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Extended Release Drug Delivery-An Effective Way of Novel Drug Delivery

System

Article in Research Journal of Pharmaceutical Dosage Forms and Technology · November 2018
DOI: 10.5958/0975-4377.2018.00035.6

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 Research Journal of Pharmaceutical Dosage Forms and Technology. 10(4): October- December, 2018

ISSN 0975-234X (Print) Available online at

0975-4377 (Online) www.anvpublication.org
DOI: 10.5958/0975-4377.2018.00035.6
Research Journal of Pharmaceutical Dosage
Vol. 10| Issue-04|
October- December, 2018 Forms and Technology
Home page www.rjpdft.com

REVIEW ARTICLE

Extended Release Drug Delivery-An Effective Way of Novel Drug Delivery

System
Debjit Bhowmik1*, Rishab Bhanot2, K.P. Sampath Kumar3
1
Himachal Pharmacy College, Nalagarh, Himachal Pradesh
2
Himachal Institute of Pharmaceutical Education and Research, Nadaun, Hamirpur, H.P.
3
Department of Pharmacy, Coimbatore Government Medical College, Coimbatore
*Corresponding Author E-mail: debjit_cr@yahoo.com

ABSTRACT:
Extended release means the pill is formulated so that the drug is released slowly over time. This has the
advantage of taking pills less often. Also means that there may be fewer side effects as the levels of the of drug
in the body are more consistent in extended release formulations. Extended-release dosage consists of sustained-
release and controlled-release dosage. Sustained release maintains drug release over a sustained period but not at
a constant rate. Controlled-release maintains drug release over a sustained period at a nearly constant rate. The
basic goal of sustained release is provide promising way to decrease the side effect of drug by preventing the
fluctuation of the therapeutic concentration of the drug in the body and increase patient compliance by reducing
frequency of dose. This article contains the basic information regarding sustained-release formulation and also
the different types of the same. Drug products designed to reduce the frequency of dosing by modifying the rate
of drug absorption. For extended release formulations the polymers need to have certain characteristics to control
and maintain the rigidity of the matrix over a prolonged period. Extended release drug delivery technology can
provide: Smooth plasma levels of drug over longer periods of time, Reduce dosing frequency and Improve the
patient compliance.

