Chapter 1

Introduction

Chapter l

Introduction

1.1 Introduction to sustained release

Drugs are rarely administered as pure chemical substances alone and are always given
as formulated preparations or medicines (i.e. drug delivery systems or dosage forms).
These can vary from relatively simple solutions to complex drug delivery systems
through the use of appropriate additives or excipient in the fonnulations. It is the
formulation additives that, modify solubility, suspend, thicken, preserve, emulsify,
modify dissolution, improve the compressibility and flavor drug substances to fonn
various acceptable preparations or dosage forms. Before a drug substance can be
successfully formulated into a dosage form, many factors must be considered. These
can be broadly grouped into the following three categories. 1

Biopharmaceutical considerations, including factors affecting the absorption

of the drug substance from different administration routes;

Drug factors, such as the physical and chemical properties of the drug
substance;

Therapeutic considerations, including consideration of the clinical indication

to be treated and patient factors.

High-quality and efficacious medicines will be formulated and prepared only when all
these factors are considered and related to each other. This is the underlying principle
of dosage fonn design. 1
The oral route of drug administration is the most important method of administering
drugs for systemic effects. The goal of any drug delivery system is to provide a
therapeutic amount of drug to proper site(s) in the body to achieve promptly and then
maintain the desired drug concentration. The drug delivery system should deliver a
drug at a rate dictated by the needs of the body over a specified period of treatment.
This idealized objective points to the two aspects most important to drug delivery,
namely spatial placement and temporal delivery o f a drug. Spatial placement relates
to targeting of a drug to a specific organ or tissue, while temporal delivery refers to
controlling the rate of drug delivery to the target tissue. A bulk of research has been
directed at oral dosage forms that satisfy temporal aspect of drug delivery, since many
drugs require constant drug blood levels within therapeutic range for the required
duration of action to be effective.2 ,3

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Chapter 1

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1.1.1 Conventional drug delivery system

The oral route of drug administration is perhaps the most appealing route for the
delivery of drugs. O f the various dosage forms administered orally, the tablet is one of
the most preferred dosage forms because of its ease of manufacturing, convenience in
administration, accurate dosing, stability compared with oral liquids, and because it is
more tamperproof than capsules. The gastrointestinal tract provides sufficient fluid to
facilitate disintegration of the dosage form and dissolution of the drug. The large
surface area of gastric mucosa favors the drug absorption. Therefore, the oral route
has continued to be the most appealing route for drug delivery despite the
advancements made in the new drug delivery systems. Banker and Anderson stated
4 5

that at least 90% of drugs used to produce systemic effect are administered orally. '

The bioavailability o f drug is dependent on in vivo disintegration, dissolution, and

various physiological factors. In recent years, scientists have focused their attention
on the formulation of quickly disintegrating tablets. The task of developing rapidly
disintegrating

tablets

is

accomplished

by

using

suitable

diluents

and

superdisintegrant.
Conventional dosage forms of a drug such as tablets, capsules, solution, suspension,
suppository etc. releases the active ingredients into the absorption pool immediately.
The drug level time profile of such a system is as shown in Fig. 1.1.1

Figure 1.1.1 Typical drug blood level versus time profiles for intravenous
injection and an extra vascular route of administration.

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Chapter 1

Introduction

As seen in the Fig. 1.1.1 administration of drug either by intravenous injection or an

extra vascular route, for e.g., orally, intramuscular or rectally administration of the
conventional dosage form does not maintain the drug blood levels within the
therapeutic range for an extended period o f time. Here, the release of drug is much
faster than the absorption (K rK a). The short duration of action is due to the
inability of conventional dosage form to control temporal delivery.
One approach to maintain drug blood levels in the therapeutic range for longer
periods, for e.g., increasing the initial dose of an i.v. injections, toxic levels may be
produced at early times. This approach is undesirable and unsuitable. An alternate
approach is to administer the drug repetitively using a constant dosing interval, as in

Rang*

BLOOD LEVEL

/O IT K M rt/

multiple dose therapy. This result are shown in Fig. 1.1.2

Tb*-uputle
(Rang*

DRUG

ZZZZZZZ22ZZZZZZZZ
I m R ic H yi
Ronga

T IM E

{ftf*}

Figure 1.1.2 Typical blood level versus time profiles following oral multiple dose
therapy. 2
The concentration of a drug in the blood fluctuates over successive doses of most
conventional single unit oral dosage forms. The main reason for this is that the drug is
released immediately after administration (i.e. burst release effect). This causes the
drug blood concentration to rise quickly to a high value (peak) followed by a
2^
sudden decrease to a very low level (trough) as a result of drug elimination.

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Chapter 1

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The potential problems associated with multiple dose therapy are:

1. If the dosing interval is not appropriate for the biological half-life o f the drug,
large peaks and valleys in the drug blood level may result. For e.g., drugs
with short half-lives require frequent dosing to maintain therapeutic levels.
2. The drug blood level may not be within the therapeutic range at sufficiently
early times, an important consideration for certain disease states.
3. Patient non-compliance with the multiple-dosing regimen^can result in failure
o f this approach.
In many instances, the potential problems associated with conventional drug therapy
can be overcome by multiple dosing. However, these problems are significant enough
to make drug therapy with conventional dosage forms is less desirable than modified
release drug delivery systems.
This fact coupled with the intrinsic inability o f conventional dosage forms to achieve
spatial placement, is a compelling motive for investigation of modified release drug
delivery.
1.1.2 Nomenclature to describe modified release dosage forms
A number o f terms and phrases have been used to describe the oral dosage forms that
portray modified release properties; which include d ela ye d release, re p e a te d action,
p ro lo n g e d release, exten ded release, co n tro lled release an d su stain ed release. Each

drug delivery system is aimed at eliminating the cyclical changes in plasma drug
7
concentration seen after administration o f conventional delivery systems.
Modified release dosage forms are designed to provide quick achievement of a drug
plasma level that remains constant (i.e. controlled release) at a value within the
therapeutic range of a drug for a significant temporal period o f time or achievement of
a plasma concentration o f a drug that delivers at a slow rate (i.e. sustained release)
that stays within the therapeutic range for a longer period o f time. Based on the
assumption that a drug, which is to be incorporated into a modified release dosage
form, confers upon the body the characteristics o f a one-compartment open model,
then the basic kinetic design o f such a product may be assumed to contain two
portions, one that provides the initial priming/loading dose, and one that provides the
maintenance or sustained dose. To ensure that the therapeutic concentration of the
drug in the body remains constant, two conditions must be fulfilled, namely 1) the
zero order rate of drug release must determine the absorption rate o f the drug, and 2)

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Chapter 1

Introduction

the rate at which the drug is released from the maintenance dose (and subsequently
the absorption rate) should be equal to the rate of drug elimination at the required
steady-state concentration. A list of important terms that describe different modified
release dosage forms are defined below.

Modified release dosage forms: defined by the USP23 (1995) as those dosage forms
whose drug release characteristics of time course and/or location are chosen to
accomplish therapeutic or convenience objectives not offered by conventional dosage
forms.
Delayed release indicates that the drug is not being released immediately after
administration but at a later time.
Repeat action indicates that an individual dose is released fairly soon after
administration, and second or third doses are subsequently released at intermittent
intervals.
Prolonged release indicates that the drug is provided for absorption over a longer
period of time than from a conventional dosage form. However, there is an
implication that onset is delayed because o f an overall slower release rate from the
dosage form.
Extended release slow release o f the drug so that plasma concentrations are
maintained at a therapeutic level for a prolonged period of time (usually between 8
and 12 hr).
Controlled release The drugs are released at a constant (zero order) rate and provide
plasma drug concentration that remains invariant with time.
Sustained release: the pharmaceutical dosage form formulated to retard the release of
a therapeutic agent such that its appearance in the systemic circulation is delayed and /
or prolonged and its plasma profile is sustained in duration. The onset o f its
pharmacological action is often delayed, and the duration of its therapeutic effect is
sustained.
1.1.3 Sustained drug delivery
A new development namely, sustained drug release dosage forms, has evolved from
the need for a prolonged drug effect, a better control of drug administration and the
reduction o f side-effects.9,10 In general, the goal o f a sustained release dosage form is
to maintain therapeutic blood or tissue levels o f drug for an extended period. This is
usually accomplished by attempting to obtain zero-order release from dosage form.

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Chapter 1

Introduction

Fig. 1.1.3 represents a typical drug kinetic pattern for immediate release, controlled

IS

cro *
15'

33

S3 *

P la s m a C o n c e n tra tio n

< 1;

release (zero order) and sustained release dosage forms.

Time

Figure 1.1.3 Drug level versus time profile showing differences between zeroorder release (controlled release), sustained release (slow first-order), and
9
immediate release (from a conventional tablet or capsule) dosage forms.
In conventional drug delivery systems, the drug concentration in the blood rises when
the drug is being administered, then peaks and declines almost to zero. Each
individual drug has a maximum safe concentration and a minimum effective
concentration. Fluctuations in plasma concentration may mean that drug levels may
swing too high leading to toxic side-effects; alternatively drug may fall too low
leading to a lack of efficacy. Furthermore, the plasma drug concentration in a patient
at a particular time depends on the compliance with the prescribed dosage interval.
Sustained drug delivery systems maintain the drug effect in desired therapeutic range
with just a single dose, simulating an intravenous infusion o f a drug, localizing drug
delivery to a particular body compartment, improving tolerability and reducing the
need to follow-up pharmaceutical care (i.e. improving patient comfort and
compliance). These dosage forms could also preserve medications that are rapidly
destroyed by the body.10,11

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Chapter 1

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1.13.1 Principle of sustained drug delivery9

The conventional dosage forms release their active ingredients into an absorption pool
immediately. The absorption pool represents a solution of the drug at the site of
absorption. The terms Kr, Ka and Ke are first order rate constants for drug release,
absorption and overall elimination respectively. Immediate release o f drug from
conventional dosage form implies that Kr >

Ka. Alternatively speaking the

absorption o f drug across a biological membrane is the rate limiting step. For nonimmediate release dosage forms, Kr < Ka, i.e., the release o f drug from the dosage
form is the rate-limiting step.
The main objective in designing a sustained release system is to deliver the drug at a
rate necessary to achieve and maintain a constant blood level. This rate should be
analogous to that achieved by continuous i.v. infusion where the drug is provided to
the patient at a constant rate just equal to its rate of elimination. This implies that the
rate o f delivery must be independent o f the amount o f drug remaining in the dosage
form and constant over time. The release o f a drug from the dosage form should
follow zero order kinetics, as shown by the equation 1,
Kr = Rate In = Rate Out = Ke x Cd x Vd

(1)

Where, Kr = Zero order rate constant for drug release (amount per time),
Ke= First order rate constant for overall drug elimination (time-1),
Cd = Desired drug level in the body (amount per volume),
Vd=Volume space in which the drug is distributed (liters).
The values o f Ke, Cj and Vd needed to calculate Kr are obtained form appropriately
designed single dose pharmacokinetic study. It is important to recognize that while
zero order release may be desired theoretically; non-zero order release may be
equivalent clinically to constant release in many cases.
1.1.3.2 Advantages of sustained drug therapy

1. Avoid patient compliance problems.

2. Employ less total drug,
a) Minimize or eliminate local side effects
b) Minimize or eliminate systemic side effects
c) Obtain less potentiation or reduction in drug activity with chronic use
d) Minimize drug accumulation with chronic dosing

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Chapter 1

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3. Improve efficiency in treatment,

a) Cure or control condition more promptly
b) Improve control o f condition i.e. reduce fluctuation in drug level
c) Improve bioavailability of some drugs
d) Make use o f special effects, e.g. sustained release aspirin for relief of
arthritis in morning by dosing before bedtime
4. Economy
Although the initial unit cost of most sustained release drug delivery systems is
usually greater than that o f conventional drug delivery systems, but the average cost
o f treatment over an extended time period may be less. Economy may result from a
decrease in nursing time, reduction in hospitalization, less lost work time, etc. The
most important reason for sustained drug therapy is improved efficiency in the
treatment i.e., optimized therapy.
1.1.3.3 Disadvantages of sustained drug therapy
1. Administration of sustain release medication does not permit the prompt
termination of therapy.
2. The physician has less flexibility in adjusting the dosage regimens. This is
fixed by the dosage form design.
3. Sustained release forms are designed for normal population i.e., on the basis of
average drug biologic half-life. Problems may be observed in diseased
conditions where drugs disposition is altered, if the liver and kidney functions
are impaired.
4. Economic factors must also be assessed, since more costly processes and
equipments are involved in manufacturing o f any sustained release dosage
forms.
1.1.4 Release pattern of drug from polymer matrices
Recently, several technical advancements have been made in the development of new
techniques for drug delivery. These techniques are capable of controlling the rate of
drug delivery, sustaining the duration of therapeutic activity, and / or targeting the
delivery o f drug to a tissue. Although these advancements have led to the
development of several novels drug delivery systems that could revolutionaries the
method o f medication and provide a number o f therapeutic benefits. It also creates

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Chapter 1

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some confusion in the terminology between controlled release and sustained

release. Unfortunately these terms have been often used interchangeably in the
scientific literature and technical presentations over the years.
1.1.4.1 Methods for preparing sustained release oral dosage form
The most acceptable technologies used to obtain sustained release oral products are as
follows:12
1. Release from slow eroding solid matrices,
2. Release from solid hydrophilic gel matrices,
3. Release from porous inert solid matrices,
4. Release from coated granules disintegrating at a controlled rate,
5. Release from granules coated with diffusion controlling membrane,
6. Release from ion exchange resin complexes, and
7. Release by reducing the solubility of drugs.
1.1.5 Formulation of modified release dosage forms
The basic principle that governs all modified release dosage forms is drug diffusion
that occurs from a region o f high concentration to a region of low concentration. This
concentration difference is the driving force for drug diffusion out of the system. The
inside o f the system should have lower water content initially than the surrounding
g

medium to control the diffusion of a drug effectively.

Different methods have been employed to provide modified drug release, which
include modifications to the physical and chemical properties o f the drug or changes
to the dosage form as indicated in Fig. 1.1.4

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Chapter 1

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1 8

Figure 1.1.4 Summarized representation of the methods to modify drug release.

1.1.5.1 Methods to modify drug release by drug modification
These methods take advantage of the changes in the physicochemical properties of
drug moieties caused by complex formation, drug adsorbate preparations and prodrug
synthesis. These modifications are possible only with drug moieties containing
appropriate functional groups. This approach is independent o f the dosage form
design.7
Fig. 1.1.5 shows the mechanisms o f sustained release based on drug modification. In
the case o f drug complexes the effective release rate o f the drug is a function o f two
processes, including the rate of dissolution and breakdown of the complex in a
solution. If the rate of dissolution is greater than the rate o f dissociation, a zero-order
release pattern might be achieved. In this case, the concentration of the complex is
maintained at its saturation point if the solubility o f the complex is sufficiently low so
that excess solid complex is present during the onset o f the maintenance time. If the
rate of dissociation is greater than the rate o f dissolution, the dissolution o f the
complex will be the rate-determining step.

