
21.Chaithanya Krishna Mylangam, Sudhakar Beeravelli,et.al, Applicability of natural
polymers in pharmaceutical drug delivery. Objective: The objective of the present investigation
was to evaluate the applicability of badamgum (BG) obtained from Terminalia catappa LINN,
to the family combretaceae as a buccoadhesive polymer using metoprolol succinate as a model
drug. Methods: Tablets were prepared by wet granulation technique. Compression coating
technique was employed for the preparation of unidirectional release buccal tablets using
cellulose acetate as an impermeable backing layer. Results: Muco/buccoadhesive properties of
the BG were increased with the increase in the concentration of polymer which was evident form
the detachment force measurement, ex vivo residence time, and swelling studies. MBG 2 was
found to be the optimized formulation based on drug dissolution studies and bioadhesion studies.
FTIR and DSC studies performed on the optimized formulation indicated no drug–polymer
interaction. MBG 2 was found to be stable after accelerated stability testing for 6 months as per
ICH guidelines. Pharmacokinetic studies of the optimized formulation were performed in six
healthy human volunteers in comparison with that of the commercial extended release oral tablet
GUDPRESS XL-25 by estimating pharmacokinetic parameters and mean residence time (MRT).
It was found that there is a significant increase in the bioavailability of metoprolol succinate
from BG formulation which was evident from the high AUC and MRT values compared with the
commercial formulation. Conclusion: The above results clearly indicated that badam gum can be
used as a mucoadhesive polymer for buccal drug delivery.
22. Nishad K. M,et.al,

The present investigation was to formulate controlled release of mucoadhesive tablets. The
tablets were formulated by using clarithromycin as drug. Which is a semi synthetic macrolide
antibiotic for the treatment of H. pylori infection in peptic ulcer. The releases of drug were
controlled by polymers of natural polysaccharide like chitosan and tamarind seed polysaccharide.
which is isolated from the seeds of Tamarindus indica. The combined form of these polymers
with drug was formulated to once daily controlled release mucoadhesive tablets. The excipients
were subjected to preformulation studies including FTIR compatibility studies. The tablets were
evaluated for in-process and in-vitro studies. The biosdhesive strength of tablets and polymers
were determined by different ex-vivo methods via HPMC K-100 comparitative study. The
selected formulations were subjected to stability studies. The study concluded that combination
 LITERATURE REVIEW

of chitosan and TSP is best natural polymer for mucoadhesion by the advantages of controlled
release and biodegradation.

23. Gore Meghana Milind , Gurav Yogesh,et.al,Propranolol is beta-blocker and it is widely

used in the management of hypertension. Propranolol is used to treat tremors angina,
hypertension, heart rhythm disorder and other heart or circulatory conditions. The mucoadhesive
buccal tablets of propranolol were papered by wet granulation method using natural polymer like
Vigna mungo powder. The compatibility studies of drug and excipient were performed by FT- IR
spectroscopy and DSC. After examining the flow properties of the powder blends the results
were found to be within prescribed limits and indicated good flowing property, hence it was
subjected to compression. The tablets were evaluated for post-compression parameters like
weight variation, hardness, thickness, friability, drug content uniformity, surface pH, in-vitro
studies like swelling, mucoadhesive strength, residence time and drug release. Formulation (F6)
containing Vigna mungo showed good muco-adhesive strength (21.75g) and maximum drug
release of 89.31% in 12 h and residence time (6.9 h). The drug content shown 92.19%, surface
pH was found to be 6.9. All the evaluation parameters given the positive result and comply with
the standards. The results indicated that the mucoadhesive buccal tablets of propranolol may be
good choice to bypass the extensive hepatic first pass metabolism with an improvement in
bioavailability of propranolol through buccal mucosa.
24.AR. Shabaraya, K. Aiswarya,et.al Labetalol hydrochloride is a lipophilic anti hypertensive
drug having poor bioavailability(25%) and shorter
biological half life (t1/2-4-6hr) Buccoadhesive tablets of Labetalol hydrochloride were
developed to prolong its release and improve the bioavailability by avoiding hepatic first pass
metabolism during the treatment . In present investigation an attempt was made to develop and
evaluate buccoadhesive tablets of Labetalol
hydrochloride using natural polymers. Different formulations were developed with varying
concentrations of polymers like Sodium alginate and Guar gum. Ethyl cellulose is used as a
backing layer. Based on the preformulation studies,formulations were prepared by direct
compression method. Prepared tablets were comparatively evaluated for their physicochemical
parameters like weight variation, hardness, thickness, and friability test. The surface pH,
swelling index, bio-adhesive strength are also carried out which has been
important aspect for success of mucoadhesive buccal tablets. In-vitro drug release rate of
Labetalol hydrochloride was studied in phosphate buffer 6.8 containing 0.2% sodium lauryl
sulphates at 37±0.50C. The data obtained from dissolution studies followed non fickian
diffusion.
25.VipulD.Prajapati,GirishK.Jani,et.al,A large number of plant based pharmaceutical
excipients are available today. Gums and mucilages are the most commonly available plant
ingredients with a wide range of applications in pharmaceutical and cosmetic industries. They
are being used due to their abundance in nature, safety and economy. They have been
extensively explored as pharmaceutical excipients. They are biocompatible, cheap and easily
 LITERATURE REVIEW