KEYWORDS: Extended Release, Drug Delivery, Novel Drug Delivery System

INTRODUCTION: A drug delivery system is defined as a formulation or a

Oral drug delivery has been known for decades as the
most widely utilized route of administration among all
the routes. All the pharmaceutical products formulated
for systemic delivery via the oral route of administration,
irrespective of the mode of delivery (Immediate,
Extended or Controlled release) and the design of dosage
forms (either solid, dispersion, or liquid), must be
developed within the intrinsic characteristics of GI
physiology.
Received on 30.06.2018 Modified on 18.08.2018
Accepted on 19.09.2018 ©A&V Publications All right reserved
Res. J. Pharm. Dosage Form. & Tech. 2018; 10(4): 233-244.
DOI: 10.5958/0975-4377.2018.00035.6
233
device that enables the introduction of a therapeutic
substance in the body and improves its efficacy and
safety by controlling the rate, time, and place of release
of drugs in the body. This process includes the
administration of the therapeutic product, the release of
the active ingredients by the product, and the subsequent
transport of the active ingredients across the biological
membranes to the site of action. The term therapeutic
substance also applies to an agent such as gene therapy
that will induce in vivo production of the active
therapeutic agent. Drug delivery system is an interface
between the patient and the drug. It may be a
formulation of the drug to administer it for a therapeutic
purpose or a device used to deliver the drug. This
 Research Journal of Pharmaceutical Dosage Forms and Technology. 10(4): October- December, 2018
distinction between the drug and the device is important,
as it is the criterion for regulatory control of the delivery
The advantage of administering a single dose of a drug
that is released over an extended period of time to
maintain a near–constant or uniform blood level of a
drug often translates in to better patient compliance, as
well as enhanced clinical efficacy of the drug for its
intended use.
System by the drug or medicine control agency. If a
device is introduced into the human body for purposes
other than drug administration, such as therapeutic effect
by a physical modality or a drug may be incorporated
into the device for preventing complications resulting
from the device, it is regulated strictly as a device.
Traditional drug delivery system has been characterized
by immediate release and repeated dosing of the drug
which might lead to the risk of dose fluctuation, this
arises the need of a formulation with control release that
maintain a near-constant or uniform blood level. The
desire to maintain a near-constant or uniform blood level
of a drug often translates into better patient compliance,
as well as enhanced clinical efficacy of the drug for its
intended use. Sustained release, sustained action,
prolong action, controlled release, extended action, depot
are terms used to identify drug delivery systems that are
designed to achieve prolong therapeutic effect by
continuously releasing medication over an extended
period of time after administration of single dose.
Some drugs are inherently long lasting and require only
once a day oral dosing to sustain adequate drug blood
levels and the desired therapeutic effect. These drugs are
formulated in the conventional manner in the form of
immediate release dosage forms. However, many other
drugs are not inherently long lasting and require multiple
daily dosing to achieve the desired therapeutic results.
Multiple daily dosing is inconvenient for the patient and
can result in missed doses, made up doses and non
compliance with the regimen. When conventional
immediate-release dosage forms are taken on schedule
and more than once daily, they cause sequential
therapeutic blood level peaks and valleys (troughs)
associated with the administration of each dose.
However, when doses are not administered on schedule,
the resulting peaks and valleys reflect less than optimum
drug therapy. For example, if doses are administered too
frequently, minimum toxic concentrations of drug may
be reached, resulting in toxic side effects. If doses are
missed, periods of sub therapeutic drug blood levels or
those below the minimum effective concentration may
result, with no benefit to the patient. Extended-release
tablets and capsules are commonly taken only once or
twice daily, compared to their counterpart conventional
forms which may have to be taken three or four times
daily to achieve the same therapeutic effect. Typically,
234
extended release products provide an immediate release
of drug that promptly produces the desired therapeutic
effect, followed by gradual release of additional amounts
of drug to maintain this effect over a predetermined
period. The sustained plasma drug levels provided by
extended release products often at times eliminate the
need for night dosing which benefits not only the patient
but also the caregiver.3 It form produces wide range of
fluctuation in drug concentration in the blood stream and
tissues with consequent undesirable toxicity and poor
efficiency. The maintenance of concentration of drug in
plasma within therapeutic index is very critical for
effective treatment.
ORAL DRUG DELIVERY SYSTEM:
Oral drug delivery is the most preferred and convenient
option as the oral route provides maximum active
surface area among all the drug delivery systems for
administration of various drugs. The attractiveness of
these dosage forms is due to awareness to toxicity and
ineffectiveness of drugs when administered by oral
conventional method in the form of tablets and capsules.
Usually conventional dosage.
Sustained release, prolonged release, modified release,
extended release or depot formulations are terms used to
identify drug delivery systems that are designed to
achieve or extend therapeutic effect by continuously
releasing medication over an extended period of time
after administration of single dose. The goal in designing
sustained delivery system is to reduce the frequency of
dosing or to increase effectiveness of the drug by
localization at the site of action, reducing the dose
required or providing uniform drug delivery. So,
sustained release dosage form is a dosage form that
release one or more drugs continuously in a
predetermined pattern for a fixed period of time, either
systemically or to a specified target organ.3
The scientific framework required for the successful
development of an oral drug delivery system consists of
a basic understanding of the following three aspects:
1. The anatomic and physiologic characteristics of the
gastrointestinal tract.
2. Physicochemical, pharmacokinetic and
pharmacodynamic characteristics of the drug.
3. Physicomechanical characteristics and the drug
delivery mode of the dosage form to be designed.
Table 1: Anatomic and physiologic characteristics of the GI track5
Region Surface pH of The Transit Time
Area(m2) Region Fluid Solid
GIT 200 - - -
Stomach 0.1-0.2 1-3.5 50 min. 8 hrs.
Small 4500 5-7.5 2-6 hrs. 4-9 hrs.
intestine
Large 0.5-0.1 6.8 2-6 hrs. 3 hrs. to 3
intestine days
 Research Journal of Pharmaceutical Dosage Forms and Technology. 10(4): October- December, 2018
Fig 1: Gastrointestinal anatomy and dynamics
Stomach:
The stomach is an organ with a capacity for storage and
mixing. Under fasting conditions the stomach is a
collapsed bag with a residual volume of 50 mL and
contains a small amount of gastric fluid (pH 1-3) and air.
The stomach has four main areas: cardia, fundus, body,
and pylorus. Within 2-4 hrs after eating a meal the
stomach has emptied its contents into the duodenum.
Intestine:
The small intestine is a tubular viscous organ and has
enormous number of villi on its mucosal surface that Drug levels in the blood with
create a huge surface area. The surface of the mucous
membrane of the small intestine possesses about 5
million villi, each about 0.5 to 1 mm long. These villi are • To overcome these problems, controlled drug
minute fingerlike projections of the mucosa and have a
length of 0.5-1.5 mm. Absorption of material occurs by
facilitate diffusion, osmosis, and active transport.
The small intestine is the largest section of the digestive
tube and it is arbitrarily divided in three parts.
Duodenum (20-30 cm), Jejunum (2-5 m) and ileum (3-5
m). The duodenum has a pH of 5 to 6 and the lower
ileum approaches a pH of 8.
• Conventional drug therapy requires periodic doses
of therapeutic agents. These agents are formulated
to produce maximum stability, activity and
bioavailability. For most drugs, conventional
methods of drug administration are effective, but
some drugs are unstable or toxic and have narrow
therapeutic ranges. Some drugs also possess
solubility problems.
• In such cases, a method of continuous
administration of therapeutic agent is desirable to
maintain fixed plasma levels as shown in Figure.
235
Drug levels in the blood with Conventional drug delivery system 6
Drug levels in the blood with Controlled drug delivery system
a) Traditional drug delivery systems and
b) Controlled drug delivery systems.
delivery systems were introduced three decades ago.
These delivery systems have a number of
advantages over traditional systems such as
improved efficiency, reduced toxicity, and improved
patient convenience. The main goal of controlled
drug delivery systems is to improve the
effectiveness of drug therapies.
• Ideally a sustained release oral dosage form is
designed to release rapidly some pre determined
fraction of the total dose in to GI tract. This fraction
(loading dose) is an amount of drug, which will
produce the desired pharmacological response as
promptly as possible and the remaining fraction of
the total dose (maintenance dose) is then release at a
constant rate. The rate of the drug absorption from
the entire maintenance dose into the body should
equal to the rate of the drug removal from the body
by all the processes over the time.
• In this system, drug concentration is maintained in
the therapeutic window for a prolonged period of
time, thereby ensuring extended therapeutic action.
Ideally two main objectives exist for these systems.
 Research Journal of Pharmaceutical Dosage Forms and Technology. 10(4): October- December, 2018