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Introduction

Chapter 1

Figure 1.1.5 Mechanisms of sustained modification.7

Another approach for drug modification is through the formulation of a prodrug. This
can be achieved through designing a bio-reversible derivative (prodrug) that can
afford an increased or selective transport of the drug to the site of action
(e.g., levodopa as prodrug for the central nervous system anti-parkinsonism agent
dopamine) or by designing a derivative that goes everywhere in the body but
undergoes bio-activation only on the target. The solubility, specific absorption rate
and elimination rate constant of an effective prodrug should be significantly lower
than that of the parent drug. In drug adsorbates, drug availability is determined only
by the rate of dissociation and by the access of the adsorbate surface to water as well
as the effective surface area of the adsorbate. 7
1.1.5.2 Methods to modify drug release by dosage form modification
The most modified release dosage forms of this class employ either an embedded
matrix or a physical barrier principle to provide slow release of the maintenance dose.
The techniques used to build this matrix or barrier into the dosage form include the

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Chapter 1

Introduction

monolithic or matrix systems, the reservoir or membrane controlled systems, the

T 8 13

osmotic pump systems, coated heads and micro encapsulation.

1.13.2.1 Monolithic or matrix systems

These systems can be divided into two groups: (1) those with drug particles dispersed
in a soluble matrix, with drug becoming available as the matrix dissolves or swells
and dissolves (hydrophilic colloid matrices); and (2) those with drug particles
dispersed in an insoluble matrix, with drug becoming available as a solvent enters the
matrix and dissolves the particles (lipid matrices and insoluble polymer matrices)
Drugs dispersed in a soluble matrix rely on slow dissolution of the matrix to provide
sustained release. Excipients used to provide a soluble matrix often are those used to
make soluble film coatings. Alternatively, slowly dissolving fats and waxes can be
used. Synthetic polymers, such as poly orthoesters and poly anhydrides, have also
been used. These polymers undergo surface erosion with little or no bulk erosion. If
the matrix is presented with conventional tablet geometry, then on contact with
dissolution media the surface area of the matrix decreases with time, with a
concomitant decrease in drug release.
Drug particles may be incorporated into an insoluble polymer matrix. Drug release
from these matrices follows penetration o f fluid into the formulation, followed by
dissolution o f the drug particles and diffusion of the solute through fluid-filled pores.
This type of delivery system would not be suitable for the release of compounds that
are insoluble or those compounds that have low aqueous solubility. Excipients used in
the preparation o f insoluble polymers include hydrophobic polymers such as
polyvinyl acetate, ethyl cellulose and some waxes. At this point each of the three main
types of monolithic/matrix systems will be discussed.
1.1.5.2.1.1 Lipid matrix systems
Wax matrices prepared by direct compression; hot-melt granulation or roller
compression; have their active agent contained in a hydrophobic substance that
remains intact during drug release. The release o f the drug depends on an aqueous
medium dissolving the channeling agent, which leaches out of the matrix forming
capillary pores. The active ingredient then dissolves in the aqueous medium and
diffuses out of the matrix, by way of the water-filled capillaries. A typical formulation
consists o f an active drug, a wax matrix former (hydrophobic material that are solids
at room temperature and do not melt at body temperature, e.g., hydrogenated

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Chapter I

Introduction

vegetable oils, cottonseed oils, soya oils, microcrystalline wax and camauba wax), a
channeling agent (soluble in the GIT, in water and leaches out of the formulation
leaving tortuous capillaries through which the dissolved drug may diffuse in order to
be released, e.g., sodium chloride and sugars), solubiliser and pH modifier, an antiadherent/glidant and a lubricant.
1.1.5.2.1.2 Insoluble polymer matrix systems
Drugs are embedded in an inert polymer, which is not soluble in the gastrointestinal
fluid. Drug release has been compared to the leaching from a sponge. The release rate
depends on drug molecules in aqueous solution diffusing through a network of
capillaries formed between compact polymer particles. The factors influencing drug
release rate from insoluble polymer matrix systems are

Pore structure - pore forming salts and compression force,

Excipients - wettability changed by the soluble and insoluble components,

Particle size of polymer component - influences the surface area exposed to

the medium.

There are three primary mechanisms by which active agents can be released from a
matrix delivery system, which involve diffusion, degradation, and swelling followed
by diffusion. Any or all of these mechanisms may occur in a given drug release
system. Diffusion occurs when a drug or other active agent passes through the
polymer that forms the modified-release device. The diffusion can occur on a
macroscopic scale - as through pores in the polymer matrix - or on a molecular level,
by passing between polymer chains. The particle size of the insoluble matrix
components influences the release rate, larger particles leading to an increase in
release rate. This is attributed to these coarser particles producing matrices with a
more open pore structure. An increase in drug loading tends to enhance release rate,
but the relationship between the two is not clearly defined. One possible explanation
may be a decrease in the tortuosity o f the matrix.
An insoluble polymer and an active agent have been mixed to form a homogeneous
system, also referred as a matrix diffusion system as shown in Fig. 1.1.6. Diffusion
occurs when the drug passes from the polymer matrix into the external environment.
As the release continues, its rate normally decreases with this type of system, since
the active agent has a progressively longer distance to travel and therefore requires a
longer diffusion time to be released.

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Chapter 1

Introduction

Increasing tints of exposure t o

T im e = 0

D r u g d iffu s io n w it h

Drug D isp ersed

in P o ly m e r

d is s o lu t io n m e d ia

Figure 1.1.6 Drug delivery from an insoluble polymer matrix diffusion system.
1.1.5.2.13 Hydrophilic colloid matrix systems
A hydrophilic matrix, controlled release system is a dynamic one involving polymer
wetting, polymer hydration, gel formation, swelling and polymer dissolution. At the
same time, other soluble excipients or drugs will also wet, dissolve, and diffuse out of
the matrix while insoluble materials will be held in place until the surrounding
polymer/excipient/drug complex erodes or dissolves away.
The mechanisms by which drug release is controlled in matrix tablets are dependent
on many variables. The main principle is that the water-soluble polymer which
present throughout the tablet, hydrates on the outer tablet surface to form a gel layer
(Fig. 1.1.7). Throughout the life o f the ingested tablet, the rate o f drug release is
determined by diffusion (if soluble) through the gel and by the rate of tablet erosion.
With soluble drugs, the primary drug release mechanism is by diffusion through the
gel layer and with insoluble drugs, the primary drug release mechanism is by surface
erosion. A fast rate o f hydration followed by quick gelation and polymer/polymer
coalescing is necessary for a rate-controlling polymer to form a protective gelatinous
layer around the matrix. This prevents the tablet from immediate disintegration,

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Chapter^

Introduction

resulting in premature drug release. Fast polymer hydration and gel layer formation
are critical when formulating with water-soluble drugs and water-soluble excipient.

Initial Wetting

Exp anti on of Gel Layer

Tablet erosion

Soluble drug

Insoluble drug

Figure 1.1.7 Drug release from a matrix tablet.

14

These swellable-soluble matrices are hydrogels that swell on hydration. The systems
are capable of swelling followed by gel formation, erosion and dissolution in aqueous
media. Their behavior is in contrast to a true hydrogel, which swells on hydration but
does not dissolve. Drug particles are dispersed in an insoluble matrix and the dmg
becomes available as the solvent enters the matrix and dissolves the drug particles.
This is enhanced by the swelling, which is followed by gel formation, erosion of the
matrix system and the dissolution of the drug. Hydrophilic polymer matrix systems
comprise a mixture of the drug, the hydrophilic colloid, release modifiers and
lubricant/glidant. Diffusion of the drug through the hydrated matrix is the rate limiting
step in drug release. The tortuosity of the diffusion path and the micro-viscosity and
interactions within the interstitial continuum govern the diffusion of the drug through
the hydrated gel layer and hence, the release of the drug.
Two common types of hydrophilic matrix systems are the true gels which are crosslinked polymeric structures formed Drug diffusion with increasing time of exposure
to dissolution media by chemical bonds (covalent) or physical bonds (helix formation
based on hydrogen bonds or ionic interactions), for which gelatin is an excellent
polymeric example, and the viscous matrices which are simple entanglements of
adjacent polymer chains, For e.g., HPMC and alginates.

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Introduction

ChagterJ'

Table 1.1.1 Comparison of different types of hydrophilic colloid matrix systems.

True gel matrices

The diffusion pathway is via the

V is c o u s m a tric e s

The diffusion pathway is via the

continuous phase in the interstices

continuous

phase

of the gel

between

the

trapped
adjacent

polymeric chains

The cross-links are more or less

fixed after the gel has formed

There are no fixed cross-links

The bulk viscosity of the gel is *

The bulk viscosity is related to

derived from the structure of the

the enlargement of adjacent

cross-linked polymeric chains with

polymer chains which are free

a contribution from the continuous

to move within the continuous

phase

phase

Bulk viscosity generally does not

Bulk viscosity correlates with

correlate with diffusion

diffusion

Diffusion in the gel correlates with

rnicroviscosify

Table 1.1.1 compares the different types of hydrophilic colloid matrix systems, which
are the true gel matrix system and the viscous matrix system. The two are more like
extreme opposites of each other in terms o f their cross-linked chain structure,
viscosity and the ways they release drug substances.
1.1,6 Polymers in drug delivery
One of the most remarkable and useful features o f a polymer's swelling ability
manifests itself when that swelling can be triggered by a change in the environment
surrounding the delivery system. Ranges o f materials have been employed to control
the release o f drugs and other active agents. The earliest o f these polymers were
originally intended for non-biological uses and were selected because of their
desirable physical properties. To be successfully used in controlled drug delivery
formulations, a material must be chemically inert and free o f leachable impurities. It
must also have an appropriate physical structure, with minimal undesired aging and
be readily processable. However, in recent years additional polymers designed
primarily for medical applications have entered the arena o f controlled release. Many
g

of these materials are designed to degrade within the body.

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Chapter 1

Introduction

Hydrophilic matrices are an interesting option when developing an oral sustained

release formulation. They can be used for controlled release of both water soluble and
water insoluble drugs. The release behavior o f drugs varies with the nature o f the
matrix and its complex interaction of swelling, diffusion and erosion process.

15-19

1.1.6.1 Classification of hydrophilic polymers

The hydrophilic polymers can be arranged into three broad groups:

20

1. Non-cellulose Natural or Semisynthetie Polymers: These are products of

vegetable origin and are generally used for pharmaceutical purpose. Agar
alginates

, chitosan

, starches

, xanthan gum

, guar gum

21

* , carrageenan

etc., are commonly used polymers.

2. Polymer of Acrylic acid: These are arranged in the earbomer group and
commercialized under the brand name of Carbopol40. The major disadvantage
o f this type of polymers is its pH dependent gelling characteristics. 41' 44
3. Cellulose Ethers: This group is semi-synthetic cellulose derivatives is the
most widely used group of polymers. Non-ionic polymers such as HPMC of
different viscosity grades are widely used. 45 47 Methylcellulose 48, in
contrast, has not proved especially use&l in this field. In the last few years a
number o f interesting applications o f the ionic sodium CMC have been found.
48 -52
3 5 3 -5 9

1.1.6.2 Advantages of hydrophilic matrix tablets

1. Proper control o f the manufacturing process, reproducible release profiles are

possible.
2. Though the structure makes the immediate release of a small amount o f active
principle, there is no risk o f dose dumping.
3. Their capacity to incorporate active principle is large, which suits them to
delivery o f large doses.
4. The manufacturing processes are notably straight forward. The usual route of
formulating tablets is done via direct compression or by wet granulation.
5. Large variety of non-expensive gelling agents is approved for oral use by the
competent official organizations.
6. Comparatively simple concept.

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ChapterJ^

Introduction

1. Excipients are generally economic and are usually GRAS (Generally

Regarded As Safe).
8. Capable of sustaining high drug loadings.
9. Erodible, so reducing the possibility of ghost matrices.
10. Well established technology.
1.1.63 Disadvantages of hydrophilic m atrix tablets
1. For a hydrophilic sustained release matrix tablet, in which the release is
mainly controlled by erosion o f the swollen polymer gel barrier at the tablet
surface, the presence of food may shear the hydrated polymer gel layer to
cause dose dumping or it may block the pores o f the matrix and inhibit the
drug release rate.
2. Release of the drug is dependent on two diffusion processes.
[a] penetration of water through the hydrated matrix into the non-hydrated
core, and
[b] diffusion of dissolved drug through the hydrated matrix,
3. Required batch-to-batch consistency in the matrix forming materials, other
components and process parameters.
4. Need optimal rate-controlling polymers for different actives.
1.1.7 M atrix diffusion-controlled drug delivery systems 60,61
In this type o f sustained release drug delivery systems, the drug reservoir results from
the

homogeneous dispersion o f drug particles in either a lipophilic or a hydrophilic

polymer matrix. Fig. 1.1.8 shows the top o f a swellable matrix tablet during drug
release showing the three fronts.
The swelling front, the boundary between the glassy polymer and its rubbery phase.
The diffusion front, the boundary between the solid as yet undissolved drug and the
dissolved drug in gel layer, and
The erosion front, the boundary between the matrix and the dissolution medium.
The mechanisms of drug release from swellable matrix are diffusion of drug though
the gel layer and drug transport due to relaxation of the polymer. The rate o f diffusion
through the gel layer depends on drug dissolution and matrix erosion, both evidently
affecting the drug concentration gradient in gel layer. Drug release from swellable
matrix tablet is strictly linked to gel layer dynamics, also where the solubility o f the

IExploitation

o f N atural (product In (Formulation (Design o f ji M odel Drug

18

CfwgterJ^

Introduction

drag is so low that the possibility exists for it to be released as solid particles from the
dissolving layer of gel.

&* firout

. .

ti* .

.-iii*.-. .

SHAs Iod front

Figure 1.1.8 Picture of the top of a swellable matrix tablet during drug release
18
showing the three fronts.
The drug dispersion in the polymer matrix is accomplished either by blending a dose
of finely ground drag particles with a viscous liquid polymer or a semisolid polymer,
followed by cross linking of polymer chains or mixing drag particles with a melted
polymer. The resultant drag-polymer dispersion is then extruded to form drag
delivery devices of various shapes and sizes designed for specific application. It can
also be fabricated by dissolving the drag and the polymer in a common solvent,
follows by solvent evaporation in a mold at an elevated temperature and/or under a
vacuum.
The rate of drag release from this matrix diffusion controlled drag delivery systems is
time dependent and defined in equation 2,

dq/dt = (A * Cr * Dp / 2 t ) 1/2

(2)

Where, A is the loading dose initially dispersed in the polymer matrix, Cr is the drag
solubility in the polymer, which is also the drag reservoir concentration in the

Exploitation o f N a tu ra l (Product In Formulation (Design ofJ4 M odel (Drug

19

Chapter 1

Introduction

polymer matrix, and Dp is the diffusivity of the drug molecule in the polymer matrix.
The following equation is obtained on integration of equation 2,

Q/t1/2 = (2A * Cr * D p )1/2

(3)

Where, Q defines the flux of drug release at steady state from matrix diffusion
controlled drug delivery system.
Hydrophilic matrix dosage forms essentially consist of a compressed blend of
hydrophilic polymer and drug. According to the generally accepted mechanism
(Fig. 1.1.8), the drug release from hydrophilic matrix dosage forms starts when the
tablet comes in contact with GI fluid. The surface of the tablet hydrates to release
exposed drug and at the same time form a viscous polymer mucilage or gel. This gel
fills the interstices within the tablet retarding further ingress of liquid.