available. Natural materials have advantages over synthetic ones since they are chemically
inert,nontoxic, less expensive, biodegradable and widely available. They can also be modified in
different ways to obtain tailor-made materials for drug delivery systems and thus can compete
with the available synthetic excipients. Recent trend toward the use of plant based and natural
products demands the replacement of synthetic additives with natural ones. In this review, we
describe the pharmaceutical applications of various natural gums, mucilages and their modified
forms for the development of various drug delivery systems
26.Girish K Jania, Dhiren P Shahb,et.al, Nature has provided us a wide variety of materials to
help improve and sustain the health of all living things either directly or indirectly. In recent
years there have been important developments in different dosage forms for existing and newly
designed drugs and natural products, and semi-synthetic as well as synthetic excipients often
need to be used for a variety of purposes. Gums and mucilages are widely used natural materials
for conventional and novel dosage forms. These natural materials have advantages over synthetic
ones since they are chemically inert, nontoxic, less expensive, biodegradable and widely
available. They can also be modified in different ways to obtain tailor-made materials for drug
delivery systems and thus can compete with the available synthetic excipients. In this review, we
describe the developments in natural gums and mucilages for use in the pharmaceutical sciences.
27.Vikas Ranaa, Parshuram Raia,et.al, Gums are naturally occurring components in plants,
which are essentially cheap and plentiful. They have diverse applications as thickeners,
emulsifiers, viscosifiers, sweeteners etc. in confectionary, and
as binders and drug release modifiers in pharmaceutical dosage forms. However, most of the
gums in their putative form are required in very high concentrations to successfully function as
drug release modifiers in dosage forms due to their high swellability/solubility at acidic pH.
Hence, gums need to be modified to alter their physicochemical properties. This article is aimed
at discussing the modification
of gums through derivatisation of functional groups, grafting with polymers, cross-linking with
ions etc. The factors influencing these processes in the pursuit of making them suitable for
modifying the drug release properties of pharmaceutical dosage forms and for other purposes is
discussed with respect to optimization of their performance
2.1.3 A LITERATURE REVIEW ON MUCOADHESIVE TABLETS OF NORFLOXACIN
USING NATURAL POLYMERS:.
28.Ritesh Rana, Rohit Bisht,et.al,
The present investigation deals with development and evaluation of mucoadhesive
gastroretentive tablet of Norfloxacin using natural polymer from Tamrind seed polysaccharide.
Natural polymers have been used widely in the sustained release of a variety of drugs to enhance
their release patterns. The hypothesis behind this work is to increase the bioavailability of drug
by gastro retentive approach. Different formulations (F1 to F12) have been prepared by wet
granulation method. Preformulation studies such as melting point, U.V. scanning, solubility
studies have been done. Drug polymer compatibility studies were done using FT-IR.
 LITERATURE REVIEW

Micromeretic studies such as bulk density, tapped density, carr’s index, hausner ratio and angle
of repose were performed. Prepared tablets were further
evaluated for mucoadhesive strength, swelling index, hardness, weight variation, friability,
thickness has also been evaluated. The in- vitro drug release studies has been done or 8hrs by
using USP-II apparatus with 0.1 N HCl. Different kinetic models were applied to study the
release pattern of drug from the tablet. Based on the results of different studies formulation F10
was selected as best formulation. All the parameters were found within the acceptance limit and
the formulated tablet shows extended release for 8 hrs.
29.G. C. Crumplin, Marion Kenwright,et.al, Examination of the mechanism of action of
norfloxacin upon susceptible strains of Escherichia coli K12 has shown that the drug exerts a
potent bactericidal effect resulting from the inhibition of the A subunit of the essential enzyme
DNA gyrase. It is also shown that the use of norfloxacin can reduce the total number of bacteria
at the site of an infection as well as having significant effects upon the metabolism of treated
cells in the interim period between the loss of viability and cell-lysis. These effects may provide
a clue to a previously unsuspected mechanism of providing symptomatic relief which functions
in parallel with the elimination of viable pathogenic bacteria.
 AIM & OBJECTIVE

CHAPTER-3

AIM:

To Formulate the Mucoadhesive tablets of Norfloxacin by using various natural polymers like
Guar gum and Xanthane gum and to evaluate these prepared mucoadhesive tablets.

OBJECTIVE:

Objective of the study:

Selection of drug & polymers

 To carryout preformulation studies for possible drug polymer interaction.

 To develop and formulate Mucoadhesive tablets of Norfloxacin.
 To carryout post compression parameters of prepared Mucoadhesive tablets like
hardness, friability, weight variation, swelling index etc.,
 To develop analytical method for the estimation of the drug in formulation.
 To evaluate the formulated dosage form by in vitro studies.

Need for the study:

Mucoadhesive system is a type of modified drug delivery system that can be used as an
alternative to conventional drug delivery system. Norfloxacin, is an antibiotic that belongs to the
class of fluoroquinolone antibiotics. Norfloxacin has shorter half life and low bioavailability,
hence it was suitable for a mucoadhesive preparation which sustain the release of drug and
prolong its action by increasing half life and bioavailability by mainataining plasma drug
concentration in theraupeutic window and increase theraupeutic action.

PLAN OF WORK:

The following experimental protocol was therefore designed to allow a systematic approach to
the study.

1. Drug selection.

2. .Literature survey

3 .Formulation Development

 Selection of the suitable excipients.

 Flow property evaluation of API.

 AIM & OBJECTIVE

 Drug excipient compatibility studies.

 To develop a method for the estimation of drug substance in the dosage form.

 Formulation of mucoadhesive norfloxacin tablets.

 Evaluation of the pre-compression parameters.

 Evaluation of the compressed tablets.

 Test for physical parameters.

 In vitro dissolution study.

 Kinetic modelling for the invitro dissolution data.

 Selection of optimized formula based on invitro evaluation parameters.

 DRUG & EXCIPIENT PROFILE

CHAPTER 4

4.1 DRUG PROFILE

NORFLOXCIN

Brand name:Noroxin.

Description: (Norfloxacin) is a synthetic, broad-spectrum antibacterial agent for oral administration.

Norfloxacin, a fluoroquinolone, is Norfloxacin is a white to pale yellow crystalline powder with Tablets
NOROXIN 400 mg are white to off-white, oval shaped, film-coated tablets, coded 705 on one side and
plain on the other

Empirical formula - C16H18FN3O3 .

Structural formula :

Chemical name:1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid.

Molecular weight- 319.34

Melting point - 221°C.

Solubility: It is freely soluble in glacial acetic acid, and very slightly soluble in ethanol, methanol and
water.

Dose:

Noroxin is available in 400-mg tablets.

Norfloxacin, a fluoroquinolone, differs from non-fluorinated quinolones by having a fluorine atom at

the 6 position and a piperazine moiety at the 7 position.
 DRUG & EXCIPIENT PROFILE

Boiling point:

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)

Dosage and administration

Tablets noroxin should be taken at least one hour before or at least two hours after a meal or ingestion
of milk and/or other dairy products.

MECHANISM OF ACTION:

Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal. At the molecular
level, three specific events are attributed to norfloxacin in E. coli cells:

1. inhibition of the ATP-dependent DNA supercoiling reaction catalyzed by DNA gyrase,

2. inhibition of the relaxation of supercoiled DNA,
3. promotion of double-stranded DNA breakage.

The fluorine atom at the 6 position provides increased potency against gram-negative organisms, and
the piperazine moiety at the 7 position is responsible for antipseudomonal activity.

USES:used to treat antibacterial infections like urinary tract infections,prostatitis.

Half life: 3-4 hours.

4.2 EXCIPIENT PROFILE:

GUAR GUM:

 Synonyms:Cal-Ban3000, Glucotard, GU-052,guar flour,guar gum,guaran ,gum

guar,slocose,supercol,Supercol GF,supercol NG 1,supercol U
 Pharmaceutical industry – as binder or as disintegrator in tablets; main ingredient in some bulk-
forming laxatives
Structure:
 DRUG & EXCIPIENT PROFILE

PHYSICAL DESCRIPTION:

Guar gum is an off-white to yellowish-white powder. Five to eight times the thickening power
of starch. Water solutions are tasteless, odorless, and nontoxic and have a pale translucent gray color
with neutral pH. Water solutions converted to gel by small amounts of borax.