These are spatial delivery, which is related to the
control over the location of drug release and
temporal drug delivery, in which the drug is
delivered over an extended period of time during
treatment.
The conventional dosage forms are immediate release
type. Non-immediate release delivery systems may be
divided conveniently into following categories:7
1) Delayed Release
2) Sustained Release
3) Controlled Release
4) Prolonged Release
5) Site-specific and Receptor release
1. Delayed Release:
Delayed release systems are those systems that use
repetitive, intermittent dosing of a drug from one or
more immediate release units incorporated into a single
dosage form. Delayed release dosage form does not
produce or maintain uniform drug blood levels within
the therapeutic range.
2. Sustained Release system:
It includes any drug delivery system that achieves slow
release of drug over an extended period of time.
3. Controlled Release system:
If the system is successful at maintaining constant drug
level in the blood or target tissues, it is considered as a
controlled release system. Drug delivery systems from
which therapeutic agents may be automatically delivered
at predetermined rates over a long period of time are
called as controlled drug delivery systems.
5. Site-Specific and Receptor Release:
In the case of site-specific release, the target is a certain
organ or tissue, while for receptor release, the target is
the particular receptor for a drug within an organ or
tissue. Both of these systems satisfy the spatial aspects of
drug delivery.
Extended Release: 9-11
Extended release drug delivery system is designed to
achieve a prolonged therapeutic effect by continuously
releasing medication over an extended period of time
after administration of a single dose.
The smaller doses which are given after loading dose are
called maintenance dose. Maintainance dose is achived
by extended release of the drug.
Advantages:
• The frequency of drug administration is reduced.
• Patient compliance can be improved, and drug
administration can be made more convenient as
well.
• The blood level oscillation occurs by multiple
dosing of conventional dosage forms is reduced,
because a more even blood level is maintained.
• Minimizing drug accumulation with chronic dosing.
• Total amount of drug administered can be reduced,
thus maximizing availability with a minimum dose.
• In addition, better control of drug absorption can be
attained, since the high blood level peaks that may
be observed after administration of a dose.
• The safety margin of high-potency drugs can be
increased, and the incidence of both local and
systemic adverse side effects can be reduced in
sensitive patient.

4. Prolonged Release system: Limitations:

In this system, without maintaining constant level, the • Administration of extended release medication does
duration of action is extended over that achieved by not permit the prompt termination of therapy.
conventional delivery, it is considered as a prolonged • The physician has less flexibility in adjusting dosage
release system. This is illustrated in Fig.1.2.1.4 regimens. This is fixed by the dosage form design.
• Extended release forms are designed for the normal
population i.e., on the basis of average drug
biological half-life. Consequently, disease states that
alter drug disposition, significant patient variation.
• Economic factors must also be assessed, since more
costly processes.
Table: 2 Types of Matrix for Extended Release
Sr. No. Matrix Material
Characteristic
1 Insoluble, Carnauba wax, Castor wax
erodible
2 Insoluble, inert Polyethylene, Polyvinyl chloride
Ethylcellulose
3 Hydrophilic Methylcellulose,
Fig. 2: Drug levels in the blood with prolonged release drug Hydroxyethylcellulose
delivery system Hydroxypropylmethylcellulose
4 Hydrophobic Ethyl cellulose, Glyceryl Behenate

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 Research Journal of Pharmaceutical Dosage Forms and Technology. 10(4): October- December, 2018