E xploitation o f N a tu ra l (product In (Formulation (Design ofjA M odel Drug

20

Chapter 1

Introduction

1.2 Introduction to disintegrants

Despite increasing interest in controlled-release drug delivery systems, the most
common tablets are those intended to be swallowed whole and to disintegrate and
release their medicaments rapidly in the GIT. The proper choice o f disintegrant and its
consistency of performance are of critical importance to the formulation development
of such tablets. In more recent years, increasing attention has been paid to fonnulating
not only fast dissolving and/or disintegrating tablets that are swallowed, but also
orally disintegrating tablets that are intended to dissolve and/or disintegrate rapidly in
the mouth.
Bioavailability o f a drug depends on absorption o f the drug, which is affected by
solubility o f the drug in GI fluid and permeability o f the drug across GI membrane.
The drugs solubility mainly depends on physical - chemical characteristics o f the
drug. However, the rate of drug dissolution is greatly influenced by disintegration of
the tablet.
The drug will dissolve at a slower rate from a nondisintegrating tablet due to exposure
of limited surface area to the fluid. The disintegration test is an official test and hence
a batch of tablet must meet the stated requirements o f disintegration. 62"64
1.2.1 Disintegrants 65,66

Figure 1.2.1 Schematic representation of tablet disintegration and subsequent

drug dissolution.

l.Exploitation o f N a tu ra l (Product In (Formulation (Design ofJL M o d el (Drug

21

Chapter^

Introduction

Disintegrant is a term applied to various agents added to tablet formulation for the
purpose o f causing the compressed tablet to break apart when placed in an aqueous
environment and this process of desegregation of constituent particles before the drug
dissolution occurs, is known as disintegration process and excipients which induce
this process are known as disintegrants. The objectives behind addition of
disintegrants are to increase surface area of the tablet fragments and to overcome
cohesive forces that keep particles together in a tablet. Fig. 1.2.1 shows schematic
diagram of disintegration.
Basically, the major function of disintegrant is to oppose the efficiency of tablet
binder and physical force that acts under compression to form the tablet.
Disintegrants, act by different mechanisms. Disintegrants that enhance the action of
capillary forces in a rapid uptake of aqueous liquids and those that swell in contact
with water are considered the more important. These mechanisms include factors like
deformation of particles, capillarity, heat of wetting, particle- particle repulsion and
hydrogen bond annihilation. Some others, less common mechanisms are: act by
melting at body temperature, releasing gases to disrupt the tablet structure and those,
which destroy the binder by enzymatic action.
To obtain a rapid disintegration a disintegrant force must develop inside the tablet that
is capable of weakening and breaking inter-particle bonds. This is generated by the
replacement of solid/air with solid/liquid interfaces. The displacement of air by water
or aqueous liquids is a wetting process that may lead to hydration of the involved
particles and produce disintegration. Particles with different properties will produce
greater disruptive shear forces and smaller disintegration times. This means that
disintegration could be a function of a given surface of contact between particles with,
different hydration properties.
1.2.2 The ideal characteristics of disintegrant

Poor solubility

Poor gel formation

Good hydration capacity

Good molding & flow property

No tendency to form complex with drug

Exploitation o f tHaturaC(product In Formulation Design o f j i !ModeC<Drug

22

Introduction

Chapter^
1.2.3 Types of disintegrants based on their working mechanisms

67 68

1.2.3.1. Disintegrants those propagate capillary effects or wicking or porosity

1.2.3.2. Disintegrants those swell
1.2.3.3. Gas producing disintegrants
1.2.3.4. Enzymes as disintegrants
1.2.3.5. Heat of wetting (air expansion) as disintegrants
1.2.3.6. Due to disintegrating particle/particle repulsive forces act as disintegrant
1.2.3.7. Deformation of particles as a disintegrant
1.2.3.1 Disintegrants those propagate capillary effects or wicking or porosity

69-74

Water uptake caused by capillary forces is crucial factor in the disintegration process
of many formulations. In such system, the pore structure o f the tablet is of prime
importance, and any inherent hydrophobicity o f the tablets mass will adversely affect
it. Therefore, disintegrants in this group must be able to maintain a porous structure in
the compressed tablet and show a low interfacial tension toward aqueous fluid. Rapid
penetration by water throughout the entire tablet matrix is essential to facilitate its
break up. Disintegration by capillary action is always the first step. When we put the
tablet into suitable media, the media penetrates into the tablet and replaces the air
adsorbed on the particles, which weakens the intermolecular bond and breaks the
tablet into fine particles.
Water uptake by tablet depends upon hydrophilicity o f the drug /excipient and on
tableting conditions. These types o f disintegrants, maintenance o f porous structure
and low interfacial tension towards aqueous fluid is necessary which helps in
disintegration by creating a hydrophilic network around the drug particles. Tablet
porosity provides pathways for the penetration of fluid into tablet. The disintegrant
particles (with low cohesiveness and compressibility) themselves act to enhance
porosity and provide these pathways into tablet. Liquid is drawn up into these
pathways through capillary action and rupture the interparticle bonds causing the
tablet to break apart. Concentrations of disintegrants that ensure a continuous matrix
o f disintegrant are desirable and level between 5 - 20 % are common. For e.g., starch,
MCC, cross-povidone etc.
1.2.3.2 Disintegrants those sw ell75 77
The most widely accepted general mechanism of action for tablet disintegration is
swelling. This class of disintegrants acts by swelling in the presence o f aqueous GI

E xploitation o f N a tu ra l (Product In Pormulation Design o f M o d e l Drug

23

Chapter 1

Introduction

fluids. Tablets with high porosity show poor disintegration due to lack o f adequate
swelling force. On the other hand, sufficient swelling force is exerted in the tablet
with low porosity. It is worthwhile to note that if the packing fraction is very high,
fluid is unable to penetrate in the tablet and disintegration is again slows down.
Main problem with this group of disintegrants is that on swelling, many disintegrants
produce a sticky or gelatinous mass that resists break up o f the tablet, making it
particularly important to optimize the concentration in the formulation. Although
untreated starches do not swell sufficiently, certain modified forms, such as SSG, do
swell in cold water and are better as disintegrant. Alginic acid, agar, karaya and
tragacanth etc., are also used as disintegrant. Fig. 1.2.2 shows disintegration
mechanism by wicking and swelling.

SWELLING

1
& &
I

S A

(a)

(b)

Figure 1.2.2 Disintegration mechanism (a) by wicking and (b) by swelling

mechanism.
Black particles in both cases are disintegrating agent.
1.2.3.3 Gas producing disintegrants

78

Gas producing disintegrants are used when rapid/extra rapid disintegration or a

readily soluble formulation is required. This group of disintegrants acts by evolution
o f a gas when tablet is exposed to the aqueous GI fluids. The most common
effervescent agents are mixture o f citric and tartaric acid plus carbonates or
bicarbonates. Carbon dioxide released within tablets on wetting due to interaction
(Exploitation o f N a tu ra l (Product In (Formulation (Design ofJL M o d el (Drug

24

J 2} o f 'M
C h a p te r 1_________________________________________________________________In tr o d u c tio n

between bicarbonate and carbonate with citric or tartaric acid. The tablet disintegrates
due to generation o f pressure within the tablet.
Their main drawback is the need for more stringent environment control during
manufacturing and storage. In particular, gas-producing disintegrants are quite
sensitive to small changes in humidity level & temperature. So, strict control of
environment is required during manufacturing o f the tablets. The effervescent blend is
either added immediately prior to compression or can be added in to two separate
fraction of formulation.
1.2.3.4 Enzymes as disintegrants

78

Such tablets are not naturally very cohesive and thus have been manufactured by a
wet granulation process. There was a requirement to involve the binders; on the same
time addition o f small quantities o f appropriate enzyme may be sufficient to produce
rapid disintegration. Some times enzymes presents in the body act as disintegrants.
These enzymes destroy the binding action of binder and helps in disintegration.
Table 1.2.1 shows list o f enzymes used in tablet formulation.
Table 1.2.1 A list of disintegrating enzymes.
ENZYME

BINDER

Amylase

Starch

Protease

Gelatin

Cellulase

Cellulose and its derivatives

Invertase

Sucrose

1.2.3.5 Heat of wetting (air expansion) as disintegrants

78

Matsumaru was the first to propose that the heat o f wetting o f disintegrat particles
could o f mechanism o f action. When disintegrants with exothermic properties gets
wetted, localized stress is generated due to capillary air expansion, which helps in
disintegration o f tablet. It has also been proposed that disintegration action might
result from expansion o f the entrapped air owing to generation o f heat o f wetting.
For e.g., starch. This explanation, however, is limited to only a few types of
disintegrants and can not describe the action o f most modem disintegrating agents.

E xploitation o f N a tu r a l (product I n Formulation <Design o f A !ModeC<Drug

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Chapter 1

Introduction

1.2.3.6 Due to disintegrating particle/particle repulsive forces act as disintegrant

IS

Researchers found that repulsion is secondary to wicking where disintegration of

tablet made with non-swellable disintegrants. Guyot-Hermann has proposed a
particle repulsion theory,

that non-swelling particle also cause disintegration of

tablets. The electric repulsive forces between particles are the mechanism of
disintegration where water is required to initiate mechanism.
1.2.3.7 Deformation of particles as a disintegrant

79

It had proved that during tablet compression, disintegrant particles get deformed and
these deformed particles get into their normal structure when they come in contact
with aqueous media or water. This increase in size o f the deformed particles produces
a break up o f the tablet. For e.g., the swelling capacity o f starch was improved when
granules were extensively deformed during compression.

D E F O R M A T IO N

R E P U L S IO N

o
o

o
o

o
o

o
o

o
o

o
o
o

Particles swell to precom pression

W a te r is drawn into the pores and

size and b re a k up the m atrix

particles repel each other because

of the resulting electrical force

Figure 1.2.3 Disintegration mechanism by deformation and repulsion.

1.2.4 Methods of addition of disintegrants

80

The method o f addition of disintegrants to a tablet is very crucial part. Disintegrating

agent can be added either prior to granulation (intragranular) or prior to compression
(after granulation i.e. extragranular) or at the both processing steps. Extragranular
fraction o f disintegrant (usually, 50% o f total disintegrant requires) facilitates breakup

Exploitation o f N atural (Product In Formulation Design ofJL M odel Drug

26

Chapter 1

Introduction

of tablets to granules and the intragranular addition o f disintegrants produces further

erosion of the granules to fine particles.
The extragranular portion ensure rapid disintegration, while the intragranular fraction
leads to harder tablets and a finer size distribution on dispersion. There are advantages
to be gained in dividing the disintegrant into both extra- and intragranular portions.
1.2.5 Factors affecting disintegration
1.2.5.1 Effect of fillers 81' 82
The solubility and compression characteristics o f fillers affect both the rate and
mechanism o f disintegration of tablet. If soluble fillers are used then it may cause
increase in viscosity o f the penetrating fluid which tends to reduce effectiveness of
strongly swelling disintegrating agents and as they are water soluble, they are likely to
dissolve rather than disintegrate. Insoluble diluents produce rapid disintegration with
adequate amount of disintegrants. Chebli and cartilier proved that tablets made with
spray dried lactose (water soluble filler) disintegrate more slowly due to its
amorphous character and has no solid planes on which the disintegrating forces can be
exerted than the tablet made with crystalline lactose monohydrate.
1.2.5.2 Effect of binder 83"86
The concentration o f binder can also affect the disintegration time o f tablet. It was
observed that as the concentration o f binder is increased there was increased in
disintegration time. The binding capacity of binder increases, disintegrating time of
tablet increases and this counteract the rapid disintegration.
1.2.5.3 Effect of lubricants 67 87
Mostly lubricants are hydrophobic in nature (Mg-stearate) and they are usually used
in smaller size than any other ingredient in the tablet formulation. When the mixture
is mixed, lubricant particles may adhere to the surface o f the other particles. This
hydrophobic coating inhibits the wetting and consequently tablet disintegration.
Lubricant has a strong negative effect on the water uptake if tablet contains no
disintegrants or even high concentration o f slightly swelling disintegrants.
On the contrary, the disintegration time is hardly affected if there is some strongly
swelling disintegrants are present in the tablet. For e.g,, SSG whose effect remains
unaffected in the presence o f hydrophobic lubricant.

(Exploitation o f N atural (product In Formulation (Design o f jl M odel Drug

27

Introduction

Chapter I
1.2.5.4 Effect of compression force or hardness of tablet

88 89

An unusual occurrence o f decreasing tablet disintegration time with increasing tablet

hardness was explored. For e.g., tablets were made with varying ratios of starch
disintegrant to starch paste and compressed with eight different forces. There was an
unusual disintegration pattern was observed.
1.2.6 Classification of disintegrating agents according to its chemical nature

90

1. Starches: Natural starch (com, potato), pregelatinized starch, modified com

starch, SSG etc.
2. Clays: Veegum HV
3. Celloluose: Purified cellulose, methyl cellulose, sodium CMC, MCC
4. Algins: Alginic acid
5. Gums: Agar, guar gum, locust bean gum, karaya gum, pectin, tragacanth etc.
6. Miscellaneous: Surfactants, natural sponge, resins, effervescent mixtures,
hydrous aluminum silicate etc.

Exploitation o f N a tu ra l (Product In form ulation (Design qfJL M o d el (Drug

28

Chapter 1

Introduction

1.3 Introduction to gums and mucilages

1.3.1 Introduction
Robbins has stated, "in spite of the problems which have beset the gums market in
recent years, the fact remains that in many cases the gums provide a valuable source
of income for many poor smallholders or itinerant labourers, either in very poor
countries or in the poorest regions o f rather more developed countries. As such they
are important commodities

This remains true today. Tens o f thousands of people

worldwide, living in regions ranging from semi-arid lands to moist rainforest, depend
on the collection of gums, resins and latexes as a means of cash income. Equally,
many millions o f people in consuming countries make use o f these products in their
everyday life .91
Mother Nature has gifted India with great variety o f flora and fauna. Since centuries
man has made an effective use of materials from natural origins in the medical and
pharmaceutical field. Now a day, the whole world is turning towards natural drugs
and excipient. The natural materials do hold advantages over the synthetic materials
because they are non toxic, less expensive and freely available. Further, it can be
modified to obtain tailor made materials for drug delivery system and then can
compete with the synthetic products available in the market. Various kind of natural
gums are used in the food industry and are regarded as safe for human consumption. It
should be noted that many old materials compete successfully today after almost a
century o f efforts to replace them. It is usual balance o f economics and performance
that determines the commercial realities.