SolubilitY: Soluble in cold water. .

Chemical name

disodium;[[[5-(6-aminopurin-9-yl)-3-hydroxyoxolan-2-yl]methoxyhydroxyphosphoryl]oxy-
oxidophosphoryl] hydrogen phosphate

MOLECULAR FORMULA: C10H14N5Na2O12P3

Functional Category:mucoadhesive sustaining agent, Suspending agent; tablet binder; tablet

disintegrant; viscosityincreasing agent.

Applications of Guar gum: Guar gum is a galactomannan, commonly used in cosmetics, food
products, and pharmaceutical formulations. It has also been investigated in the preparation of sustained-
release matrix tablets in the place of cellulose derivatives such as methylcellulose.

(1) In pharmaceuticals, guar gum is used in solid-dosage forms as a binder and disintegrant,; in oral and
topical products as a suspending, thickening, and stabilizing agent; and also as a controlled-release
carrier. Guar gum has also been examined for use in colonic drug delivery. Guar-gum-based three-layer
matrix tablets have been used experimentally in oral controlled-release formulations. Therapeutically,
guar gum has been used as part of the diet of patients with diabetes mellitus. It has also been used as an
appetite suppressant.

XANTHAN GUM:

Nonproprietary Name: Xanthan Gum .

 DRUG & EXCIPIENT PROFILE

Synonyms: Corn sugar gum; E415; Grindsted; Keldent; Keltrol; polysaccharide B-1459; Rhodicare S;
Rhodigel; Vanzan NF; xanthani gummi; Xantural.

Chemical Name: Xanthan gum .

Molecular formula (C35H49O29)n

Description:Describes xanthan gum as a high molecular weight polysaccharide gum. It contains D-

glucose and D-mannose as the dominant hexose units, along with D-glucuronic acid, and is prepared as
the sodium, potassium, or calcium salt..Functional Category:Gellingagent;stabilizingagent; suspending

agent;sustained releasing agent or viscpsity increasing agent.

Structure:

Applications in Pharmaceutical or Technology

Xanthan gum is widely used in oral and topical pharmaceutical formulations, cosmetics, and foods as a
suspending and stabilizing agent) It is also used as a thickening and emulsifying agent. It is nontoxic,
compatible with most other pharmaceutical ingredients, and has good stability and viscosity properties
over a wide pH and temperature range; Xanthan gum gels show pseudoplastic behavior, the shear
thinning being directly proportional to the shear rate. The viscosity returns to normal immediately on
release of shear stress.
Xanthan gum has been used as a suspending agent for conventional, dryand sustained-
releasesuspensions. When Although primarily used as a suspending agent, xanthan gum has also been
used to prepare sustained-release matrix tablets. Controlled-release tablets of diltiazem hydrochloride
prepared using xanthan gum have been reported to sustain the drug release in a predictable manner, and
the drug release profiles of these tablets were not affected by pH and agitation rate. Xanthan gum has
 DRUG & EXCIPIENT PROFILE

also been used to produce directly compressed matrices that display a high degree of swelling due to
water uptake, and a small amount of erosion due to polymer relaxation. It has also been used in
combination with chitosan, guar gum, galactomannan, and sodium alginate to prepare sustained-release
matrix tablets. Xanthan gum has been used as a binder.
Description
Xanthan gum occurs as a cream- or white-colored, odorless, freeflowing, fine powder

Microcrystalline cellulose:
Microcrystalline cellulose (MCC) is a term for refined wood pulp and is used as a texturizer, an anti-
caking agent, a fat substitute, an emulsifier, an extender, and a bulking agent in food production.[1
Advantages:
 Chemical Purity / Low Reactivity
 Excellent Binding Capability
 Filler
 Better Disintegrating Property
 Greater Flowability
 Rapid wicking action

Description: Microcrystalline Cellulose Powder is a white fine powder free from all foreign
matter. Fine, white or almost white, odourless, free flowing crystalline powder.

Structure:

APPLICATIONS:

 Excipient in Tableting

 It is Multifunctional Excipient

 It is used as binder / diluent in tableting

Solubility:soluble in water, ethanol, ether and dilute mineral acids. Slightly soluble in sodium
 DRUG & EXCIPIENT PROFILE

hydroxide solution.

Chemical formula:(C6H10O5)n

Synonyms:Cellulose gel.

Talc:
Nonproprietary Names Purified Talc ,talc.

Synonyms
Altalc; E553b; hydrous magnesium calcium silicate; hydrous magnesium silicate; talcum.
Empirical Formula and Molecular Weight Talc is a purified, hydrated, magnesium silicate,
approximating to
the formula Mg6(Si2O5)4(OH)4. It may contain small, variable amounts of aluminum silicate and iron.
.
Functional Category
Anticaking agent; glidant; tablet and capsule diluent; tablet and capsule lubricant.
Applications in Pharmaceutical Formulation or
Technology
Talc was once widely used in oral solid dosage formulations as a lubricant and diluent, although today
it is less commonly used. However, it is widely used as a dissolution retardant in the development of
controlled-release products. Talc is also used as a lubricant in tablet formulations; in a novel powder
coating for extended-release pellets; and as an adsorbant. In topical preparations, talc is used as a
dusting powder, although it should not be used to dust surgical gloves; Talc is a natural material; it
may therefore frequently contain microorganisms and should be sterilized when used as a dusting
powder;. Talc is additionally used to clarify liquids and is also used in cosmetics and food products,
mainly for its lubricant properties.
Description
Talc is a very fine, white to grayish-white, odorless, impalpable, unctuous, crystalline powder. It
adheres readily to the skin and is soft to the touch and free from grittiness.

MAGNESIUM STERATE

Nonproprietary Names : Magnesium Stearate

Synonyms
Dibasic magnesium stearate; magnesium distearate; magnesii
stearas; magnesium octadecanoate; octadecanoic acid, magnesium salt; stearic acid, magnesium salt;
Synpro 90.
Chemical Name
Octadecanoic acid magnesium salt
 DRUG & EXCIPIENT PROFILE

Empirical Formula and Molecular Weight

C36H70MgO4 591.24
Structural Formula
[CH3(CH2)16COO]2Mg
Functional Category
Tablet and capsule lubricant.
Applications in Pharmaceutical Formulation or Technology
Magnesium stearate is widely used in cosmetics, foods, and pharmaceutical formulations. It is primarily
used as a lubricant in capsule and tablet manufacture at concentrations between 0.25% and 5.0% w/w.
It is also used in barrier creams.
Description
Magnesium stearate is a very fine, light white, precipitated or milled, impalpable powder of low bulk
density, having a faint odor of stearic acid and a characteristic taste. The powder is greasy to the touch
and readily adheres to the skin.
Flowability Poorly flowing, cohesive powder.
Melting range
117–1508C (commercial samples);
Solubility Practically insoluble in ethanol, ethanol (95%), etherand water; slightly soluble in warm
benzene and warm ethanol (95%).
Stability and Storage Conditions
Magnesium stearate is stable and should be stored in a well-closed container in a cool, dry place.