Insoluble, inert material containing matrix tablets are not Mechanism of drug release from ER Tablet: 12, 13
useful for high milligram potency formulations in which Extended release tablets are often classified according to
the polymer content would be sufficient to form a the mechanism of drug release. The following are the
matrix, or for highly water-insoluble drugs in which most common means used to achieve a slow controlled
dissolution in the matrix would become rate-limiting. release of the drug from tablets,
A. Dissolution control
Hydrophilic matrix former represents non-digestible B. Drug transport control by diffusion
materials that form gels in situ. Drug release is C. Erosion control
controlled by penetration of water through a gel layer D. Combination of Diffusion & Dissolution System
produced by hydration of the polymer and diffusion of E. Drug transport control by convective flow
drug through the swollen, hydrated matrix, in addition to (accomplished by, for example, osmotic pumping)
erosion of the gelled layer.
A) Dissolution controlled release systems:
The hydrophilic polymers can be arranged into three In dissolution controlled extended release systems the
broad categories: rate of dissolution of drug in the GI juices or another
1. Non-cellulose natural or semi synthetic polymer ingredients is the release controlling process. Sparingly
These are products of vegetable origin and are generally water-soluble drug can form a preparation of a
used as such agar, alginate, guar gum, chitosan and dissolution controlled extended release type.
modified starches are commonly used polymer.
Dissolution controlled extended release systems can also
2. Polymers of acrylic acid obtained by covering drug particles with a slowly
These are arranged in carbomer group and dissolving coating. The release of the drug from such
commercialized under the name of carbopol. The major units occurs in two steps.
disadvantage of this type of polymer is its pH dependent 1- The liquid that surrounds the release unit dissolves
gelling characteristics. the coating (rate limiting dissolution step).
2- The solid drug is exposed to the liquid and
3. Cellulose ether subsequently dissolves.
This group of semi-synthetic cellulose derivatives is the Extended release oral products employing dissolution as
most widely used group of polymer. Non-ionic such as the rate-limiting step. A drug with a slow dissolution rate
HPMC of different viscosity grades are widely used is inherently extended. Some example of these drugs
group of polymers. includes digoxin, griseofulvin, and salicylamide.
Advantages of matrix system: For those drugs with high water solubility and therefore
• Easy to manufacture high dissolution rate, one can decrease solubility through
• Versatile, effective, low cost appropriate salt of derivative formation. Unfortunately,
• Can be made to release high molecular weight forms such as these do not meet the criterion of constant
compounds availability rate because their surface area decreases with
• This device can offer zero-order release of the drug. time. Nevertheless, extended drug release can be
• Kinetics of a particular drug can be controlled by achieved by coating drug particles or granules with
changing the characteristics of the polymer to meet materials of varying thickness or by dispersing them in a
the particular therapeutic conditions. polymeric matrix.

Disadvantages of matrix system:

• Difficult to deliver high molecular weight
compounds.
• Generally increased cost per dosage unit.
• The remaining matrix must be removed after the
drug has been released.
• The drug release rate varies with the square root of
time.
• Release rate continuously diminishes due to an
increase in diffusion resistance and/ or a decrease in Fig. 3: Dissolution control of drug release via thickness and
effective area at the diffusion front. dissolution rate of the membrane barrier coat

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 Research Journal of Pharmaceutical Dosage Forms and Technology. 10(4): October- December, 2018

Release depends on drug solubility and pore structure

membrane. Constant release resulted when GI fluid
passes through barrier to dissolve drug.

B) Diffusion Controlled Release:

There are basically two types of diffusion controlled
systems which have been developed over the past two
decades:
• Reservoir devices and Fig. 4: Schematic illustration of the mechanism of drug release
• Matrix devices systems (monolithic systems). from a diffusion based reservoir tablet (t = time)