92 - 95

Gums are considered to be pathological products formed upon injury o f the plant or
owing to unfavorable conditions, such as drought, by a breakdown of cell walls (extra
cellular formation; gummosis). Conversely, mucilages are generally normal products
o f metabolism, formed within the cell (intracellular formation) and/or are produced
without injury to the plant. An effort has made to distinguish between mucilage and
gums on the basis that gums readily dissolve in water, whereas, mucilage form slimy
masses. Other investigators have tried to distinguish them on the basis that mucilages
are physiological products and gums are pathological products.

Acacia, tragacanth,

guar gum etc, are examples of gums while mucilages are often found in different parts

Exploitation o f N a tu ra l (Product In Permutation (Design ofJL Mode [(Drug

29

Chagte)^

Introduction

of plants. For e.g., in epidermal cells of leaves (senna), in seed coats (linseed,
psyllium), roots (marshmallow), barks (slippery elm) and middle lamella (aloe).

97

Gums and mucilage are plant hydrocolloids. They are translucent amorphous
substances. They are polymers of monosaccharide or mixed monosaccharide and
many of them are combined with uronic acids. Gums and mucilage have similar
constituents and on hydrolysis yield a mixture of sugars and uronic acids. Mucilages
are neutral or acidic or mixtures of both.
Gums and mucilages have hydrophilic molecules, which can combine with water to
form viscous solutions or gels. The nature of the molecules influences the properties
of the various gums. Linear polysaccharide molecules occupy more space and are
more viscous than highly branched molecules of the same molecular weight. The
branched compounds form gels more easily and are more stable because extensive
interaction along the chains is not possible.
Mucilage is a thick gluey substance produced by many plants and some
microorganisms. Mucilage is an exopolysaccharide a polymer composed of sugar
residues and secreted by a microorganism into the surrounding environment.
Mucilage in plants act as water storage, protection for seed germination, as a
membrane thickener and food reserve. Mucilage has a unique purpose in some
carnivorous plants. The plant genera Drosera (Sundews), Pinguicula, and others have
leaves studded with mucilage-secreting glands, and use a "flypaper trap" to capture
insects. Exopolysaccharides are the most stabilising factor for micro aggregates and
are widely distributed in soils. Therefore exopolysaccharide-producing "soil algae"
play a vital role in the ecology of the worlds soils.
1.3.2 Reasons for developing new excipients
Due to certain reasons there was an increase in interest for the development of new
excipient/diluents.
1. Some drugs show incompatibilities with many of the current range of excipients.
For e.g., Atenolol-PVP, Atenolol-Mg-stearate.

98

One of the more common drug-

excipient incompatibilities is the reaction between aldehydic sugars, such as

lactose and primary and secondary amines, leading to the formation of Schiff s
bases. These complex series of reactions lead to browning and discoloration of
the dosage form. Despite being a carrier of choice for dry powder aerosol

fExploitation o f N a tu ra l (product In TormuCation Design o f jl N o d e! Drug

30

Chapter 1

Introduction

formulations, lactose may need to be replaced with a different carrier, such as

mannitol or sucrose, when formulating primary and secondary amines.4 Mgstearate is incompatible with aspirin, some vitamins and most alkaloidal salt.

99

2. There is a need for excipients that will allow faster manufacturing of

formulations. For e. g., in tablet dosage form, new excipients having better
compressibility at very high compression speeds are need of today. Today, it is
not unheard o f to have tableting equipment compressing 8,000 to 10,000 tablets
per min. It is critical under these conditions to have an excellent flowing
granulation/powder blend. Many sugar-based excipients, such as maltose,
mannitol, and sorbitol are not compressible in their natural state and need to be
modified for use in direct compression tableting.
3. Some future developments may require new delivery systems. For e.g., new
drug delivery systems for oral administration of biotechnology products need
new excipient, which will avoid the inconvenience o f multiple daily injections.
Progress in the development o f peptides as useful drugs has been impeded in
part by their rapid excretion, resulting in short circulating lifetimes. This
generated considerable interest in improving the duration o f action o f drugs
through conjugation with the water-soluble, biocompatible excipient, poly
(ethylene glycol). Such conjugates have reduced enzymatic degradation rates
and lengthened circulating lifetimes compared to the native compounds. There
are six FDA-approved PEGylated products on the market, vouching for the
safety and commercial viability o f this technology. Other novel lipophilic
carbohydrate excipients, termed oligosaccharide ester derivatives (OEDs), have
been used to modify pharmacokinetic profiles o f drugs. This technology is quite
flexible, offering the ability to formulate drug molecules with modified-release
characteristics and improved bioavailability. In other technology, use of selected
carbohydrate excipient, such as trehalose and sucrose to stabilize molecules in
the dry state, there by preventing their physical and chemical degradation at
ambient temperatures and above. These patent-protected drug delivery
technologies are suited to the delivery o f macromolecules, such as proteins and
peptides by the pulmonary, oral, and injectable routes.
4. Drug targeting systems like liposome delivery systems need newer excipient,
because the existing excipients for liposome are too costly.

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31

Chapter 1

Introduction

1.3.3 Disadvantages of synthetic polymers

The synthetic polymers have certain disadvantages such as high cost, toxicity,
environmental pollution during synthesis, non-renewable sources, side effects, less
patient compliance.
1 Acute and chronic adverse effects (skin and eye irritation) have been observed
in workers handling the related

substances methyl methacrylate

and

poly-(methyl methacrylate) (PMMA).100

2

Reports on adverse reactions to povidone primarily concern the formation of

subcutaneous granulomas at the injection site formulated with povidone.
Evidence also exist that povidone may accumulate in organs following
intramuscular injections.101

Acute oral toxicity studies in animals indicated that carbomer-934P had a low
oral toxicity at a dose up to 8 g/kg when administered without fatalities
occurring. Carbomer dust is irritating to the eyes, mucous membranes and
respiratory tract. So, gloves, eye protection and dust respirator are recommended
during handling.102

Studies in rats have shown that 5% polyvinyl alcohol aqueous solution injected
subcutaneously can cause anemia and can infiltrate into various organs and
..

tissues.
5

103

Some disadvantages o f biodegradable polymers in tissue engineering application

are their poor biocompatibility, release o f acidic degradation products, poor
process ability and loss of mechanical property very early during degradation. It
was studied that poly glycolides, polylactides and their co-polymers have an
acceptable biocompatibility but shown systemic or local reactions due to acidic
degradation products. An initial mild inflammatory response has been reported
by using poly-(propylene fumarate) on rat implant studies.

1.3.4 Advantages of natural gums & mucilages

104

93 95

The advantages of natural plant based materials includes1. Biodegradable

2. Biocompatible and non toxic
3. Low cost
(Exploitation o f N a tu ra l (Product In Formulation (Design ofJL (Model Drug

32

Chapter 1

Introduction

4. Renewable source
5. Environmental-friendly processing
6. Local availability (especially in developing countries)
7. Better patient tolerance as well as public acceptance
8. From edible sources
1.3.5 Disadvantages of natural gums & mucilages

80

1. Microbial contamination
2. Batch to batch variation
3. Uncontrolled rate of hydration
4. Thickening nature
5. Drop in viscosity on storage
1.3.6 Classification of mucilages105 110
Polysaccharides are widely distributed in nature. The polysaccharides are complex
carbohydrates containing one or more monosaccharide or their derivatives linked in a
bewildering linkages and structures. Polysaccharides are abundantly present in plants,
animals, seaweeds, fungi and other microbial sources, where they perform diversified
structural and metabolic functions, with the plant sources being the largest. The
polysaccharides can be classified according to their sources, nature etc.
1.3.6.1 According to Sourees[a] Algal (seaweed) polysaccharides: Agar, Carrageenan, Alginic acid, Laminarin
[b] Plant polysaccharides: Exudates - Gum Arabica, Gum ghatti, Gum karaya,
Gum tragaeanth
Seed polysaccharides: Guar gum, Locust bean gum
Extracts: Pectin, Larch gum
[c] Animal polysaccharides: Chitin and Chitosan
[d] Microbial polysaccharides: Xanthan, Dextran, Scleroglucan, Curdian, Pullulan, Zanflo,
Bakers yeast Glycan, Sehizophyllan, Lentinan, Krestin
[e] Cellulose derivatives: CMC, Hydroxy ethyl cellulose, HPMC, MC, MCC

E xploitation o f N a tu ra l (Product In EormuCation Design ofJL M odel Drug

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Chapter 1

Introduction

1.3.6.2 According to Sourcefa] Starch Polysaccharides: Starch, Amylose,Cellulose.

[b] Polysaccharides from plant source: Pectins, Inulin, Guar gum, Locust Bean
gum, Glucomannan, Khaya and Albizia
gums,
[e] Polysaccharides from animal source: Chondroitin sulfate, Hyaluronic acid, Chitosan
[d] Polysaccharides from bacterial source: Dextrans, Curdlan
[e] Polysaccharides from Algal source: Alginates
[f] Polysaccharides from fungal source: Scleroglucan
1.3.6.3 According to nature1. Natural:
[a] Seed gum: Guar, Locust, Psyllium
[b] Shrubs OR Tree exudates: Acacia, Karaya, Tragacanth
[c] Plant extract: Pectin
[d] Marine gums: Agar, Alginates, Carragennans
[e] Microbial gums: Dextran, Xanthan, Gellan, Emulsan, Pullulan
2. Semi-synthetic:
Starch and other cellulose derivatives - Hetastarch, CMC, Ethyl Cellulose, HPMC
1.3.6.4 Other ways of classification of polysaccharides
1.3.6.4.1 By Shape
fa] Linear: Algins, Amylose, Cellulose, Pectins.
[b] Branched: i. Short branches - Xanthan, Xylan, Galactomanan.
ii. Branch-on-branch - Amylopectin, gum Arabic, Tragacanth.
1.3.6.4.2 By Manomeric Units
[a] Homoglycans: Amylose, Arabinanas, Cellulose.
fb] Di-heteroglycans: Algins, Carragennans, Galactomannans.
[c] Tri-heteroglycans: Arabinoxylans, gellan, xanthan.
[d] Tetra-heteroglycans: Gum arabie, Psyllium seed gum.
fe] Penta-heteroglycans: Ghatti gum, Tragacanth.

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Chapter 1

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1.3.6.4.3 By Charge
[a] Neutral: Amylose, Arabinans, Cellulose, Galactomannans.
[b] Anionic: Algin, Carrageenans, Gellan, Arabic, Pectic acid, Xanthan.
1.3.6.4.4 Polysaccharides
[a] Starch: Amylose, Amylopectin, Modified food starch.
[b] Non-starch: Pectins, Hemicellulose, Cellulose, P-glucan, Fructans, Gums,
Mucilages, Algal polysaccharides.
1.3.6.4.5 Polysaccharide by Source
[a] Seaweed extract: Agar, Algin, Carragennans.
[b] Higher plants: i. Insoluble - Cellulose
ii. Extract - Pectins
iii. Seeds - Starch, Guar
iv. Tuber and Roots - Potato starch
v. Exudates - Gum Arabic, Tragacanth
vi. Microorganism (Fermenting Gums) Xanthan, Gellan
vii. Derived - [A] Cellulose - CMC, Methyl Cellulose
[B] Starch, - Starch acetate, Starch Phosphates
[C] Synthetic - Polydextrose
1.3.7 Applications of gums and mucilages 111-114
There are growing concerns for the safety on pharmaceutical excipients derived from
natural sources. Plant gums and exudates are getting screened for their use as
pharmaceutical adjutants. Mucilages are used for their binding, thickening, stabilizing
and humidifying properties in medicine. Newer uses in cosmetics and textiles had
hiked up demand and screening of gums had become a vital pharmaceutical interest.
However pharmaceutical adjutants have stringent specifications, which few natural
agents can fulfill. Gums and mucilages have following various applications;
1. Applications in food industry- In confectionery food, flavoring and soft drinks,
as gelling, stabilizing, and suspending agents.
2. Pharmaceutical applications- Gums and mucilages find diverse applications in
pharmacy. It is used in medicine for its demulcent properties for cough
supression. They are ingredients in dental and other adhesives and as bulk
laxatives. These hydrophilic polymers are useful as tablet binders,
disintegrants, emulsifiers, suspending agents, gelling agents, stabilizing
E xploitation o f N a tu ra l (Product In Formulation (Design o f j l M o d el (Drug

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Chapter 1

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agents, thickening agents, film forming agents in transdermal and periodontal

films, buccal tablets, sustaining agents in matrix tablets and coating agents in
microcapsules including protein delivery has been demonstrated. Various
natural materials with their common name, biological sources, family and
applications are listed in Table 1.3.1.
3. Industrial uses- are for cosmetics, textiles, adhesives, lithography, paints,
papers and inks.
1.3.8 Precautions
They deteriorate when kept, especially in warm weather. So, preservatives are added,
such as solution of formaldehyde (10 minims to each pint) or benzoic acid (10 grains
to each pint).
1.3.9 Identification of gums and mucilage
1. The powder samples are mounted on glass slide with ruthenium red. After few
seconds, it gives pink color.
2. Molischs test is carried out on the sample solutions gives purple color at
junction.
1.3.10 Characterization
1. To determine the purity of the selected gum and mucilage, tests for alkaloids,
glycosides, carbohydrates, flavanoids, steroids, amino acids, terpenes,
saponins, oils and fats, and tannins and phenols were carried out.
2. The gum and mucilage are characterized by various organoleptic and
physicochemical properties such as color, odor, shape, taste, touch, texture,
solubility, pH, swelling index, loss on drying, hygroscopic nature, angle of
repose, bulk and true densities, porosity and surface tension. Different ash
values are also estimated. The microbial load and presence of specific
pathogens are also determined. In vitro cytotoxicity is also determined.
3. Rheological properties of excipients are important criteria in deciding their
commercial use. The flow behavior of the samples is determined using
Brookfield RVDV 11+ viscometer.
4. The compatibility studies of gum/mucilage/drugs are performed by using
spectrophotometer/FTIR/DSC.

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ChapterJ^

Introduction

Table 1.3.1 Pharmaceutical applications or uses of natural gums and mucilages.