Structure:
 METHODOLOGY
CHAPTER 5

5.1 MATERIALS & METHODOLOGY:

5.1.1 Ingredients used and their manufacturers:

The following materials that were either AR/LR grade or the best possible available were used as supplied by
the manufacturer.

Table:5.1.1 Ingredients used and their manufacturers.

Materials Company

NORFLAXACIN YARROW CHEMICALS,MUMBAI

XANTHUM GUM YARROW CHEMICALS,MUMBAI

GUAR GUM YARROW CHEMICALS,MUMBAI

MICRO CRYSTALLINE CELLULOSE YARROW CHEMICALS,MUMBAI

TALCUM POWDER YARROW CHEMICALS,MUMBAI

MAGNESIUM STEARATE YARROW CHEMICALS,MUMBAI

Table: 5.2 Instruments and equipments used

Equipment Manufacturer

Electronic balance Hicon

pH meter Hicon
UV-visible spectrophotometer Shimadzu

Tapped D ensity Tester USP Hicon

Disintegration apparatus Hicon

Fr iabilator Hicon
Hardness tester Monsanto
Dissolution tester Electro lab
 METHODOLOGY
Hot Air oven KEMI-KOS-1

Table 5.3 Ingredients and their purpose:

INGREDIENTS PURPOSE

Norflaxacin Active ingredient, Anti bacterial agent.

Xanthum gum Sustained release agent, stabilizer

(Polymer)

Guar gum sustained release agent(Polymer)

Microcrystalline cellulose Binder, Diluent

Magnesium sterate lubricant

Talc Glidant ,Diluent

METHODOLGY:

5.4 Determination of λmax:

Procedure:
 METHODOLOGY
10mg of pure drug was taken and known concentration of drug solution was prepared by s
olubilizing in methanol then suitably diluting drug solution in pH 7 Phosphate buffer and in 0.1N HCl. The
solutions were scanned from 200-400 nm against the reagent blank to fix absorption maxima. Spectrum of the
model drug was obtained and λmax of model drug was found to be 273 nm. Hence all further investigations were
carried out at the same wavelength

5.4.1 construction of Calibration curve for Norfloxacin by UV-visible spectrophotometer :

a) Preparation of pH 7 phosphate buffer

Dissolve 28.8 g of potassium dihydrogen phosphate and 11.45 g of sodium hydroxide in sufficient water
to produce 1000 ml.

b) 0.1N HCl:

Transfer 8.5 ml of concentrated HCl to 1000ml volumetric flask and make up to 1000ml with Distilled
water

c)Preparation of stock solution of drug:

Stock solution of norfloxacin was prepared by weighing 100mg of Norfloxacin and dissolved it in methanol to
made the volume 100ml.the concentration of the prepared stock solution was 1000µg /ml.

d)preparation of standard solution:

From the stock solution suitable aliquots were taken and solutions in concentration range of Norfloxacin such as
5,10,15,20,25,30,35,40,50,60µg/ml were prepared by diluting with phosphate buffer Ph 7.4 .The absorbance
was measured at 279 nmagainst phosphate buffer Ph7.4 as blank. The method was found linear in the
concentration range of 5-60µg/ml .The concentration of norfloxacin and the corresponding absorbance values
are given

5.5 Pre-Formulation studies:

It is one of the important prerequisite in development of any drug delivery system. Preformulation studies
where performed on the drug, which included
 Melting point determination.
 Drug-polymer compatibility studies.
5.5.1 Determination of melting point
 METHODOLOGY
Melting point of Norfloxacin was determined by capillary method. Fine powder of norfloxacin was filled in
glass capillary tube (previously sealed on one end). The capillary tube is tied to thermometer and the
thermometer was placed in fire. The powder at what temperature it will melt was noticed.
5.5.2 Drug polymer compatibility studies

The drug and polymer compatibility studies were carried out using IR studies.

5.6 Formulation of mucoadhesive tablets of Norfloxacin:

Table 5.6: Composition of drug and polymers (in mg)

Formulation Norfloxacin(mg) Polymer Polymer Microcrystalline Magnesium Talc Total

code (guargum) (xanthangum) cellulose(mg) stearate (mg) weight
(mg) (mg) (mg) of
tablet.
(mg)
F1G 400 30 _ 207 6.5 6.5 650

F2G 400 70 _ 167 6.5 6.5 650

F3G 400 120 _ 117 6.5 6.5 650

F4G 400 220 _ 17 6.5 6.5 650

F5G 400 240 _ 07 6.5 6.5 650

F6X 400 _ 30 207 6.5 6.5 650

F7X 400 _ 70 167 6.5 6.5 650

F8X 400 _ 120 117 6.5 6.5 650

F9X 400 _ 220 17 6.5 6.5 650

F10X 400 _ 6.5

240 07 6.5 650

5.7. Methods of preparation of Mucoadhesive Tablets of Norfloxacin.

 Weighing
 METHODOLOGY
All the ingredients were weighed accurately as per the manufacturing formula.
 Formulation of sustained granules by using wet granulation method:
Norfloxacin was passed through # 40 and all the ingredients (as per the formula) were weighed accurately
and passed through #60 then thoroughly mixed and then granulated with 20%w/w pvp k30 paste.the wet Mass
passed through #10 and the resulted granules were dried at 45 degrees celsius for a period of 1 hr in hot air
oven,then the dried granules were passed through #20 and lubricated with magnesium sterate for further
blending for 3 mins and finally talc,were added to the above blend then compressed.

5.7.1 Formulation Development Process Flow Diagram

WEIGHING

SIEVING

MIXING

WETTING

SIEVEING

DRYING

SEIVEING
 METHODOLOGY
MIXING(Lubricants)

GRANULATION.

5.7.2. Precompressonal Evaluation of Mucoadhesive Sustained release Granules:

 Angle of repose:
Angle of repse for different formulations was measured according to fixed funnel standing method.
Granules were weighed passed through the funnel, which was kept at a height ‘h’ from horizontal surface. The
passed Granules formed a pile of the height ‘h’ above the horizontal surface and the pile was measured and the
angle of repose was determined for all the formulation using the formula (n = 3).