In diffusion controlled extended release systems the This film is normally formed from a high molecular
transport by diffusion of dissolved drug in pores filled weight polymer. The diffusion distance will be constant
with gastric or intestinal juice or in a solid (normally during the course of the release and, as long as a constant
polymer) phase is the release controlling process. drug concentration gradient is maintained, the release
rate will be constant, i.e. a zero order release. One
The release unit can be tablet or a nearly spherical possible process for the release of the drug from a
particle of about 1 mm in diameter (a granule or a reservoir system involves partition of the drug dissolved
milisphere). In both cases the release unit should stay inside the release unit to the solid membrane, followed
more or less intact during course of the release process. by transport by diffusion of the drug within the
membrane. Finally, the drug will partition to the solution
In Matrix Systems diffusion occurs in pores located surrounding the release unit. The driving force for the
within the bulk of the release unit, and in Reservoir release is the concentration gradient of dissolved drug
Systems diffusion takes place in a thin water-insoluble over the membrane.
film or membrane, often about 5-20 µm thick, which
surrounds the release unit. In this system, a water-insoluble polymeric material
encases a core of drug. Drug will partition into the
Drug is release from a diffusion controlled release unit in membrane and exchange with the fluid surrounding the
two steps- particle or tablet. Additional drug will enter the
1. The Liquid that surrounds the dosage from membrane, diffuse to the periphery, and exchange with
penetrates in release unit and dissolves the drug. A the surrounding media.
concentration gradient of dissolved drug is thus
established between the interior and the exterior of Coefficient is defined as the concentration of drug in the
the release unit. membrane over the concentration of drug in the core. If
2. The dissolved drug will diffuse in the pores of the the partition coefficient is high, the core will be depleted
release unit or the surrounding membrane and thus, of drug in a short time so that zero order release will be
dissolved drug will partition into the membrane observed only over a short segment of the time course of
surrounding the dose unit and diffuse in the drug release.
membrane.
b) Matrix Devices:
A dissolution step is normally involved in the release In a matrix system the drug is dispersed as solid particles
process but the diffusion step is the rate controlling step. within a porous matrix formed of a water insoluble
The rate at which diffusion will occur depends on four polymer, such as polyvinyl chloride. Initially, drug
variables: particles located at the surface of the release unit will be
dissolved and the drug released rapidly. Thereafter, drug
• concentration gradients over the diffusion distance.
particles at successively increasingly distances from the
• area
surface of the release unit will be dissolved and released
• distance over which diffusion occurs by diffusion in the pores to the exterior of the release
• diffusion co-efficient of the drug in the diffusion unit. Thus, the diffusion distance of dissolved drug will
medium increase as the release process proceeds. The drug
release, in terms of the cumulative amount of drug (M)
a) Reservoir system: release from a matrix in which drug particles are
In a reservoir system the diffusion occurs in a thin film suspended is proportional to the square root of time i.e.
surrounding the release unit.
M=kt1/2

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 Research Journal of Pharmaceutical Dosage Forms and Technology. 10(4): October- December, 2018

The main formulation factors by which the release rate
from a matrix system can be controlled are
• The amount of drug in the matrix,
• The porosity of the release unit, The length of the
pores in the release unit
• The solubility of the drug (which regulates the
concentration gradient). The
characteristics of the pore system can be affected by,
In a hydrophilic matrix, there are two competing
mechanisms involved in the drug release: Fickian
diffusional release and relaxation release. Diffusion is
not the only pathway by which a drug is released from
the matrix; the erosion of the matrix following polymer
relaxation contributes to the overall release. The relative
contribution of each component to the total release is
primarily dependent on the properties of a given drug.

For example: - The addition of soluble excipients and by For example, the release of a sparingly soluble drug from
the compaction pressure during tabletting. hydrophilic matrix involves the simultaneous absorption
of water and desorption of drug via a swelling-controlled
diffusion mechanism. As water penetrates into a glassy
polymeric matrix, the polymer swells and its glass
transition temperature is lowered. At the same time, the
dissolved drug diffuses through this swollen rubbery
region into the external releasing medium.

Fig. 5: Schematic illustration of the mechanism of drug release

from a diffusion based matrix tablet (t = time)

Fig. 6:Drug release from hydrophilic matrix tablet

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 Research Journal of Pharmaceutical Dosage Forms and Technology. 10(4): October- December, 2018

C) Erosion controlled release systems Swelling-controlled matrixes exhibit a combination of

In erosion controlled extended release systems that rate
of drug release is controlled by the erosion of a matrix in
which drug is dispersed.
The matrix is normally a tablet, i.e. the matrix is formed
by a tabletting operation and the system can be described
as a continuous liberation of matrix material (both drug
and excipients) from the surface of the tablet, i.e. surface
erosion.
diffusion & dissolution mechanisms. Here the drug is
dispersed in a polymer, but instead of an insoluble or
non-erodable polymer, swelling of the polymer occurs.
This allows for the entrance of the water, which causes
dissolution of the drug & diffusion out of the swollen
matrix. In these type of systems the release rate is highly
dependant on the polymer swelling-rate and drug
solubility. Mainly used excipients for these type of drug
delivery systems are HPMC, Xanthan Gum etc.

The consequence will be a continuous reduction in tablet The swelling behavior of heterogeneous swellable
weight during the course of the release process. matrixs is described by front positions, where ‘front’
indicates the position in the matrix where the physical
conditions sharply change. Three fronts are present, as
shown in Fig.1.3.2.6

The ‘swelling front’ clearly separates the rubbery region

from the glassy region.

The ‘erosion front’, separates the matrix from the

solvent. The gel-layer thickness as a function of time
Fig. 7: Schematic illustration of the mechanism of drug release is determined by the relative position of the swelling
from erosion based matrix tablet (t=time) and erosion moving fronts.