Abelmoschus

Botanical
name
Abelmoschus

mucilage

esculentus

Agar

Gelidium

Common name

Family
Malvaceae

Pharmaceutical
Applications
Binder in tablets,

Reference
115,116

Sustained release
Gelidaceae

amansii

Suspending agent,

117

emulsifying agent,
gelling agent in
suppositories,
surgical lubricant,
tablet disintegrants,
medium for bacterial
culture, laxative

Albizia gum

Albizia zygia

Leguminoseae

Tablet binder

118

Aloe mucilage

Aloe species

Liliaceae

Gelling agent,

119

sustained release
agent
Asario mucilage Lepidum

Cruciferae

sativum

Suspending agent,

120,121

emulsifying agent,
controlled release
tablet

Bavchi

Ocimum

mucilage

canum

Carrageenan

Chondrus

Labiatae

Suspending agent,

120

emulsifying agent
Gigarginaceae

cryspus

Gelling agent,

122,123,

stabilizer
in
0

124

emulsions and
suspensions, in tooth
paste, demulcent and
laxative
Cashew gum

Anacardium

Anacardiaceae

Suspending agent

125, 126

Binding agent

127

Gelling agent, tablet

128, 129,

occidentale
Cassia tora
Fenugreek

Cassia tora Linn Leguminosae

Trigonella

Leguminoseae

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Introduction

Chapter 1
mucilage

foenum

binder, sustaining

graecum

agent, emollient and

130

demulcent
Guar gum

Cyamompsis

Leguminoseae

tetraganolobus

Binder, disintegrant,

131,132,

thickening agent,

133,134

emulsifier, laxative,
sustained release
agent
Gum acacia

Acacia

Leguminoseae

arabica

Suspending agent,

129,135

emulsifying agent,
binder in tablets,
demulcent and
emollient in
cosmetics

Gum ghatti

Anogeissus

Combretaceae

latifolia
Gum tragacanth

Astragalus

Binder, emulsifier,

129,136

suspending agent
Leguminoseae

gummifer

Suspending agent,

129, 137

emulsifying agent,
demulcent, emollient
in cosmetics and
sustained release
agent

Hibiscus

Hibiscus

mucilage

Malvaceae

Emulsifying agent,

129,138,

esculentus

sustained release

139

Linn

agent, suspending
agent

Hibiscus

Hibiscus

mucilage

rosasinensis

Malvaceae

Suspending agent

140

Plantaginaceae

Cathartic, lubricant,

130,141,

Linn
Ispagol

Plantago

mucilage

psyllium,

demulcent, laxative,

142,143,

Plantago

sustaining agent,

144, 145

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Chapter

Introduction
binder, emulsifying

ovata

and suspending agent

Karaya gum

Sterculia

Sterculiaceae

urens

Suspending agent,

146, 147

emulsifying agent,
dental adhesive,
sustaining agent in
tablets, bulk laxative

Khaya gum

Khaya

Meliaceae

Binding agent

148

grandifolia
Leucaena seed

Leucaena

Emulsifying agent,

149, 150,

gum

leucocephata

suspending agent,

151,152,

binder in tablets,

153

disintegrating agent
in tablet
Locust bean

Ceratania

gum

siliqua

Leguminoseae

Thickener, stabilizer,

154,155

controlled release
agent

Ocimum seed

Ocimum

mucilage

gratissimum

Labiatae

Suspending agent,

156, 157

binding agent

Linn
Pectin

Citrus

Rutaceae

aurantium

Thickening agent,

158, 159,

suspending agent,

160, 161,

protective agent,

162

carrier in
microspheres
Satavari

Asparagus

mucilage

racemosus

Aapocynaceae

Binding agent and

163

sustaining agent in
tablets

Sodium alginate

Macrocytis
pyrifera

Lessoniaceae

Suspending agent,

155,164,

gelation for dental

165, 166,

films, stabilizer,

167

sustained release
agent, tablet coating

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Introduction

Chapter 1
Tamarind seed

Tamarindus

polysaccharide

indica

Leguminoseae

Binding agent,

17,168,

emulsifier,

169

suspending agent,
sustaining agent
Xanthan gum

Xanthomonas

Suspending agent,

lempestris

emulsifier, stabilizer

147, 170

in tooth paste and

ointments, sustained
release agent

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Chapter 1

Introduction

1.4 Introduction to Drug - Diclofenac sodium

Diclofenac sodium (DS) is a non-steroidal anti-inflammatory drug (NSAID) with
analgesic and antipyretic properties. The number o f new drugs and the marketing of
NSAIDs have dynamically increased in the past decades. Today more than 100
preparations are on the market or under clinical investigation.
1.4.1 Description
1.4.1.1 Generic Name:

Diclofenac sodium

1.4.1.2 Synonyms:

Voltran, Voltarol, Voldal, Voveran, Orthophen, Diclon,

Dicloflex Difen, Difene.

1.4.1.3 Chemical Name:

2- [(2, 6-dichlorophenyl) amino ] benzene acetic acid

monosodium

salt,

Sodium-[o-[(2,6-dichlorophenyl)-

aminoJ-phenyl]-acetate,[o- (2,6-dichloroaniline)phenylJ
amino-phenyl acetate.
1.4.1.4 CAS Registry N o .: 15307-79-6.
1.4.1.5 Empirical Form ula: C ^H io C y S ^N a (salt)
Ci4H10Cl2NO2 (free acid)
1.4.1.6 Structural Formula

1.4.1.7 M olecular W eight: 318.14 (salt)

1.4.2 Physical Properties
1.4.2.1 Appearance, Color, O dor and Taste
It is white to off-white in color, odourless, crystalline, salty bitter taste and slightly
hygroscopic powder.
1.4.2.2 Melting Point: 283-285C (salt) and 156-158C (free acid)
1.4.2.3 Solubility

171

172

: The equilibrium solubility performed in various solvents at

the room temperature is shown in Table 1.4.1.

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Introduction

Chapter 1

Table 1.4.1 Solubility of Diclofenac sodium in various solvent.

Solvent

Solubility (mg/mL)

Deionized water (pH 5.2)

>9

Methanol

>24

Acetone

Acetonitrile

<1

Cyclohexane

<1

HC1 (pH 1.1)

<1

Phosphate Buffer (pH 7.2)

1.4.2.4 Stability:
It can be frozen for at least two weeks without degradation in biological fluid (serum).
DS is stable at 130C for 8 hr. DS tablets film coated with Acrylate Hydroxypropyl
Cellulose were reported to be stable after storage for one week at 30C at 80% RH.
1.4.2.5 Dissociation Constant:
The pKa is 4.2 in aqueous solution at 30 C.
1.4.2.6 Partition Co-efficient:
The octanol-water partition co-efficient at 25C is reported as 4 to 4.17.

173

1.4.3 Pharmacology
1.4.3.1 Properties 172
DS is potent non-steroidal, anti-inflammatory drug with pronounced analgesic and
antipyrete properties. Its potency is much greater than that o f indomethacin, naproxen,
phenylbutazone. DS

appears to reduce intra-cellular concentration o f free

arachidonate in leukocytes.
1.4.3.2 Mechanism of actions 172,176,177
DS inhibits cyclooxygenase enzyme. It inibits the conversion of arachidonic acid to
unstable endoperoxide intermediate, PGG2 , a reaction catalyzed by cyclooxygenase.
Thus, it inhibits production of prostaglandin content o f human serum, urine and
synovial fluid o f arthritic knee joint and it acts as a potent anti-inflammatory agent.
The primary mechanism responsible for its anti-inflammatory, antipyretic and

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Introduction

Chapter 1
analgesic

action is inhibition of prostaglandin synthesis by inhibition of

cyclooxygenase (COX).
Diclofenac has a low to moderate preference to block the COX-2-isoenzyme
(approximately 10-fold) and therefore a somewhat lower incidence o f gastrointestinal
complaints than noted with indomethacin and aspirin.
Diclofenac inhibits the lipooxygenase pathways, thus reducing fonnation o f the
leukotrienes (also pro-inflammatory autacoids). There is also speculation that
diclofenac may inhibit phospholipase Kz as part of its mechanism o f action. These
additional actions may explain the high potency o f diclofenac.
1.4.3.3 Therapeutic uses 178 181
Diclofenac sodium is potent non-steroidal, anti-inflammatory drug with pronounced
analgesic and antipyretc properties. It is used for musculoskeletal complaints,
especially arthritis (rheumatoid arthritis, osteoarthritis, spondylarthritis, ankylosing
spondylitis), gout attacks, and pain management in case o f kidney stones and
gallstones. An additional indication is the treatment o f acute migraines. Diclofenac is
used commonly to treat mild to moderate post-operative or post-traumatic pain,
particular when inflammation is also present, and is effective against menstrual pain.
1.4.3.4 Adverse effects 182 183
Adverse reactions reported in clinical trials and spontaneous reports are summarized
in Table 1.4.2. Table shows adverse reactions reported in clinical trails.

Table 1.4.2 Adverse reactions associated with Diclofenac sodium.

Type of reactions

Systems
Occasional

Rare

Isolated

Gastric or

Gastrointestinal

Lower gut disorders

abdominal pain,

bleeding (bloody

(e.g., non-specific

abdominal

diarrhoea, melena,

hemorrhagic colitis and

Gastrointestinal

cramps, nausea,

hematemesis)

exacerbation o f ulcerative

System

dyspepsia,

gastric and

colitis or Crohn's

anorexia,

intestinal

disease), diaphragm-like

diarrhea,

ulcerations with or

intestinal strictures,

vomiting,

without bleeding

hyperacidity, stomatitis,

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Chapter 1

Introduction

flatulence.

or perforation.

glossitis, coated tongue,

esophageal lesions,
constipation, pancreatitis.
Sensory disturbances
including paresthesia,

Central
Nervous System

Dizziness,

Drowsiness,

memory disturbance,

headache,

malaise, impaired

disorientation, insomnia,

vertigo.

concentration.

irritability, convulsions,
depression, anxiety,
nightmares, tremor,
psychotic reactions,
aseptic meningitis.

Palpitation,

Cardiovascular

angina,

System

arrhythmias.

Exacerbation of cardiac
failure, hypertension.
Vision disturbances
(blurred vision, diplopia),

Special senses

impaired hearing,
tinnitus, taste alteration
disorders.
Bullous eruption,
erythema, eczema,
erythema multiforme,
Stevens-Johnson
Syndrome, Lyell

Dermatologic

Rash, pruritus.

Urticaria.

Syndrome (toxic
epidermal necrolysis),
erythroderma (exfoliative
dermatitis), loss of hair,
photosensitivity reactions,
purpura including allergic
purpura.

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Introduction

Chapter 1

Acute renal failure,

nephrotic syndrome,

Renal System

*********

Edema (facial,

urinary abnormalities

general,

(e.g,, hematuria and

peripheral).

proteinuria), interstitial
nephritis, papillary
necrosis.
Thrombocytopenia,
leukopenia,
agranulocytosis,

Hematologic

***********

***********

hemolytic anemia,
aplastic anemia, anemia
secondary to
gastrointestinal bleeding.

Elevations of
serum
Hepatic

aminotransferase
enzymes (SGOT
or AST, SGPT
or ALT).

Liver function
disorders
including hepatitis

Fulminant hepatitis

with or without
jaundice.
Hypersensitivity
reactions such as
asthma in patients
sensitive to ASA
e.g.

Hypersensitivity

bronchospasm,

Vasculitis, pneumonitis.

anaphylactic,
anaphylactoid
systemic reactions
including
hypotension.

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45

Chapter 1

Introduction

1.4.3.5 Contradiction
Diclofenac is contraindicated in patients with known or suspected hypersensitivity to
diclofenac. Since cross-sensitivity has been demonstrated, Diclofenac should not be
given

to

patients

in

whom

acetylsalicylic

acid

or

other

non-steroidal

anti-inflammatory agents have induced asthma, rhinitis, urticaria or other allergic

manifestations.
Diclofenac sodium is contraindicated in active stomach and/or duodenal ulceration or
gastrointestinal bleeding, third-trimester pregnancy, inflammative intestinal disorders
such as Crohn's disease or ulcerative colitis, severe liver insufficiency (Child-Pugh
Class C), caution in patients with preexisting hepatic porphyria, as diclofenac sodium
may trigger attacks.
Recently, a warning has been issued by FDA not to treat patients recovering from
heart surgery.
1.4.3.6 Dosage and Administration
The maximum recommended daily dose is 150 mg. Diclofenac should be taken with
food and the tablets should be swallowed whole.
1.4.3.7 Container and Closures
DS was kept in an airtight container, should be protected from light.
1.4.4 Pharmacokinetics 184,185
1.4.4.1 Absorption: In humans, orally-administered DS is rapidly and almost
completely absorbed and distributed to blood, liver, and kidneys.

The plasma

concentrations show a linear relationship to the amount o f drug administered.

1.4.4.2 Protein Binding and Distribution: At therapeutic concentration, the drug is
extensively bound to plasma protein (albumin 99.7%). Apart from liver, bile and
kidney, highest levels of diclofenac are found in blood, heart and lung. The apparent
volume o f distribution is 0.17 + 0.11 L/kg.
1.4.4.3 Biotransformation:

DS is metabolised liver. The principal metabolite is 4

hydroxyl Diclofenac. Diclofenac undergoes single and multiple hydroxylation and

methoxylation, producing 3-, 4 -, 5-hydroxy, 4'- 5-hydroxy and 3'-hydroxy-4methoxy derivatives o f diclofenac. These phenolic metabolites are largely inactive,
and (along with the parent compound) are mostly converted to glucuronide
conjugates.

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Introduction

ChapterJ^

1.4.4.4 Elimination: DS and its metabolites are excreted through bile (33%) and
urine (67%). Unchanged drug is about 0.7% in urine. The clearance rate is reported as
4.2 + 0.9 mL/min. kg., and elimination rate as 1.2 to 1.8 hr. The mean terminal drug
half-life in plasma is 1.8 hr after oral doses.
1.4.5 Drug-Drug & Drug-Food interaction 186-190
Diclofenac, like other NSAIDs, may increase the toxicity of some drugs. Serum level
o f digoxin and methotreaxate are increased. Though studies have not revealed any
interactions with warfarin type of anticoaulants, but close monitering may be
desirable during concurrent therapy. Lithium renal clearance is reduced by diclofenac
and side effects of lithium salts may occur during concurrent treatment. Efficacy of
diuretics may be reduced by NSAIDs including diclofenac. Concomitant use o f
potassium - sparing diuretics may reults in increased serum potassium levels. Aspirin
displaces diclofenac from its binding sites.
Foods delays but does not reduce absorption from enteric coated tablets. This is o f no
clinical significance in long term therapy with DS.
1.4.6 Method of analysis
DS

has

been

quantitatively

analysed

by

UV

Spectrophotometry,

visible

spectrophotometry, thin layer chromatography, gas liquid chromatography, HPLC,

NMR, Gas and Mass Chromatography.
1.4.6.1 Visible Spectrophotometry (colorimetric determination)
1.4.6.1.1 This is a sensitive method based on the reaction of DS with potassium
ferrocyanide (1% w/v) in basic medium.The yellow color developed after addition of
sodium hydroxide (6% w/v) shows maximum absorbance at 450 nm. The beers curve
shows linear relation in the concentration range of 2 to 10 jig/mL o f DS.

191

1.4.6.1.2 DS gives yellow color when treated with sodium nitrite in the presence of
HC1 with a maximum absorbance at 390nm. The Beers law is governs in the range of
0.05-0.60 mg/mL of DS.192
1.4.6.1.3 DS when reacted with p-dimethyl aminobenzaldehyde and ammonium ceric
sulphate in acidic medium gives an orange color, which exhibits maximum
absorbance at 440 nm. It governs Beers law in concentration range of 2 to 16 jig/mL.
The color is reported to be stable for 50 min.193

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Chapter 1

Introduction

1.4.6.1.4 DS may be reacted with 3-methyl-2-benzothiazolinone hydrazone hydro

chloride and cerium ammonium sulfate to form a colored complex which exhibited
maximum absorbance at 600 nm.