-1
Angle of repose (θ) = tan (h / r)

Whereas,

h is the height of pile and r is the radius.

Table 1:Flow properties and corresponding Angle of repose

Angle of repose (θ)

S.No Flow
(degrees)
1 <25 Excellent
2 25-30 Good
3 30-40 Passable
4 >40 Very poor

 Bulk density and Tapped density:

Bulk density and Tapped density were measure by using 10ml graduated cylinder. The sample poured in
the cylinder was tapped mechanically for 100 times, then tapped volume was noted. Then, bulk density and
tapped density were calculated. Each experiment was performed in triplicate manner.
 METHODOLOGY
Bulk density = Mass of powder / Bulk volume

Tapped density = Mass of powder / Tapped density

 Carr’s index and Hausner’s ratio:

Compressibility index and Hausner’s ratio was determined according to the following equations.

Carr’s index (%) = (Tapped density-Bulk density / Tapped density) X 100

Values of CI below 15% usually give rise to good flow characteristics, but readings above25% indicate poor
flow ability.

Hausner’s index = Tapped density / Bulk density

Table 2: Scale of Flowability (USP)

CARR’S INDEX FLOW PROPERTY HAUSNER’S

(%) RATIO

≤10 Excellent 1.00-1.11

≤11-15 Good 1.12-1.18
16-20 Fair 1.19-1.25
21-25 Passable 1.26-1.34
26-31 Poor 1.35-1.45
3 2-37 Very poor 1.46-1.59
>38 Very, very poor >1.60
5.7.3 Compression of mucoadhesive tablet:
 Blended material was loaded in a hopper and compresses the powder into tablets by using (cad mach)
compression machine with (10mm) mm standard flat punches.
 Check for weight variation, hardness, friability, thickness to meet the parameters.
Collect the tablets in a cleaned double poly bag.

Compression:
 METHODOLOGY
Compress the lubricated blend using punches mentioned along with the tablet parameters

Table No 3: Punches Specification

S.No Punch dimension 10mm

1 Punch shape Flat punches

2 Upper punch Plain

3 Lower punch Plain

5.8 Evaluation

5.8.1 post compression parameters:

The tablets were evaluated for Appearance, Weight variation, Thickness, Diameter, Hardness and
Friability to meet the Pharmacopoeial standards.

Tablet description

General appearance of tablet involves the measurement of a number of attributes such as a tablets size, shape,
colour, presence or absence of an odour, taste, surface texture, physical flaws.

 Determination of Weight Variation of the tablets

Ten tablets were selected at random from each batch and were weighed accurately and average weights
were also calculated. Then the deviations of individual weights from the average weight and the standard
deviation were calculated by using the formula,

Percentage deviation = (X- X*/X) x 100

Where as,

X → Actual weight of the tablet

X*→ Average weight of the tablet

 METHODOLOGY
Limit for weight variation is ± 10%

Table 4 : USP STANDARDS FOR WEIGHT VARIATION TEST

AVERAGE WEIGHT OF TABLETS Maximum percentage deviation

130 or less 10
130 – 324 7.5
324mg or more 5

 Determination of Thickness and Diameter of the tablets

Thickness and diameter of five randomly selected tablets from each batch were measured with a Vernier
Callipers. Then the average diameter, thickness and standard deviation were calculated.

 Determination of Hardness of the tablets

Hardness (diametric crushing strength) is a force required to break a tablet across the diameter. It
indicates the ability of a tablet to withstand mechanical shocks while handling and transportation. Five tablets
were sampled randomly from each batch and the hardness was determined by using Monsanto Hardness Tester.
Then average hardness and standard deviation was calculated. It is expressed in kg/cm2.

 Determination of Friability of the tablets

Friability is the loss of weight of tablet in the container/package, due to removal of fine particles from the
surface. This In-process quality control test is performed to ensure the ability of tablets to withstand the shocks
during processing, handling, transportation and shipment. The friability was determined using Roche type
Friabilator. It is expressed in percentage (%). Ten tablets were initially weighed (W initial) and transferred into
Roche friabilator. The friabilator was operated at 25 rpm for 4 minutes or run up to 100 revolutions. The tablets
were deducted and weighed again (Wfinal). The % friability was calculated by using the formula,

Friability index = (I - F/I) x 100

Where as,

I → Initial weight
 METHODOLOGY
F → Final weight

Limit not more than 1%

 Drug content
Three tablets were selected randomly from each batch and taken separately into three 100 ml volumetric
flasks. In each flask 100 ml of Phosphate buffer of pH 7 was poured and kept for 24 hrs. After that filter the
solution. From the filtrate, 1ml was transferred to 10ml volumetric flask and the volume was made up to 10ml
with pH 7.0 Phosphate buffer. The sample was analyzed against blank by UV spectrophotometer at 250 nm.
From these absorbance, drug content was determined and average and standard deviation was calculated

Drug content = concentration × dilution factor × conversion factor × amt. of stock sol.

 IN-VITRO DRUG RELEASE STUDIES

These tests serve 2 important functions. First, data from such tests are required as a guide for formulation
during the development stage, prior to clinical testing; Second, in-vitro testing is necessary to ensure batch-to-
batch uniformity in the production of a proven dosage form.

Dissolution (By UV Method)

Instrument : UV-spectrophotometer

Wave length : 273nm

Table 7: Dissolution parameters

S.No Parameters Acidic medium

1 Dissolution apparatus USP type -II apparatus (Paddle type)

2 Temperature 370C ± 0.50C

3 Rotation speed 50 rpm

 METHODOLOGY
4 Dissolution medium 0.1 N HCl

5 Volume of dissolution medium 900ml

6 Volume of sample removed 5ml

7 Volume of dissolution medium 5ml

replaced (Sink)

8 Sampling interval 30mins,1 hr,2hr,3hr,4hr,6hr,8hr,10hr,12hr.

5. 9 KINETIC MODELLING

The results of in vitro release profiles obtained for all formulations were fitted into three kinetic models
of data treatment as follows:

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

2. Log cumulative percentage drug released versus time (first-order kinetic model).
3. Cumulative percentage drug released versus square root of time (Higuchi’s model).
4. Log cumulative percentage drug released versus log time (Korsmeyer-Peppas equation).
5.9.1 Drug release kinetics for prepared mucoadhesive tablets of Norfloxacin.
To study the release kinetics, data obtained from in vitro release were plotted in various kinetic models.
a) Zero order equation
The graph was plotted as % drug release Vs time in days.
C=K0 t
Whereas,
KO -Zero order rate constant in conc/time
T- Time in days.
The graph would yield a straight line with a slope equal to KO and intercept the origin of the axis. The results
were tabulated and graph was shown.