Drug release from an erosion system can thus be The ‘diffusion front’ located between the swelling and
described in two steps. erosion fronts, and constituting the boundary that
1. Matrix material, in which the drug is dissolved or separates solid from dissolved drug, has been identified.
dispersed, it is liberated from the surface of the
tablet. During drug release, the diffusion front position in the
2. The drug is subsequently exposed to the GI fluids gel phase is dependent on drug solubility and loading.
and mixed with or dissolved in the fluid. The diffusion front movement is also related to drug
dissolution rate in the gel.
One example is lipids or waxes, in which the drug is
dispersed. Another example is polymers that gel in
contact with water (Hydroxy ethyl cellulose), the gel will
subsequently erode and release the drug dissolved.
Diffusion of the drug in the gel may occur in parallel.

D) Combination of Diffusion & Dissolution System:

Strictly speaking, therapeutic system will never be
dependent on dissolution or diffusion only. In practice,
the dominant mechanism for release as either dissolution
rate-limited or diffusion controlled release.

This type of drug delivery system combines diffusion &

dissolution of both drugs as well as matrix material.
Drug can not only diffuses out of dosage form; as
described in previous matrix system, but matrix itself
also under goes dissolution process. The complexity of
the system arises from the fact that as the polymer
dissolves the diffusional path length for the drug may
change. This usually results in a moving boundary
diffusion system. Zero-order release is possible only if
surface erosion occurs and surface area does not change
with time.
Fig. 8: Fronts in a swellable HPMC matrix
Drug release is controlled by the interaction between
water, polymer and drug. The delivery kinetics depends
on the drug gradient in the gel layer. Therefore, drug
concentration and thickness of the gel layer governs the
drug flux. Drug concentration in the gel depends on drug
loading and solubility. Gel-layer thickness depends on
the relative contributions of solvent penetration, chain
disentanglement and mass (polymer and drug) transfer in