171

1.4.6.2 Spectroflorimetry method

194

A spectrofluorometric method for the micro determination o f DS has been developed

through its reaction with cerium (IV) in an acidic solution and measurement o f the
fluorescence o f the Ce (III) ions produced. Under the optimum experimental
conditions for the oxidation reaction, 1.0 M H2SO4 with 90 min o f heating time
(100C), the range o f application is 124.3 - 600 ng/mL and the limit o f detection is
72.7 ng /mL. The proposed method was applied to the determination o f DS in
pharmaceutical tablets.
1.4.6.3 UV spectrophotometric determination

171

This method is based on the measurement o f approprate diluted DS drug solution in

UV light in a 1 cm matched quartz tube. The wavelength o f maximum absorption is
276 nm.
1.4.6.4 Gas Liquid Chromatography

171

This method was used to analyzed DS or its metabolized using electron capture
detector, before injecting into the column.
1.4.6.5 High Performance Liquid Chromatography
1.4.6.5.1 Determination o f DS in biological fluids is done by HPLC technique.171
1.4.6.5.2 A HPLC method for determination o f paracetamol, chlorzoxazone and DS
has been developed. The chromatography system used a reversed phase C8 column
with UV- Vis detection at 280 nm. Mobile phase consisted o f acetonitrile - 0.05 M
ammonium dihydrogen ortho phosphate (60:40 v/v) (pH adjusted to 4.06 using 10%
ortho phosphoric acid) at a flow rate o f 1.5 mL/min. The calibration curve was linear
m the concentration range o f 4-20 jig/mL for DS.

195

1.4.6.5.3 A reverse phase HPLC method has been developed for the simultaneous
estimation o f DS and rabeprazole sodium from pharmaceutical formulations. The
method was developed using a HiQ SiL C l 8 (250 mm x 4.6 mm i.d.) column with a
mobile phase consisting o f methanol: water, (80:20 v/v), at a flow rate o f
1.25 mL/min. Detection was carried out at 284 nm.

196

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48

Chapter 1_______________________________________________________ Introduction

1.4.6.6 Nuclear Magnetic Resonance

171

Proton magnetic method to quantify Diclofenac sodium in pure tablet form has been
described. Diclofenac has a well defined sharp peak at 3.62 ppm, which is chosen for
quantitative measurement. Internal standard used is anhydrous sodium acetate (1.85
ppm). The amount o f DS can be calculated by comparing the peak ratio o f Diclofenac
to that o f the internal standard.

1.4.6.7 HPTLC method

1.4.6.7.1 A HPLC method for the determination o f DS in pharmaceutical formulations
was developed. The sample were spotted automatically by means o f Camag Linomat
IV (Switzerland) on a silica gel 60 F254 aluminium plate, using a mixture o f toluene :
ethyl acetate : glacial acetic acid (60:40:1, v/v/v) as mobile phase. The spot areas were
quantified by densitometry at 282 nm. Linear calibration curve was obtained over the
range 5-80 pg/mL (r2 = 0.9993). The proposed method is simple, rapid, sensitive,
reproducible and accurate.

197

1.4.6.7.2 DS from serum was determined by a novel HPTLC method. Standard DS

was spotted on Silica Gel 60 F254 precoated plates, which were developed using the
O

mobile phase toluene:acetone:glacial acetic acid (80:30:1,v/v/v). Densitometric

analysis o f DS was carried out at 280 nm with diclofenac being detected at an Rf o f
0.58. The method was subsequently developed to estimate DS from serum. The
calibration curve o f DS in serum was found to be linear in the range o f
200-800 ng . 198

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Chapter 1

Introduction

1.5 References
1. York P. The design o f dosage forms. In: Aulton ME, ed. Pharmaceutics: The
Science o f Dosage Form Design. United Kingdom: Churchill Livingstone;
2002 : 1- 12.
2. Xuan D, Adam WKA, Joseph RR. Extended release and targeted drug delivery
systems. In: Gennaro AR, ed. Remington: The Science and Practice of
Pharmacy. New Delhi, India: Wolters Kluwer Health (India) Pvt. Ltd;
2007:939-964.
3. Swarbrick J, Boylan JC. Encyclopaedia o f Pharmaceutical Technology. New
York, NY: Marcel Dekker, Inc, 1990.
4. Banker GS, Anderson NR. Tablets. In: Lachman L, Lieberman HA, Kanig JL,
ed. The Theory and Practice o f Industrial Pharmacy. Mumbai, India: Varghese
Publishing House; 1987:293-345.
5. Gohel MC, Jogani PD. A review o f co-processed directly compressible
excipients. J Pharm Pharmceut. Sci. 2005; 8(l):76-93.
6. Ainaoui A, Vergnaud JM. Effect o f the nature o f the polymer and o f the
process of drug release (diffusion or erosion) for oral dosage forms.
Computational & Theoretical Polym Sci. 2000; 10(5): 383-390.
7. Lordi, NG. Sustained Release Dosage Forms. In: Lachman, L, Lieberman HA,
Kanig JL, ed. The Theory and Practice o f Industrial Pharmacy.

Mumbai,

India: Vaghese Publishing House; 1987:430-456.

8. Collet J, Moreton C. Modified-release peroral dosage forms. In: Aulton ME,
ed. Pharmaceutics: The Science o f Dosage Form Design. United Kingdom:
Churchill Livingstone; 2002:289-305.
9. Jantzen GM, Robinson JR. Sustained-and Controlled Release Drug Delivery
Systems. In: Banker GS, Rhodes CT, ed. Modem Pharmaceutics. Revised and
Expanded. Drags and The Pharmaceutical Sciences. New York: Marcel
Decker, Inc; 2002:501-528.
10. Das NG, Das SK. Controlled-Release of Oral Dosage Forms. Formulation, Fill
& Finish. 2003.

Exploitation ofUfaturaC (Product In EormuCation Design o f j l M o d el (Drug

50

Chapter 1

Introduction

11. Vasudev SC, Chandy T, Sharma CP. Development of chitosan/polyethylene

vinyl acetate co-matrix: controlled release of aspirin-heparin for preventing
cardiovascular thrombosis. Biomaterials. 1997; 18(5): 375-381.
12. Robinson JR, Lee VH. Controlled Drug Delivery: Fundamentals and
Applications. New York: Marcel Dekker, Inc; 1987.
13. Block LH, YU ABC. Pharmaceutical principles and drug dosage forms. In:
Shargel L, Mutinick AH, Souney PF, Swanson LN, ed. Comprehensive
Pharmacy Review. Lippinicott Williams & Wilkins; 2001:28-77.
14. Using Methocel Cellulose Ethers for controlled release of drugs in hydrophilic
matrix system: Technical Handbook, Product Information, Form No. 19201062-697GW, The Dow Chemical Company, Midland, MI, 2000.
15. Ughini F, Andreazza IF, Ganter JLMS, Bresolin TMB. Evaluation of xanthan
and highly substituted galactomannan from M. Scabrella as a sustained release
matrix. Int J Pharm. 2004; 271(1-2): 197-205.
16. Md Salim Reza, Mohiuddin Abdul Quadir, Syed Shabbir Haider. Comparative
evaluation of plastic, hydrophobic and hydrophilic polymers as matrices for
controlled release drug delivery. J Pharm Pharmceut Sci. 2003; 6(2): 282-291.
17. Sumath S, Roy AR. Release behavior of drugs from tamarind seed
polysaccharide tablets. J Pharm Pharmaceut Sci. 2002; 5(1): 12-18.
18. Gohel MC, Patel MM. Release rate modulation of diltiazem HCL from
hydrophilic matrix of tartaric acid treated guar gum. Int J Phann Expt. 2001;
April-June: 39-45.
19. Colombo PR, Bettini GM, Catellani PL, Santi P, Peppas NA. Drug diffusion
front movement is important in drug release control from swellable matrix
tablets. J Pharm Sci. 1995; 84(8): 991-997.
20. Vazquez MJ, Perez-Marcos B, Gomez-Amoza JL, Martinez-Pacheco R, Soute
C, Concheiro A. Influence of technological variables on release of drugs from
hydrophilic matrices. Drug Dev Ind Phann. 1992; 8(11-12): 1355-1375.
21. Ishrat N, Chowdhury JA, Mia Mohammad Dulal. Effect of electrolytes on
release of Diclofenac sodium from agarose beads. The Dhaka Uni J Pharm
Sci. 2005; 4(2): 1816-1839.
22. Rodney H, Michael B, Thomas HH. Slow release solid preparation. U S

E xploitation o f N a tu ra l (product In EormuCation (Design ofJi N o d e! Drug

51

Chapter 1

Introduction

23. Choudhury PK, Mousumi Kar. Preparation of alginate gel beads containing
metformin hydrochloride using emulsion-gelation method. Trop J Pharm Res,
2005,4(2): 489-493.
24. Takka S, Acarturk F. Calcium alginate microparticles for oral administration I:
effect o f sodium alginate type on drug release and drug entrapment efficiency.
J Microencapsulation. 1999; 16(3): 275-290.
25. Kawashima Y, Handa T, Kasai A, Takenaka H, Lin S Y, Ando Y. Novel
method for the preparation o f controlled-release theophylline granules coated
with a polyelectrolyte complex of sodium polyphosphate-chitosan. J Pharm
Sci. 1985; 74(3): 264-268.
26. Bodmeier R, Kyoung-Hee Oh, Pramar Y. Preparation and evaluation o f drugcontaining chitosan beads. Drug Dev Ind Pharm. 1989; 15(9): 1475-1494.
27. Nigalaye AG, Adusumilli P, Bolton S. Investigation o f prolonged drug release
from matrix formulations o f chitosan. Drug Dev Ind Pharm. 1990; 16(3):
449-467.
28. Chaubal M. Excipient update: using chitosan as an excipient for oral drug
delivery. Int J Pharm Expt. 2003; April-June: 29-32.
29. Jaleh V, Naser T, Fatemeh K. Use o f hydrophilic natural gums in formulation
of sustained release matrix tablets o f tramadol HC1. AAPS PharmSciTech.
2006; 7(1): article:24, doi: 10.1208/pt070124.
30. Krishnaiah YSR, Satyanarayana V, Kumar BD, Karthikeyan RS. In-vitro drug
release studies on guar gum based colon targeted oral drug delivery system of
5-fluorouracil. Eur J Pharm Sci. 2002; 16(3): 185-192.
31. Xiaoheng Mu, Michael JT, John NS. Influence of physiological variables on
the in-vitro drug release behavior o f a polysaccharides matrix controlled
release system. Drug Dev Ind Pharm. 2003; 29(1): 19-29.
32. Momin M, Pundarikaksudu K. In-vitro studies on guar based formulation of
for the colon targeted delivery o f sennosides. J Pharm Pharmaceut Sci. 2004;
7(3): 325-331.
33. Nevy LR, Evone SG. Matrices of water-soluble drug using natural polymers
and direct compression method. Drug Dev Ind Pharm. 2002; 28(8): 975-988.
34. Bonferoni MC, Rossi S, Ferrari F, Stavik E, Pena-Romero A, Caramella C.
Factorial analysis o f the influence o f dissolution medium on drug release from

E xploitation, o f n a tu r a l (Product In F ormulation (Design ofJL M o d el Drug

52

Introduction

Chapter 1
carrageenan-diltiazem

complexes.

AAPS

PharmSciTech.

2000;

1(2):

article: 15.
35. Mulhbacher J, Alexandru MM. Cross linked high amylase starch derivatives
for drug release III: Diffusion properties. Int J Pharm. 2005; 297(1-2): 22-29.
36. Herman J, Remon JP, De, Vilder J. Modified starches as hydrophilic matrices
for controlled oral delivery I. Production and characterisation of thermally
modified starches Int J Pharm. 1989; 56(1): 51-63.
37. Herman J, Remon JP. Modified starches as hydrophilic matrices for controlled
oral delivery. II. In vitro drug release evaluation of thermally modified
starches. Int J Pharm. 1989; 56(1): 65-70.
38. Herman J, Remon JP. Modified starches as hydrophilic matrices for controlled
oral delivery III. Evaluation o f sustained-release theophylline formulations
based on thermal modified starch matrices in dogs. Int J Pharm. 1990; 63(3):
201-205.
39. Visavarungroj N, Herman J, Remon JP. Crosslinked starch as sustained
release agent. Drug Dev Ind Pharm. 1990; 16(7): 1091-1108.
40. Carbomer-934, Water Soluble Resins, BF Goodrich Co. Bulletin, Cleveland,
1985.
41. Kolen JJ, McGinity JW, Wilber WR. Carbomer; In: Raymond CR, Paul JS,
Paul JW, ed. Handbook o f Pharmaceutical Excipients. The Pharmaceutical
Press and The American Pharmaceutical Association; 2003:89-92.
42. Patel M, Patel B, Patel R, Patel JK, Bharadia PD, Patel MM. Carbopol: A
versatile polymer. Drug Delivery Tech. 2006; 6(3): 32.
43. Bulut-oner F, Capan Y, Kas S, Oner L, Hincal AA. Sustained release isoniazid
tablets I- formulation and in vitro evaluation. Farmaco. 1989; 44(7-8):
739-752.
44. Gohel MC, Parikh RK, Padshala MN, Sarvaiya KG, Jena DG. Formulation
and optimization of directly compressible isoniazid modified release matrix
tablet. Indian J Pharm Sci. 2007; 69(5): 640-645.
45. Baveja SK, Ranga Rao KV, Singh A, Gombar VK. Release characteristics of
some bronchodilators from compressed hydrophilic polymeric matrices and
their correlation with molecular geometry. Int J Pharm. 1988; 41(1-2): 55-62.
46. Velasco M, Ford JL, Rowe P, Rajabi-Siahboomi AR. Influence o f drug:
hydroxypropylmethylcellulose ratio, drug and polymer particle size and
E xploitation o f N atural (Product In Formulation Design o fM o d e l(D ru g

53

Introduction

Chapter 1

compression force on the release o f diclofenac sodium from HPMC tablet. J

Controlled Release. 1999; 57(1): 75-85.
47. Ranga Rao KV, Padmalatha Devi K, Buri P. Cellulose matrices for zero-order
release o f water soluble drugs. Drug Dev Ind Pharm. 1988; 14: 2299-2320.
48. Jaleh V, Naser T, Ali Eram S. Use o f natural gums and cellulose derivatives in
production of sustained release metoprolol tablets. Drug Delivery. 2006;
13(2): 113-119.
49. Baveja SK, Ranga Rao KV, Arora J. Examination of natural gums and
mucilages as sustaining materials in tablet dosage forms. Indian J Pharm Sci.
1988; 50(2): 89-92.
50. Singh J. Effect of sodium carboxymethylcelluloses on the disintegration,
dissolution and bioavailability of lorazepam from tablets. Drug Dev Ind
Pharm. 1992; 18(3): 375-382.
51. Padmalatha Devi K, Baveja SK, Ranga Rao KV, Fathi M, Roth M. Zero-order
release formulation o f oxprenolol hydrochloride with swelling and erosion
control. Pharm Res. 1989; 6: 313-317.
52. Padmalatha Devi K, Ranga Rao XV, Buri P. Influence o f molecular size and *
water solubility of the solute on its release from swelling and erosion
controlled polymeric matrices. J Controlled Release. 1990; 12(2): 133-141.
53. Franz RM, Sytsma JA, Smith BP, Lucisano LJ. In vitro evaluation of a mixed
polymeric sustained release matrix using response surface methodology. J
Controlled Release. 1987; 5(2): 159-172.
54. Baveja SK, Ranga Rao KV, Padmalatha Devi KV. Relationship between gum
content and half-life of soluble p blockers from hydrophilic matrix tablets. Int
J Pharm. 1988; 47(1-3): 133-139.
55. Ranga Rao KV, Padmalatha Devi KV. Swelling controlled-release systems:
recent developments and applications. Int J Pharm. 1988; 48(1-3): 1-13.
56. Buri P, Doelker E. Formulation of sustained-release tablets. II. Hydrophilic
matrices. Pharm AetaHelv. 1980; 55: 189-197.
57. Velasco MV, Munoz A, Jimenez-Castellanos MR, Castellano I, Goni I,
\

Gurruchaga M. In vitro evaluation o f sustained-release matrix tablets prepared

with new modified polymeric carbohydrates. Int J Pharm. 1996; 136(1-2):
107-115.