b) First order equation

The graph was plotted as log cumulative % drug remaining Vs time in days.
Log C=log CO-Kt/2.303
Whereas,
CO-Initial concentration of drug.
 METHODOLOGY
K – First order constant.
T – Time.
C) Higuchi kinetics
The graph was plotted as cumulative % drug release Vs square root of time
Q=Kt1/2
Whereas,
K- Constant reflecting design variable of system. (Differential rate constant)
t- time in days.(95)
Hence drug release rate is proportional to the reciprocal of square root of time. If the plot yields a
straight line, and the slope is one, then the particular dosage form is considered to follow Higuchi kinetics of
drug release. The results were tabulated.

d) Korsmeyer – Peppas equation

To evaluate the mechanism of drug release, it was further plotted in Peppas equation as log cumulative
% of drug released Vs time.
Mt /Mα = Ktn
Log Mt /Mα = log K + n logt
Where as,
Mt/Mα-fraction of drug released at time t
t – Release time
K – Kinetic constant (incorporating structural and geometric characteristics of
Preparation)
n – Diffusional exponent indicative of the mechanism drug release.
If n value is 0.5 or less, the release mechanism follows “Fickian diffusion” and higher values of 0.5<n<1
for mass transfer follow a non-Fickian model (anomalous transport). The drug release follows zero-order drug
release and case II transport if the n value is 1. For the values of n higher than 1, the mechanism of drug release
is regarded as super case II transport. The model is used to analyze the release of pharmaceutical polymeric
dosage forms when the release mechanism is not known or more than one type of release phenomenon was
involved. The n value could be obtained from slop of the plot of log cumulative % of drug released Vs log time.
The results were tabulated.
5.10 Invitro mucoadhesion studies: The mucoadhesive strength of the tablets was measured on
modified physical balance .the apparatus consists of a modified double beam physical balance in which the right
and left pan were with lighter pans. The left side of the balance was made heavier than the right side by placing
 METHODOLOGY
a 5g weight on left side pan. Another Teflon block of 3.8 cm diameter and 2 cm height was fabricated with an
upward protrusion of 2 cm height and 1.5 cm diameter on one side. This was kept in a beaker, which was then
placed below the left hand set of balance. The goat gastric mucus membrane was used as the model membrane
and Ph 1.2 buffer solution was used as the moistening fluid. The goat stomach mucosa was kept in tyrode at 37
degrees for 2 hr.the underlying mucus membrane was separated and washed thoroughly with a Ph 1.2buffer
solution. It was then tied to a Teflon- coated glass slide and this slide was fixed over the protrusion in the Teflon
block using a thread. The block was then kept in a beaker containing Ph 1.2 buffer solution at a level that
touches the membrane so as to moisten the membrane. By keeping a 5 g weight on the right pan that two sides
were balanced, the beaker with the Teflon block was kept below the left hand setup of the balance. The tablet
stuck on to the lower side of the left hand side pan. The 5 g weight from the right was then removed. This
lowered the left pan along with the tablet over the membrane with the weight of 5g. this was kept undisturbed
for 3 min.then the weight on the right side was added in an increment of 0.5g until the tablet just seperates from
the membrane surface. The excess weight on the right pan i.e. total weight minus 5g was taken as the measure
of the mucoadhesive strength from the
Mucoadhesive strength,the force of adhesion was calculated using following formula;
Force of adhesion(N) =mucoadhesion strength/100*9.81.

5.10.1 Measurement of in-vitro residence time:

The invitro residence time determined by using a modified usp disintegration apparatus, for this study
the time for complete erosion or detachement of the tablet from the mucosal surface was recorded as the
mucoadhesion time.The total experiment was carried out for 6 hours to see the retention timeand correlate this
value with the sustaining property of the formulation.
5.11Swelling studies:
 METHODOLOGY
Norfloxacin tablets were weighed individually (designated as W1) and placed separately in Petri dishes
containing water. At regular intervals (1, 2, 4,8,10,12hr) the tablets were removed from the Petri dishes and
excess surface water was removed carefully by using the filter paper.
The swollen tablets were then reweighed (designated as W2),The swelling index (water uptake) calculated
according to the following Equation.

Swelling index(S.I) = W2 – W1/W1× 100

 EXPERIMENTAL PART

CHAPTER-6

EXPERIMENTAL PART:

6.1 Preformulation studies:

 Drug and polymer compatibility studies:

FIG:1 FTIR Graph of Norfloxacin.

 EXPERIMENTAL PART

FIG2 FTIR Spectra of guar gum

FIG 3 FTIR spectra of xanthan gum

 EXPERIMENTAL PART

FIG 4 FTIR Spectra of drug +polymers

Results and discussion: FTIR spectrum of the drug powder exhibits peaks at wavenumbers
2957cm-1(C-H stretching),2839cm-1 (C-H stretching of CH3O). 2541.49cm-1 (n-h
stretching),236cm-1 (C=Nstretching).the spectra of drug and polymer mixture exhibited all the
principle peaks present in the norfloxacin pure drug. The results revealed that no interaction
between drug and excipients usd in the formulation of osmotic tables. The IR spectra of pure drug
and optimized formulation were shown in figures.

6.2 STANDARD PLOT OF NORFLOXACIN

Table :1 Standard plot of Norfloxacin in 0.1N HCl.

S.NO CONCENTRATION(µg/ml) ABSORBANCE(nm)

1 2 0.175
2 4 0.324
3 6 0.513
4 8 0.675
5 10 0.914
 EXPERIMENTAL PART

1
y = 0.0915x - 0.0285
0.9 R² = 0.9934
0.8

Absorbance(nm)
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 2 4 6 8 10 12
concentration(µg/ml)

FIG:5

EVALUATION STUDIES

6.3 Precompression parameters:

Table 2: Pre- compression parameters:

Formulatio Loss on Bulk Tapped Carr’s Hausne Angle of

n code drying( density(g/ml) density(g compressabil r’s ratio repose
%LOD) /ml) ity index
)
FG1 1.1 1.013 1.071 5.84 1.063 31.9

FG2 1.4 1.065 1.148 6.40 1.051 29.4

FG3 1.6 1.034 1.128 7.66 1.065 27.1

FG4 2.6 1.092 1.302 13.81 1.176 23.4

FG5 2.8 1.084 1.351 17.78 1.231 21.6

FX6 1.3 1.015 1.075 5.88 1.065 32.7

 EXPERIMENTAL PART

FX7 1.5 1.071 1.156 7.31 1.056 24.6

FX8 1.7 1.031 1.126 8.91 1.068 26.26

FX9 2.7 1.099 1.305 15.86 1.189 24.720

FX10 2.9 1.085 1.356 19.97 1.274 23.7

6.4 Post compression parameters:

Table 3: post compression parameters:

Formulation Weight Hardness(kg/cm2 Thickness(mm) Friability(5)

code variation(mg)

F1(G) 649.15±0.13 5.1±0.39 3.87±0.18 0.20

F2(G) 648.13±0.12 5.8±0.55 3.89±0.32 0.23
F3(G) 651.15±0.14 6.2±0.43 3.85±0.23 0.22
F4(G) 646.15±0.15 5.7±0.16 3.88±0.04 0.24
F5(G) 649.12±1.18 6.5±0.76 3.90±0.14 0.28
F6(X) 648.13±0.14 6.9±0.27 3.86±0.22 0.30
F7(X) 647.14±0.14 6.1±0.38 3.93±0.11 0.32
F8(X) 648.12±0.16 5.6±0.15 3.91±o.27 0.27
F9(X) 649.17±0.11 6.9±0.13 3.97±0.10 0.34
F10(X) 648.16±1.12 6.2±0.17 3.94±0.16 0.32
 EXPERIMENTAL PART

Table 4:Invitro mucoadhesion strength and post compression parameters

Formulati Mucoadhesive Swelling index(%) Mucoadhesio

on code strength(gm)(mean±Sd Drug 12HRS n force
content(%)(Mean±S.D
).
F1(G) 6.120±0.547 97.14±0.29 168 0.600
F2(G) 6.069±0.334 96.24±0.40 190 0.595
F3(G) 5.86±0.143 96.00±0.17 195 0.574
F4(G) 6.140±0.145 96.11±0.13 224 0.602
F5(G) 7.829±0.011 97.02±0.45 237 0.768
F6(X) 6.210±0.335 95.01±0.31 185 0.609
F7(X) 10.38±0.523 95.99±0.28 192 1.018
F8(X) 7.34±0.117 96.71±0.23 205 0.720
F9(X) 11.120±0.061 97.75±0.18 253 1.090
F10(X) 10.385±0.156 95.53±0.03 248 1.018

Table 5:In vitro dissolution profile of mucoadhesive tablets of Norfloxacin:

TIME CUMULATIVE %DRUG RELEASE.

FG1 FG2 FG3 FG4 FG5 FG6 FX7 FX8 FX9 FX10
(MINS)
0 0 0 0 0 0 0 0 0 0 0

20.3 18.2 16.7 14.8 13.4 21.2 16.7 15.2 12.4 16.6
0.5
1 35.8 23.1 25.6 20.6 18.4 34.6 24.4 23.6 18.3 23.8

1.5 43.9 34.1 34.8 32.7 28.9 44.5 37.6 38.4 22.4 38.5
2 52.8 43.2 59.6 38.9 32.6 56.7 48.3 47.3 32.7 46.2
2.5 65.4 57.8 62.7 42.8 42.8 63.2 58.2 57.1 42.6 50.2
3 72.5 65.3 68.9 50.3 50.6 71.6 64.3 63.4 56.8 58.3
3.5 80.7 75.2 78.4 58.9 56.2 82.5 72.4 77.2 68.2 65.2
4 87.9 82.6 84.6 65.7 68.5 89.3 85.2 84.4 75.9 79.1
6 90.8 90.5 88.3 74.8 79.9 91.3 91.3 90.3 84.9 86.3
8 94.2 93.2 94.1 87.1 86.5 94.7 96.5 95.6 90.3 90.5
10 - - - 95.3 96.2 - - - 97.3 94.3
 EXPERIMENTAL PART

Zero order(FG1-FG5)
120
Cumulative % drug release.

F1
100
F2
80 F3
60 F4
40 F5

20 Linear (F1)
Linear (F2)
0
0 2 4 6 8 10 12 Linear (F3)

Time(hr) Linear (F4)

FIG -6 Zero order release kinetics of FG1-FG5.

Zero order plot (FX6-FX10)

140
Cumulative% drug release

F6
120
F7
100
F8
80
F9
60
F10
40
Linear (F6)
20
Linear (F7)
0
0 2 4 6 8 10 12 Linear (F8)

Time(hrs) Linear (F9)

FIG 7 :Zero order release kinetics of FX6-FX10

 EXPERIMENTAL PART

First order graph(FG1-FG5)

2.5
Log % drug remaining
F1
2 F2

1.5 F3
F4
1
F5
0.5 Linear (F1)
Linear (F2)
0
0 2 4 6 8 10 12 Linear (F3)
Time(hrs) Linear (F4)

FIG:8 First order release rate of drug FG1-FG5

First order F6X-F10X)

2.5
Log % drug remaining

F6
2
F7
1.5 F8
F9
1
F10
Linear (F6)
0.5
Linear (F7)
0 Linear (F8)
0 2 4 6 8 10 12
Linear (F9)
Time(hrs)

FIG:9First order release rate of drug(F6x-F10x)

 EXPERIMENTAL PART

Higuchi plot for FG1-FG5

120
F1
Cumulative % drug

100
F2
80
F3
release.

60 F4
40 F5

20 Linear (F1)

0 Linear (F2)
0 1 2 3 4 Linear (F3)
-20
Time(hrs) Linear (F4)

FIG:10 Higuchi model release rate of drug FG1-FG5.

Higuchi plot( F6X-F10X)

120
cumulative % drug release

F6
100
F7
80 F8
60 F9
40 F10

20 Linear (F6)

0 Linear (F7)
0 1 2 3 4 Linear (F8)
-20
sq root time Linear (F9)

FIG:11 Higuchi model release rate of drug F6X-F10X

 EXPERIMENTAL PART

Koreshmeyer peppa's model release rate

of drug (FG1-FG5)
2.5
Log %cumulative drug

F5
2
F7
1.5 F8
release

1 F9

0.5 F10
Linear (F5)
0
-0.5 0 0.5 1 1.5 Linear (F7)
Log time Linear (F8)

FIG:12 Koreshmeyer peppa’s model release rate of drug FG1-FG5

Koreshmeyer peppa's model release rate

of drug (FX6-FX10)
2.5
Log %cumulative drug

F5
2
F7
1.5 F8
release

1 F9

0.5 F10
Linear (F5)
0
-0.5 0 0.5 1 1.5 Linear (F7)
Log time Linear (F8)

FIG:13 Koreshmeyer peppa’s model release rate of drug FX6-FX10

Table 6:Kinetic data of prepared formulations(correlation cofficient)

Formulation Zero order First order higuchi Koreshmeyer

code. peppa’s(N)
F1 0.7785 0.9528 0.9434 0.0194
F2 0.8416 0.9711 0.9439 0.0239
F3 0.7886 0.9672 0.929 0.5075
F4 0.909 0.9768 0.9841 0.5179
 EXPERIMENTAL PART

F5 0.9084 0.9704 0.9693 0.5219

F6 0.7761 0.9448 0.9419 0.0135
F7 0.8544 0.9849 0.9574 0.0271
F8 0.843 0.983 0.9493 0.4615
F9 0.8571 0.9763 0.9333 0.5419
F10 0.8246 0.9803 0.9563 0.4829
 RESULTS AND DISCUSSION

RESULT AND DISCUSSION:

The Norfloxacin sustain release granules of different formulations are preformulated by using
FTIR studies which showed that there is no interaction between drug and polymers.