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 Research Journal of Pharmaceutical Dosage Forms and Technology. 10(4): October- December, 2018
the solvent. Initially solvent penetration is more rapid
than chain disentanglement, and a rapid build- up of
gel-layer thickness occurs. However, when the solvent
penetrates slowly, owing to an increase in the
diffusional distance, little change in gel thickness is
observed since penetration and disentanglement rates are
similar. Thus gel-layer thickness dynamics in swellable
matrix tablets exhibit three distinct patterns. The
thickness increases when solvent penetration is the
fastest mechanism, and it remains constant when the
disentanglement and water penetration occur at a similar
rate. Finally, the gel-layer thickness decreases when
the entire polymer has undergone the glassy–rubbery
transition. In conclusion, the central element of the
release mechanism is a gel-layer forming around the
matrix in response to water penetration. Phenomena that
govern gel-layer formation, and consequently drug-
release rate, are water penetration, polymer swelling,
drug dissolution and diffusion, and matrix erosion.
Drug release is controlled by drug diffusion through the
gel layer, which can dissolve and/or erode.
E) Osmotic controlled release systems:
Drug delivery from these systems to a large extent is Parameter
independent of the physiological factors of the GI tract Elimination half life
and it can be utilized for systemic as well as targeted Total clearance
delivery of drugs.
The osmotic pump is similar to a reservoir device but
contains an osmotic agent (e.g., the active agent in salt
form) which acts to imbibe water from the surrounding
medium via a semi-permeable membrane. Such a device,
called the 'elementary osmotic pump', has been
described by Theeuwes. Pressure is generated within the
device which forces the active agent out of the device via
an orifice. The internal volume of the device remains
constant, and there is an excess of solid (saturated
solution) in the device, then the release rate remains
constant delivering a volume equal to the volume of
solvent uptake.
The release of drug(s) from osmotic systems is governed
by various formulation factors such as solubility and
osmotic pressure of the core component(s), size of the
delivery orifice and nature of the rate controlling
membrane.
Fig. 9: Osmosis Pump
Drug selection for oral controlled release drug
delivery systems
The biopharmaceutical evaluation of a drug for potential
use in controlled release drug delivery system requires
knowledge on the absorption mechanism of the drug
form the G.I. tract, the general absorbability, the drug’s
molecular weight, solubility at different pH and apparent
partition coefficient.14, 15
Table: 3 Physicochemical Parameters for drug selection
Parameter Preferred value
Molecular weight/ size < 1000 daltons
Solubility > 0.1 mg/ml for pH 1 to pH 7.8
Apparent partition coefficient High
Absorption mechanism Diffusion
General absorbability From all GI segments
Release Should not be influenced by pH
and enzymes
The pharmacokinetic evaluation requires knowledge on a
drug’s elimination half-life, total clearance, absolute
bioavailability, possible first- pass effect, and the desired
steady concentrations for peak.
Table: 4. Pharmacokinetic parameters for drug selection
Comment
Preferably between 0.5 and 8 h
Should not be dose dependent
Apparent volume of The larger Vd and MEC, the larger will
distribution Vd be the required dose size.
Absolute bioavailability Should be 75% or more
Intrinsic absorption rate Must be greater than release rate
Therapeutic The lower Css av and smaller Vd, the
concentration Css av loss among of drug required
Toxic concentration Apart the values of MTC and MEC,
safer the dosage form. Also suitable for
drugs with very short half-life.
Basic kinetics of controlled drug delivery:
To influence of drug properties and the route of
administration on controlled drug delivery, following
mechanisms need a fair mention,
1. Behavior of drug within its delivery systems
2. Behavior of the drug and its delivery system jointly in
the body.
For conventional systems, the rate-limiting step in drug
availability is usually absorption of drug across a
biological membrane such as the gastro intestinal wall.
However, in sustained/controlled release product, the
release of drug from the dosage form is the rate limiting
step, thus, drug availability is controlled by the kinetics
of drug release than absorption.23
Bilayer Tablet16-19
Bi-layer tablets are tablets made by compressing several
different granules fed into a die in succession, one on top
of another, in layers. Each drug blend comes from a
separate feed frame with individual weight control. Ro-
241
 Research Journal of Pharmaceutical Dosage Forms and Technology. 10(4): October- December, 2018
tary tablet presses can be set up for two or three layers. • Monograms and other distinctive markings may be
More are possible but the design becomes very special.
Ideally, a slight compression of each layer and individual • Analytical work may be simplified by separating of
layer ejection permits weight checking for control
purposes. They have the appearance of a sandwich
because the edges of each layer are exposed.
Fig. 10: General Concept of Bilayer Tablets
Advantages:
• Physical/chemical separation :
It is possible to avoid the incompatibility in between
active-excipients and excipient-excipient by mean of
physical separation.
• Multiple release profile:
Bilayer tablets are able to provide multiple release
kinetics of same/different Drugs of same or different
physico-chemical property by application of multiple
tablets. Each layer was formulated in order to parcel out
the delivery of drug dose by means of different release Tablet Layer Press:
control mechanism.
• Immediate release ( disintegrating monolith):
Bilayer tablet can deliver the initial fast release required
to achieve peak plasma concentration.
• Delay release ( Erodible and swelling monolith):
Delay release can also be achived by bilayer tablet by
applying either erodible or swelling mechanism from
which the drug were continuously released throughout
the GIT.
For synergetic therapeutic effect:
In the management of disease condition where
synergetic therapeutic effect from two or more drugs is
essential and that are not compatible with each other in
such condition bilayer tablet is the only option.
• Layers may be colored differently to identify the
product.
242
impressed on the surfaces of the multi-layer tablets.
the layers prior to assay.
Quality and GMP-requirements for bilayer tablet:
To produce a quality bi-layer tablet, in a validated and
GMP-way, it is important that the selected press is
capable of
• Preventing capping and separation of the two
individual layers that constitute the bi-layer tablet.
• Providing sufficient tablet hardness.
• Preventing cross-contamination between the two
layers.
• Producing a clear visual separation between the two
layers.
• High yield.
• Accurate and individual weight control of the two
layers.
For good-quality tablets with sharp definition
between the layers, special care must be taken as
follows:
• Dusty fines must be limited. Fines smaller than 100
meshes should be kept at a minimum.
• Maximum granule size should be less than 16
meshes for a smooth, uniform scrape-off at the die.
• Low moisture is essential if incompatibles are used.
• Weak granules that break down easily must be
avoided. Excessive amounts of lubrication,
especially metallic stearates, should be avoided for
better adhesion of the layers.
• Formulation of multilayer tablets is more