(Exploitation o f N a tu ra l (Product In Formulation (Design o f J l Model(Drug

54

Introduction

Chapter 1

58. Ford JL, Rubinstein MH, Hogan JE. Formulation of sustained release
promethazine hydrochloride tablets using hydroxypropyl-methylcellulose
matrices. Int J Pharm. 1985; 24(2-3): 327-338.
59. Doelker E. Hydrogels in Medicine and Pharmacy. In: Pappas NA, ed.
i

Polymers. Boca Raton: CRC; 1987:115.

60. Colombo PR, Gazzaniga CC, Conte U, La, Manna A. In vitro programmable
zero-order release drug delivery system, Acta Pharm Technol. 1987; 33:
15-20.
61. Colombo P, Santi P, Bettini R, Brazel CS, Peppas NA. Drug release from
swelling-controlled

systems.

In: Donald L Wise,

ed.

Handbook of

Pharmaceutical Controlled Release Technology. New York: Marcel Dekker,

Inc, 2005:183-209.
62. Bi Y X, Sunada H, Yonezawa Y, Danjo K. Evaluation o f rapidly
disintegrating tablets prepared by a direct compression method. Drug Dev Ind
Pharm. 1999; 25(5): 571-581.
63. Sallam E, Ibrahim H, Abu Dahab R, Shubair M, Khalil E. Evaluation o f fast
disintegrants in terfenadine tablets containing a gas-evolving disintegrant.
Drug Dev Ind Pharm. 1998; 24(6): 501-507.
64. Bi Y, Sunada H, Yonezawa Y, Danjo K, Otsuka A, Iida K. Preparation and
evaluation of a compressed tablet rapidly disintegrating in the oral cavity.
Chem Phann Bull. 1996; 44(11): 2121-2127.
65. Fred JB. Compressed tablets by wet granulation. In: Lieberman HA, Lachman
L, Schwartz JB, ed. Pharmaceutical Dosage Forms: Tablet, Vol. 1, New York:
Marcel Dekker, Inc, 1989: 131-193.
66. Goran A. Tablets and Compaction. In: Aulton ME, ed. Pharmaceutics: The
science o f dosage form design. United Kingdom: Churchill Livingstone;
2002:397-440.
67. Rudnic EM. Oral solid dosage form. In: Gennaro AR, ed. Remington: The
Science and Practice o f Pharmacy. New Delhi, India: Wolters Kluwer Health
(India) Pvt. Ltd.; 2007:889-918.
68. Lowenthal W. Mechanisms of action of tablet disintegrants. Pharm Acta Helv.
1973; 48(11): 589-609.
69. Lowenthal W. Disintegration of tablets. J Pharm Sci. 1972; 65(11):1695-1711.

(Exploitation o f N a tu ra l (Product In (Formulation (Design o f j l M odelD rug

55

Chapter 1

Introduction

70. Guyot-Hermann A M. Tablet disintegration and disintegrating agent. S T P

Pharm Sci. 1992; 2(6): 445-462.
71. Ferrari F, Bertoni M, Bonferoni MC, Rossi S, Caramella C, Nystrom C.
Investigation on bonding and disintegration properties of pharmaceutical
materials. Int J Pharm. 1996; 136(1-2): 71-79.
72. Patel N, Hopponen R. Mechanism of action of starch as disintegrating agent
in aspirin tablets. J Pharm Sci. 1966; 55(10): 1065-1068.
73. Nogami H, Hagai T, Fukuola E, Sonobe T. Disintegration o f aspirin tablets
containing

potato

starch

and

microcrystalline

cellulose

in

various

concentrations. Chem Pharm Bull. 1969; 17(7): 1450-1455.

74. Lowenthal W, Burruss RA. Mechanism o f action of starch as a tablet
disintegrant IV: Effect o f medicaments and disintegrants on mean pore
diameter and porosity. J Pharm. Sci. 1971; 60(9):1325-1332.
75. Ringard J, Guyot-Hermann AM. Disintegration mechanisms o f tablets
containing starches: Hypothesis about the particle-particle repulsive forces.
Drug Dev Ind Pharm. 1981; 7(2): 155-177.
76. Kanig JL, Rudnic C. The mechanisms o f disintegrant action. Pharm Tech.
1984;8:50-62.
77. Shangraw R, Mitrevej A, Shah M. New era of tablet disintegrants. Powder
Tech. 1980; 4(10): 49-57.
78. Matsumaru H, Yakugaku Z. Mechanism o f tablet compression and
disintegration, IV. Evolution o f wetting heat and its relation to compressional
force. J Pharm Sci. 1959; 79:63-64. [through chem. Abstr., 5 3 ,7505f, 1959.]
79. Lowenthal W. Mechanism o f action o f starch as a tablet disintegrant V: Effect
of starch grain deformation. J Pharm Sci. 1972; 61(3): 455-459.
80. Kottke KM, Edward MR.Tablet Dosage Forms. In: Banker GS, Rhodes CT,
ed. Modem Pharmaceutics. New York: Marcel Dekker, Inc; 2002:287-333.
8 1 . Aslam A, Parrott E. Effect o f aging on some physical properties of
Hydrochlorthiazide tablets. J Pharm Sci. 1971; 60(2): 263-266.
82. Chebli C, Cartilier L. Crosslinked cellulose as a tablet excipient: A
binding/disintegrating agent. Int J Pharm. 1998; 171(1): 101-110.
83. Sharma S, Reddy S, Kulkami PK. Evaluation of sericin as a binder in tablet.
Int J Pharm Expt. 2005; April-June: 44-48.

E xploitation o f N a tu ra l (Product In EormuCation (Design o f j l M o d el (Drug

56

Chapter^

Introduction

84. Ofoefule SI, Chukwu A, Anyakoha N, Ebebe IM. Application of

Abelmoschus esculentus in solid dosage formulation 1: Use as a binder for a
poorly water soluble drug. Indian J Pharm Sci. 2001; 63(3): 234-238.
85. Kulkami GT, Gowthamrajan K, Rao BG, Suresh B. Evaluation of binding
properties o f Plantago ovata and Trigonella foenumgraecum mucilage. Indian
Drugs. 2002; 39(8): 422-425.
86. Chowdary KPR, Radhika I. Effect o f selected binders on the dissolution rate
of sparfloxacin from tablets. Int J Pharm Expt. 2000; Jail-March: 159-162.
87. Geerhard L, Robert HG. Effect of certain tablet formulation factor on
dissolution rate of the active ingredient III. Tablet lubcrieants. J Pharm Sci.
1963; 52(12): 1139-1144.
88. Phillip MH. Effect o f compression force and com starch on tablet
disintegration time. J Pharm Sci. 1976; 65(11): 1694-1697.
89. Andries FM, Mingna S, Melgardt M devilliers. Effect o f compression force,
humidity and disintegrant concentration on the disintegration and dissolution
of directly compressed furosemide tablets using croscarmellose sodium as
disintegrant. Trop J Pharm Res. 2003; 2(1): 125-135.
90. Peck GE, Baley GJ, Banker GS. Tablet Formulation and Design. In:
Lieberman HA, Laehman L, Schwartz JB, ed. Pharmaceutical Dosage Forms:
Tablets. V ol.l. New York: Marcel Dekker, Inc; 1989:75-130.
91. Robbins SRJ. Gum arabic. In A Review o f Recent Trends in Selected Markets
for Water-Soluble Gums. ODNRI Bulletin; (2): 108. London: Overseas
Development Natural Resources Institute [now Natural Resources Institute,
Chatham], 1988; 18-33.
92. Nakano M, Nakamura Y, Juni K, Kouketsu M. Sustained release of
sulfamethizole from agar beads after oral administration to humans. Chem
Pharm Bull. 1980; 28(10): 2905-2908.
93. Durso DF, Handbook o f Water Soluble Gums and Resins. New York, NY:
McGraw Hill, Kingsport Press; 1980:12
94. Bhardwaj TR, Kanwar M, Lai R, Gupta A. Natural gums and modified natural
gums as sustained release carriers. Drug Dev Ind Pharm. 2000; 26(10):
1025-1038.

TjqiCoitation o f Natural(Product In (Formulation (Design ofy? Model(Drug

57

Chapter 1

Introduction

95. Desai A, Shidhaye S, Malke S, Kadam V. Use o f natraal release retardant in

drug delivery system. Indian Drugs. 2005; 42(9): 565-575.
96. Qadry JS. Shah and Qadrys Pharmacognosy. Ahmedabad, India: B S Shah
Prakashan; 2008.
97. Evans WC. Trease and Evans - Pharmacognosy. New York: WB Saunders;
2004.
98. Marini A, Berbenni V, Pegoretti M, Bruni G, Coffancesco P, Sinistri C, Villa
M. Drug-excipient compatibility studies by physico-chemical techniques: The
case of Atenolol. J Thermal Analysis and Calorimetry. 2003; 73(2): 547-561.
99. Allen LV, Luner PE. Mg-stearate. In: Raymond CR, Paul JS, Paul JW, ed.
Handbook of Pharmaceutical Excipients. The Pharmaceutical Press and The
American Pharmaceutical Association; 2003:354-357.
100. Chang RK, Shukla AJ. Polymethacrylates. In: Raymond CR, Paul JS, Paul
JW, ed. Handbook o f Pharmaceutical Excipients. The Pharmaceutical Press
and The American Pharmaceutical Association; 2003:462-468.
101. Hizawa K, Otsuka H, Inaba H, Izumi K, Nakanishi S. Subcutaneous
pseudosarcomatous PVP granuloma. Am J Surg Path. 1984; 8:393-398.
102. Kolen JJ, McGinity JW, Wilber WR. Carbomer -934P. In: Raymond CR, Paul
JS, Paul JW, ed. Handbook o f Pharmaceutical Excipients. The Pharmaceutical
Press and The American Pharmaceutical Association; 2003:89-92.
103. Weller PJ, Owen SC. Polyvinylalcohol. In: Raymond CR, Paul JS, Paul JW,
ed. Handbook of Pharmaceutical Excipients. The Pharmaceutical Press and
The American Pharmaceutical Association; 2003:491-492.
104. Khaled Al-T, Jagdish S. Recent Patents on Drug Delivery and Formulation.
2007;1:65-71.

'

105. Kokate CK, Purohit AP, Gokhale SB. Pharmacognosy. Pune, India: Nirali
Prakashan; 2006.
106. Rangari VD. Pharmacognosy & Phytochemistry. Nashik, India: Career
Publication; 2006.
107. Wallis TE. Text Book o f Pharmacognosy. New Delhi, India: C B S Publishers
and Distributors; 2004.
108. Mohammed Ali. Text Book of Pharmacognosy. New Delhi, India: C B S
Publishers and Distributors; 2005.

Exploitation o f N a tu ra l Product In Formulation Design ofJL M o d el Drug

58

Chapter 1

Introduction

109. Ansari SH. Essential of Pharmacognosy. New Delhi, India: Birla Publications
Pvt. Ltd.; 2006.
110. Venkata Rao E. Chemical and biological aspects o f selected polysaccharides.
Indian J Pharm Sci. 1992; 54(3):90-97.
111. Aoshima H, Miyagisnima A, Nozawa Y, Sadzuka Y, Sonbe T, Glycerin fatty
acid esters as a new lubricant o f tablets. Int J Pharm. 2005; 293(1-2): 25-34.
112. Monif T, Malhotra AK, Kapoor VP. Cassia fistula seed galactomannan:
potential binding agent for pharmaceutical formulation. Indian J Pharm Sci.
1992; 54(6): 234-240.
113. Odeku OA, Itiola OA. Evaluation o f Khaya gum as a binder in a paracetamol
tablet formulation. Pharm Pharmacol Commun. 1998; 4:183-188.
114. Gowthamrajan K, Kulkami GT, Vijaykumar RS, Suresh B. Evaluation of
Borassus flabellifer mucilage as gelling agent. Indian Drugs. 2003; 40(11):
640-644.
115. Ofoefule SI, Chukwu A, Anyakoha N. Application o f Abelmoschus esculents
in solid dosage formulation: use as a binder for a poorly water soluble drug.
Indian J Pharm Sci. 2001; 63(3): 234-238.
116. Ofoefule SI, Chukwu A. Application o f Abelmoschus esculents gum as a
mini-matrix for furosemide and diclofenac sodium tablets. Indian J Pharm Sci.
2001; 63(6): 532-535.
117. John GL, Declan MD, James EK, Luke MG, OSullivan P, Clement LH. The
use o f Agar as a novel filler for monolithic matrices produced using hot melt
extrusion. Eur J Pharm Biopharm. 2006; 64(1): 75-81.
118. Oluwatoyin AO. Assessment o f Albizia zygia gum as a binding agent in tablet
formulations. ActaPharm.2005; 55: 263-276
119. Jani GK, Shah DP, Jain VC, Patel MJ, Vithalani DA. Evaluating mucilage
from Aloe barbadensis Miller as a pharmaceutical excipient for sustainedrelease matrix tablets. Pharm Tech. 2007; 31(11): 90-98.
120. Patel MM, Chauhan GM, Patel LD. Mucilage o f lepidium sativum, Linn
(Asario) and ocimum canum, sims. (Bavchi) as emulgents. Indian J Hosp
Pharm. 1987; 24: 200-202.
121. Avachat MK, Dhamne AG. Oral controlled release drug delivery system with
husk powder from Lepidium Sativum seeds. Patient No. W002100438.