For FG1-FG5 Results:

FormulationsFG1-G5 were tested for their pre-compression parameters (as shown in the
tables).the results of Bulk density and Tapped density range from 1.013±0.25 to
1.092±0.32g/cm3 and 1.071±0.11 to 1.351,Angle of repose ,carr’s index and Hausners ratio was
found to be 21.6±0.21 to 31.9±0.31,5.84±0.23 to 17.78±0.11,1.063±1.231 respectively.

The prepared mucoadhesive tablets were evaluated for different physical properties.All the
batches were produced under similar conditions to avoid processing variables.The optimized
formulations were further evaluated for weight variation,drug content,hardness and friability as
shown in respective table.Hardness was uniformly maintained and found to be 5.1±0.39 to
6.5±0.76kg/cm2.%friability 0.20±0.006 to 0.28±0.0004,thickness ranges from 3.87±0.18 to
3.90±0.14mm.the % drug content for each formulation was 96.00±0.17 to97.14±0.29.

The mucoadhesive strength ranged from 5.86 to 7.829,where as force of adhesion was 0.574 to
0.768 this may be due to mucoadhesive polymer guar gum that accentuates mucoadhesiveness
and adhesion strength,% of swelling for each formulation found to be within 168-237.this may
be due to varying concentrations of polymer utilized in the formulations .In case of F5 maximum
swelling was found because of increased polymer concentration.as F5 Showed the highest
swelling and mucoadhesiveness,these effects sustaining the release from the formulation.

The data of invitro dissolution study in 0.1N HCL For all optimized batches was reported in the
table, as we see thatwhen the concentration of guargum increased for F5(240mg) rate of release
also increased than other formulations.

The dissolution of Norfloxacin mucoadhesive tablets ,from all the tables F5 followed Zero order
kinetics,It showed best correlation by Higuchi equation proving that the release is by diffusion
mechanism and koresmeyer peppa’s equation revealed that F5 has n value 0.5219 indicating the
Non-fickian diffusion.

For FX6-FX10 Results:

The Norfloxacin sustain release granules of different formulations from FX1-FX5were tested for
their pre-compression parameters (as shown in the tables).the results of Bulk density and
Tapped density range from 1.015±0.25 to 1.085±0.32g/cm3 and 1.075±0.11 to 1.356,Angle of
repose ,carr’s index and Hausners ratio was found to be 23.7±0.21 to 32.7±0.31,5.88±0.23 to
19.97,1.056±0.11,1.274±1.231 respectively.
 RESULTS AND DISCUSSION

The prepared mucoadhesive tablets were evaluated for different physical properties.All the
batches were produced under similar conditions to avoid processing variables.The optimized
formulations were further evaluated for weight variation,drug content,hardness and friability as
shown in respective table.Hardness was uniformly maintained and found to be 5.6±0.15 to
6.9±0.13kg/cm2.%friability 0.27±0.006 to 0.34±0.0004,thickness ranges from 3.86±0.22 to
3.97±0.10mm.the % drug content for each formulation was 95.01±0.31 to97.75±0.18.

The mucoadhesive strength ranged from 6.210 to 11.120where as force of adhesion was 0.609 to
1.090. this may be due to mucoadhesive polymer Xanthan gum that accentuates
mucoadhesiveness and adhesion strength,% of swelling for each formulation found to be within
185-253 .This may be due to varying concentrations of polymer utilized in the formulations .In
case of F9 maximum swelling was found because of increased polymer concentration.as F9
Showed the highest swelling and mucoadhesiveness,these effects sustaining the release from the
formulation.

The data of invitro dissolution study in 0.1N HCL For all optimized batches was reported in the
table, as we see thatwhen the concentration of xanthan gum increased for F9(220mg) rate of
release also increased than other formulations.

The dissolution of Norfloxacin mucoadhesive tablets ,from all the tables F9 followed Zero order
kinetics,It showed best correlation by Higuchi equation proving that the release is by diffusion
mechanism and koresmeyer peppa’s equation revealed that F9 has n value 0.5419 indicating the
Non-fickian diffusion.

From the above results it was concluded that FG5 and FX9 Showed better sustained release and
increase bioavailability of drug …From the both formulations it concluded that xanthan gum
shows more sustained release in mucoadhesive preparation than guar gum by exhibiting more
swelling index and mucoadhesion…From my studies FX9 showed best results……
 Summary and conclusion

SUMMARY AND CONCLUSION:

SUMMARY:

An effort was made to formulate,and evaluate mucoadhesive tablets of Norfloxacin using

natural polymers FT-IR studies were carried out to find the possible interaction between the
selected drug Norfloxacin and the polymers Guar gum and Xanthan gum. The study reveales that
no interaction between the selected drug and the polymers. Norfloxacin tablets were prepared by
wet granulation method. The effect of polymer concentration was studied by using different
polymer ratios. Total 10 formulations were prepared by using Guar gum and Xanthan gum as
natural polymers and Microcrystalline cellulose as diluent ,Magnesium sterate as lubricant,talc as
glidant .The prepared granules were studied for various precompression parameters like angle of
repose,tapped density ,bulk density , carr’s index,and hausner’s ratio.all the parameters of
granules showed good flow properties and passed for processing of tablets.Tablets were punched
and evaluayed for post compression parameters like hardness , thickness, friability , drug content
and weight variation.All the parameters were found to be within limits as per standards, and the
invitro dissolution have been performed the better sustained release shown formulations are FG5
and FX9 ,to know the better formulations in both evaluated for mucoadhesion strength,swelling
index,invitro gastric residence time and among the formulations FX9 were shown good
swelling index and mucoadhesion.

Conclusion: From the above results it was concluded that FG5 and FX9 Showed better
sustained release and increase bioavailability of drug …From the both formulations it concluded
that xanthan gum shows more sustained release in mucoadhesive preparation than guar gum by
exhibiting more swelling index and mucoadhesion…From my studies FX9 showed best result.
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