demanding than that of single-layer tablets. For this
reason, selection of additives is critical.
• A tablet multilayer press is simply a tablet press that
has been modified so that it has two die-filling and
compression cycles for each revolution of the press.
In short, each punch compresses twice, once for the
first layer of a two-layer tablet and a second time for
the second layer.
• There are two types of layer presses presently in
use-one in which each layer can be ejected from the
press separately for the purpose of weight checking,
and the second in which the first layer is compressed
so hard that the second layer will not bond to it, or
will bond so poorly that upon ejection the layers are
easily separated for weighing. Once the proper
weight adjustments have been made by adjusting the
die fill, the pressure is adjust to the proper tablet
hardness and bonding of the layers.
• Once hazard of layer tablet production is the lack of
proper bonding of layers. This can result in a lot of
 Research Journal of Pharmaceutical Dosage Forms and Technology. 10(4): October- December, 2018
100,000 tablets ending up as 200,000 layers after •
several days if the layers are not sufficiently bonded.
• In a two layer tablet press, two hoppers above the
rotary die table feed granulated material to two
separate feed frames without intermixing.
Continues, gentle circulation of the material through
the hoppers and feed frames assures uniform filling •
without segregation of particle sizes that would
otherwise carry over to the second layer and affect
layer weight, tablet hardness, and, in the case of •
differently colored granulations, the press with three
hoppers for the tree granulations instead of two.
Limitations of the single-sided press:
• The simplest design is a single-sided press with both
chambers of the double feeder separated from each
other. Each chamber is gravity or forced-fed with a
different powder, thus producing the two individual
layers of the tablet. When the die passes under the
feeder, it is at first loaded with the first-layer
powder followed by the second-layer powder. Then
the entire tablet is compressed in one or two steps
(two=pre- and main compression).
• The two layers in the die mix slightly at their
interface and in most cases bond sufficiently so that
no layer-separation occurs when the tablet is
produced. This is the simplest way of producing a
bi-layer tablet. The limitations of such single-sided
press are:
• No weight monitoring/control of the individual
layers
• No distinct visual separation between the two layers
• The fact that it is not possible to monitor and control
the weight of the individual layers raises the
question whether we can consider this production
GMP? Individual layer-weight control on a single-
sided press requires some form of measurement of
the first layer. The first control loop indirectly
monitors weight and controls the fill depth of the
first layer. The second loop indirectly monitors the
total tablet weight, but adjust only second-layer fill
depth. In general, compression force is used to
monitor tablet-or layer-weight. But to do so it is
necessary to apply a compression force to the first
layer before adding the second layer-powder. To
apply a compression force to the first layer prior to
adding the second layer, it is necessary to use two
separate powder feeders with a compression station
in- between. This can be achieved on a single-sided
press by installing an additional feeder between the
pre- and main- compression station. Very often the
precompression roller must be reduced to a much
smaller size in order to create the pace required for
the second feeder. Additional limitations of such
single-sided press are:
243
Very short first layer dwell time due to the small
compression roller, possibly resulting in poor de-
aeration, capping and hardness problems. This may
be corrected by reducing the turret-rotation speed (to
extend the dwell time) but with the consequence of
lower tablet output.
Very difficult first-layer tablet sampling and sample
transport to a test unit for in-line quality control and
weight recalibration.
To eliminate these limitations, a double-sided tablet
press is preferred over a single-sided press. A
double-sided press offers an individual fill station,
precompression and main compression for each
layer. In fact, the bi-layer tablet will go through 4
compression stages before being ejected from the
press.
Limitations of “compression force” - controlled tablet
presses
• Separation of the two individual layers is the
consequence of insufficient bonding between the
two layers during final compression of the bi-layer
tablet. Correct bonding is only obtained when the
first layer is compressed at a low compression force
so that this layer can still interact with the second
layer during final compression of the tablet.
Bonding is severely restricted if the first layer is
compressed at a too-high compression force. The
low compression force required when compressing
the first layer unfortunately reduces the accuracy of
the weight monitoring/control of the first layer in
the case of tablet presses with “compression force
measurement”.
• Most double-sided tablet presses with automated
production control use compression force to monitor
and control tablet weight. The effective peak
compression force exerted on each individual tablet
or layer is measured by the control system at main-
compression of that layer.
Release Patten of bilayer tablets having immediately
release part and extended release part.
Fig. 11: Release pattern of bilayer Tablet
 Research Journal of Pharmaceutical Dosage Forms and Technology. 10(4): October- December, 2018
Fig. 12: Compression cycle of bi-layer tablet
Steps of compression of bi-layer tablet:
1. Filling of first layer.
2. Compression of first layer.
3. Ejection of upper punch.
4. Filling of second layer.
5. Compression of both layer together.
6. Ejection of bi-layer tablet.
Fig. 13: Bilayer Rotary Machine
CONCLUSION:
The most widely used measure of the margin of a drug’s
safety is its therapeutic index, that is, the median toxic
dose divided by the median effective dose. For very
potent drugs, the therapeutic index may be narrow or
very small. They are used in the treatment of chronic
rather than acute conditions. Drugs for acute conditions
require greater adjustment of the dosage by the physician
than that provided by extended-release products.
Modified-release products including extended-release,
prolonged-release, controlled-release, controlled-
delivery, slow-release and sustained-release. These
preparations, by definition, have a reduced rate of release
244
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of active substance. In general, these terms are
interchangeable. Extended release tablet are Designed to
release their medication in controlled manner, at pre-
determined rate, duration and location in the body to
achieve and maintain optimum therapeutic blood levels
of drug. Among the various routes of drug delivery oral
route is most preferred route. But conventional dosage
form offers few limitations which could be resolved by
modifying the existing dosage form. Sustained and
controlled drug delivery system helps in maintaince of
constant plasma drug concentration and retards the
release rate of drug therby extending the duration of
action. There are various formulation strategies for
sustained release tablets among which matrix tablet
serves as an important tool. Hence the problem like poor
patient compliance, multiple dosing, see-saw
fluctuations can be easily minimized.
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