(Exploitation o f N a tu ra l (Product In Formulation Design o f j l M o d el Drug

59

Chapter 1

Introduction

122. Ahmed Bani-Jaber, Mutasim Al-Ghazawi. Sustained release characteristics of

tablets prepared with mixed matrix o f sodium carragennan and chitosan:
Effect of polymer weight ratio, dissolution media and drug type. Drug Dev Ind
Pharm. 2005; 31(3): 241-247.
123. Bonferoni MC, Rossi R, Tamayo M, Pedrez JL, Domnguez G, Caramella C.
On the employment of k-carrageenan in a matrix system. I. Sensitivity to
dissolution medium and comparison with Na-carboxymethylcellulose and
xanthan gum. J Controlled Release. 1993; 26(2): 119-127.
124. Bonferoni MC, Rossi S, Tamayo M, Pedrez JL, Domnguez G, Caramella C.
On the employment of X-carrageenan in a matrix system. II. ^-Carrageenan
and hydroxypropylmethylcellulose mixtures. J Controlled Release. 1994;
30(2): 175-182.
125. Pontes UR. Determination of HLB o f Anacardium gum. Rev Farm Bioquim.
(German), 1971; 2: 83-91.
126. Zakaria MB, Zainiah Ab. Rahman. Rhelological properties o f cashew gum.
Carbohydrate Polym. 1996; 29(1): 25-27.
127. Pawar H, Dmello PM. Isolation o f seed gum from cassia tora and preliminary
studies of its applications as a binder for tablets. Indian Drugs. 2004; 41(8):
465-468.
128. Gowthamrajan K, Kulkami GT, Muthukumar A, Mahadevan N, Samanta MK,
Suresh B. Evaluation o f Fenugreek mucilage as gelling agent. Int J Pharm
Expt. 2002; 3(1): 16-19.
129. Baveja SK, Ranga Rao KV, Arora J. Examination o f natural gums and
mucilages as sustaining materials in tablet dosage forms. Indian J Pharm Sci.
1988; 50(2): 89-92.
130. Kulkami GT, Gowthamarajan K, Rao BG, Suresh B. Evaluation o f binding
property o f Plantago Ovata Sc Trigonella Foenum Gracecum mucilage. Indian
Drags. 2002; 39(8): 422 - 425.
131. Kale W , Kasliwal R, Parida SK, Awari JG. Formulation and release
characteristics of guar gum matrix tablet containing metformin HC1. Int J
Pharm Expt. 2004; July-Sept: 75-80.
132. Khullar P, Khar RK, Agrawal SR. Evaluation o f guar gum in the preparation
o f sustained-release matrix tablets. Drag Dev Ind Pharm. 1998; 24(11):
1095-1099.
E xploitation o f N atural (Product In Formulation (Design o f Jl M odel Drug

60

Chapter 1

Introduction

133. Kibbe AH. Guar gum. In: Raymond CR, Paul JS, Paul JW, ed. Handbook of
Pharmaceutical Excipients. The Pharmaceutical Press and The American
Pharmaceutical Association; 2003:271-273.
134. Heda A, Shivhare U. Study of some natural hydrophilic polymers as matrix
forming materials for sustained release tablet formulation. Int J Pharm Expt.
2004; July-Sept: 69-74.
135. Shelter E. Gum Acacia. In: Raymond CR, Paul JS, Paul JW, ed. Handbook of
Phannaceutical Excipients. The Pharmaceutical Press and The American
Pharmaceutical Association; 2003:1-2.
136. Jain NK, Dixit VK. Studies on gums and their derivatives as binding agent.
Indian J Pharm Sci. 1988; 50(2): 113-114.
137. Owen SC. Gum Tragacanth. In: Raymond CR, Paul JS, Paul JW, ed.
Handbook of Pharmaceutical Excipients. The Pharmaceutical Press and The
American Pharmaceutical Association; 2003:654-656.
138. Wahi SP, Sharma VD, Jain VK, Sinha P. Studies on emulsifying property of
mucilages of Hygrophila spinosa and Hibiscus esculentus. Indian J Natural
Product. 1985; 1: 3-6.
139. Wahi SP, Sharma VD, Jain VK, Sinha P. Studies on suspending property of
mucilages o f Hygrophila spinosa T anders and Hibiscus esculentus Linn.
Indian Drugs. 1985; 22(9): 500-502.
140. Edwin J, Edwin S, Dosi S, Amal R, Gupta S. Application o f Hibiscus leaves
mucilage as suspending agent. Indian J Pharm Education Res. 2007; 41(4):
373-375.
141. Desai A, Shidhaye S, Kadam VJ. Possible use o f psyllium husk as a release
retardant. Indian J Pharm Sci. 2007; 69(2): 206-210.
142. Prajapati ST, Prajapati VD, Acharya SR, Patel CN. Characterization of
disintegration properties of Plantago ovata mucilage in the formulation of
dispersible tablets. Indian J Pharm Education Res. 2006; 40(6): 208-211.
143. Srinivas K, Prakash K, Kiran HR, Prasad PM, Rao MEB. Study o f Ocimum
basilicum and Plantago ovata as disintegrants in the formulation of dispersible
tables. Indian J Pharm Sci. 2003; 65(2): 180-183.
144. Mithal BM, Kasid JL. Evaluation of the emulsifying properties of plantago
ovata (Ispaghula) seed husk. Indian J Pharm Sci. 1964; 26(12): 316-319.

E xploitation o f N a tu ra l (Product In EormuCation Design ofJL M odelD rug

61

Chapter 1

Introduction

145. Mithal BM, Kasid JL. Evaluation o f the suspending properties of Plantago
ovata (Ispaghula) seed husk. Indian J Pharm Sci. 1965; 27(12):331-335.
146. Sreenivasa Rao B, Prasanna RY, Mary S, Murthy SKVR. Design and studies
of gum karaya matrix tablet. Int J Pharm Expt. 2000; Oct-Dec: 239-242.
147. Munday DL, Philip JC. Compressed xanthan and karaya gum matrices:
hydration, erosion and drug release mechanisms. Int J Pharm. 2000; 203(1-2):
179-192.
148. Odeku OA, Itiola OA. Evaluation o f the effects o f khaya gum on the
mechanical and release properties o f paracetamol tablets. Drug Dev Ind
Pharm. 2003; 29(3): 311-320.
149. Verma PRP, Razdan B. Studies on Leucaena leucocephala seed gum:
emulsifying properties. J Sci & Ind Res. 2003; 62: 198-206.
150. Verma PRP, Razdan B. Evaluation o f Leucaenea leucocephata seed gum as
suspending agent in sulphadimidine suspensions. Indian J Pharm Sci. 2003;
65(3): 665-668.
151. Verma PRP, Razdan B. Evaluation o f Leucaena leucocephala seed gum in
tabletting I. Binding properties in granules and tablets.

S T P Pharm Sci.

2002; 12: 113-119.

152. Verma PRP, Razdan B. Evaluation o f Leucaena leucocephala seed gum in
tabletting. I. Disintegrant properties. S T P Pharm Sci. 2002; 12: 109-112.
153. Verma PRP, Razdan B. Studies on leucaena leucocephala seed gum:
evaluation of suspending properties. S T P Pharm Sci. 2001; 11(4): 289-293.
154. Xiaohong MG, Michae JT, John NS. Influence o f physiological variables on
the in-vitro drug-release behavior o f a polysaccharide matrix controlledrelease system. Drug Dev Ind Pharm. 2003; 29(1): 19-29.
155. Alison CH, John RM, Martyn CD, Colin DM. Structure and behavior in
hydrophilic matrix sustained release dosage forms: 3. The influence of pH on
the sustained-release performance and internal gel structure of sodium alginate
matrices. J Controlled Release. 1995; 33(1): 143-152.
156. Anroop B, Bhatnagar SP, Ghosh B, Parcha V. Studies on Ocimum
gratissimum seed mucilage: evaluation o f suspending properties. Indian J
Pharm Sci. 2005; 67(2): 206-209.

(Exploitation of^Natural (Product In Formulation Design o f jl M odel Drug

62

Chapter 1

Introduction

157. Anroop B, Ghosh B, Parcha V, Vasanti S. Studies on Ocimum gratissimum

seed mucilage: Evaluation of binding properties. Int J Pharm. 2006; 325(1-2):
191-193.
158. www.cpkelco.com/nectin/applications.html
159. http://www.ippa.info/applications_for_pectin.htm
160. Pomsak S. Investigation o f pectin as a carrier for oral delivery o f proteins
using calcium pectinate gel beads. Int J Pharm. 1998; 169(2): 213-220.
161. Pomsak S, Srisagul S, Satit P. Use of pectin as a carrier for intragastric
floating drag delivery: Carbonate salt contained beads. Carbohydrate Polym.
2007; 67(3): 436-445.
162. Vandamme Th. F, Lenourry A, Charrueau C, Chaumeil JC. The use of
polysaccharides to target drags to the colon. Carbohydrate Polym. 2002;
48(3): 219-231.
163. Kulkami G T, Gowthamrajan K, Bramaji Rao G, Suresh B. Evaluation of
binding properties o f selected natural mucilages. J Sci & Ind Res. 2002; 61:
529-532.
164. Howard JR, Timmins P. Controlled release formulations. U S Patent 4792452,
1988.
165. Seiyaku F. Sustained-release dilazep hydrochloride tablets, containing sodium
alginate. Jpn. Patent 01025721 [English summary], 1989.
166. Viemstein H. Retarded-release drag tablet with alginic acid - sodium aiginate
matrix. Austrian Patent 385200 [English Summary], 1988.
167. Thierry N, George C, John F. Alginate and gellan gum as tablet coating. U S
Patent 6326028 B l.
168. Kulkami GT, Gowthamarajan K, Dhobe RR, Yohanan F, Suresh B.
Development o f controlled release spheroids using natural polysaccharide as
release modifier. Drag Delivery. 2005; 12(4): 201-206.
169. Kulkami D, Dwivedi AK, Sarin JPS, Singh S. Tamarind seed polyose: A
potential polysaccharides for sustained release o f verapamil hydrochloride as a
model drag. Indian J Pharm Sci. 1997; 59(1): 1-7.
170. Dhopeshwarkar V, Zatz JL. Evaluation o f xanthan gum in the preparation of
sustained release matrix tablets. Drag Dev Ind Pharm. 1993; 19(9): 999-1017.
171. Christianah MA, Pui-kai Li. Diclofenac sodium. In: Florey K, ed. Analytical
Profile of Drag Substance. INC: Academic Press; 123-144.
E xploitation o f N atural (Product In Formulation Design o f jl (Model(Drug

63

Chapter 1

Introduction

173. Gilman AG, Ralf TW, Nile A S. The Pharmacological Basis o f Therapeutics.
Maxwell Publishing Corporation; 1991.
174. Lund W. Principles and Practice o f Pharmaceutics. The Pharmaceutical
Codex, XXIIth edi., London: The Pharmaceutical Press; 1994:835.
175. Diclofenac sodium. United State Pharmacopoeia / National Formulary. Asian
Edn., Rockville, MD: USP Convention, Inc; 2004:595-596.
176. Diclofenac sodium. Martindales The Complete Drug Reference. Sweetman
SC; 2002:30-32.
177. Wang Da Peng, Yeh MK, Yao-Hsuch CT. Chemical Abstracts. 1991; 114
(6):150308.
178. Srivastava DN, Bhattacharaya SK, Sanyal AK. Effect o f some prostaglandin
synthesis inhibitors on the antinociceptive action o f morphine in albino rats.
Clin Exp Pharmacol Physiol. 1978; 5: 503-509.
179. Kearney P, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do
selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti
inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of
randomised trials. Br Med J. 2006; 332(7553): 1302-1308.
180. Brogden RN, Heel RC, Pakes GE, Speight TM, Avery GS. Diclofenac
sodium: A review of its pharmacological properties and therapeutic use in
rheumatic diseases and pain o f varying origin. Drugs. 1980; 20(1): 24-48.
181. Ciccolunghi SN, Chaudri HA, Schubiger BI, Reddrop R. Report on a long
term tolerability study o f up to two years with diclofenac sodium (Voltaren).
Scand J Rheumatol. 1978; 22: 86-96.
182. Fowler PD. Voltarol: Diclofenac sodium. Clin Rheum. Dis. 1979, 5 (2):
427-464.
183. 185. Osnes M, Larsen S, Eidsaunet W, Thom E. Effect o f diclofenac and
naproxen on gastroduodenal mucosa. Clin Pharmacol Ther. 1979; 26(3):
399-405.

(Exploitation o f N atural Product In Formulation (Design o f A M odel (Drug

64

Chapter 1

Introduction

184. Stierlin H, Faigle JW, Colombi A. Pharmacokinetics o f diclofenac sodium

(Voltaren) and metabolites in patients with impaired renal function. Scand J
Rheumatol. 1978; 22:30-35.
185. Menasse R, Hedwall PR, Krawtz J, Pericin C, Riesterer L, Sallmann A, Ziel R,
Jaques R. Pharmacological properties o f diclofenac sodium and its
metabolites. Scand J Rheumatol. 1978; 22: 5-15.
186. Riess W, Stierlin H. Pharmacokinetics and metabolism o f the anti
inflammatory agent Voltaren. Scand J Rheumatol. 1978; 22: 17-29.
187. Todd

PA,

Sorkin

EM.

Diclofenac

sodium.

reappraisal

o f its

pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy.

Drugs. 1988; 35(3): 244-285.
188. Small R E. Diclofenac sodium. Clin Pharmaceutics. 1989; 8: 545-548.
189. Wilikens RF. World wide clinical safety experience with diclofenac. Semin
Arthritis Rheum. 1985; 15: 105-110.
190. Altman R. International experiences with diclofenac in osteoarthritis. Am J
Med! 1986; 80(4B): 48-52.
191. Kantor TG. Use of diclofenac in analgesia. Am J Med. 1986; 80(433): 64-69.
192. Sane RT, Samant RS, Nayak VG. Indian Drugs. 1986; 24(3): 161-162.
193. Agrawal YK, Upadhyay VP, Menon SK. Spectrophotometric determination of
diclofenac sodium. Indian J Pharm Sci. 1988; 50(l):58-60.
194. Kannababu S, Udayshankar P, Madhukumar G. The Eastern Pharmacist. 1995;
3 8(447): 147.
195. Marcela AC, Liliana B. Indirect fluorometric determination o f Diclofenac
sodium. Analytical Sciences. 2006; 22:431-433.
196. Goyall A, Jain S. Simultaneous estimation o f Paracetamol, Chlorzoxazone
and Diclofenac sodium in pharmaceutical formulation by a novel HPLC
method. Acta Pharmaceutica Sciencia. 2007; 49: 147- 151.
197. W isanuT, Boonsom L, Chalermpom T, Theeraphan M. High Performance
Thin Layer Chromatographic Method for the Determination of Diclofenac

Exploitation o f N atural (Product In <Femulation (Design o /Jl M odel Drug

65

Chapter 1

Introduction

Sodium in Pharmaceutical Formulations. Chiang Mai J. Sci. 2006; 33(1):

123-128.
198. Lala LG, D'Mello PM, Naik SR. HPTLC determination o f diclofenac sodium
from serum. J of Pharmaceutical and Biomedical Analysis. 2002; 29(3):
539-544.

E xploitation o f N a tu r a l (Product I n (Formulation CDesign o f j l (M odel (Drug

66