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

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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 device that enables the introduction of a therapeutic
most widely utilized route of administration among all substance in the body and improves its efficacy and
the routes. All the pharmaceutical products formulated safety by controlling the rate, time, and place of release
for systemic delivery via the oral route of administration, of drugs in the body. This process includes the
irrespective of the mode of delivery (Immediate, administration of the therapeutic product, the release of
Extended or Controlled release) and the design of dosage the active ingredients by the product, and the subsequent
forms (either solid, dispersion, or liquid), must be transport of the active ingredients across the biological
developed within the intrinsic characteristics of GI membranes to the site of action. The term therapeutic
physiology. 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
Received on 30.06.2018 Modified on 18.08.2018 between the patient and the drug. It may be a
Accepted on 19.09.2018 ©A&V Publications All right reserved formulation of the drug to administer it for a therapeutic
Res. J. Pharm. Dosage Form. & Tech. 2018; 10(4): 233-244.
DOI: 10.5958/0975-4377.2018.00035.6
purpose or a device used to deliver the drug. This
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 Research Journal of Pharmaceutical Dosage Forms and Technology. 10(4): October- December, 2018

distinction between the drug and the device is important, extended release products provide an immediate release
as it is the criterion for regulatory control of the delivery of drug that promptly produces the desired therapeutic
The advantage of administering a single dose of a drug effect, followed by gradual release of additional amounts
that is released over an extended period of time to of drug to maintain this effect over a predetermined
maintain a near–constant or uniform blood level of a period. The sustained plasma drug levels provided by
drug often translates in to better patient compliance, as extended release products often at times eliminate the
well as enhanced clinical efficacy of the drug for its need for night dosing which benefits not only the patient
intended use. but also the caregiver.3 It form produces wide range of
fluctuation in drug concentration in the blood stream and
System by the drug or medicine control agency. If a tissues with consequent undesirable toxicity and poor
device is introduced into the human body for purposes efficiency. The maintenance of concentration of drug in
other than drug administration, such as therapeutic effect plasma within therapeutic index is very critical for
by a physical modality or a drug may be incorporated effective treatment.
into the device for preventing complications resulting
from the device, it is regulated strictly as a device. ORAL DRUG DELIVERY SYSTEM:
Traditional drug delivery system has been characterized Oral drug delivery is the most preferred and convenient
by immediate release and repeated dosing of the drug option as the oral route provides maximum active
which might lead to the risk of dose fluctuation, this surface area among all the drug delivery systems for
arises the need of a formulation with control release that administration of various drugs. The attractiveness of
maintain a near-constant or uniform blood level. The these dosage forms is due to awareness to toxicity and
desire to maintain a near-constant or uniform blood level ineffectiveness of drugs when administered by oral
of a drug often translates into better patient compliance, conventional method in the form of tablets and capsules.
as well as enhanced clinical efficacy of the drug for its Usually conventional dosage.
intended use. Sustained release, sustained action,
prolong action, controlled release, extended action, depot Sustained release, prolonged release, modified release,
are terms used to identify drug delivery systems that are extended release or depot formulations are terms used to
designed to achieve prolong therapeutic effect by identify drug delivery systems that are designed to
continuously releasing medication over an extended achieve or extend therapeutic effect by continuously
period of time after administration of single dose. releasing medication over an extended period of time
after administration of single dose. The goal in designing
Some drugs are inherently long lasting and require only sustained delivery system is to reduce the frequency of
once a day oral dosing to sustain adequate drug blood dosing or to increase effectiveness of the drug by
levels and the desired therapeutic effect. These drugs are localization at the site of action, reducing the dose
formulated in the conventional manner in the form of required or providing uniform drug delivery. So,
immediate release dosage forms. However, many other sustained release dosage form is a dosage form that
drugs are not inherently long lasting and require multiple release one or more drugs continuously in a
daily dosing to achieve the desired therapeutic results. predetermined pattern for a fixed period of time, either
Multiple daily dosing is inconvenient for the patient and systemically or to a specified target organ.3
can result in missed doses, made up doses and non The scientific framework required for the successful
compliance with the regimen. When conventional development of an oral drug delivery system consists of
immediate-release dosage forms are taken on schedule a basic understanding of the following three aspects:
and more than once daily, they cause sequential 1. The anatomic and physiologic characteristics of the
therapeutic blood level peaks and valleys (troughs) gastrointestinal tract.
associated with the administration of each dose. 2. Physicochemical, pharmacokinetic and
However, when doses are not administered on schedule, pharmacodynamic characteristics of the drug.
the resulting peaks and valleys reflect less than optimum 3. Physicomechanical characteristics and the drug
drug therapy. For example, if doses are administered too delivery mode of the dosage form to be designed.
frequently, minimum toxic concentrations of drug may
be reached, resulting in toxic side effects. If doses are Table 1: Anatomic and physiologic characteristics of the GI track5
missed, periods of sub therapeutic drug blood levels or Region Surface pH of The Transit Time
those below the minimum effective concentration may Area(m2) Region Fluid Solid
GIT 200 - - -
result, with no benefit to the patient. Extended-release Stomach 0.1-0.2 1-3.5 50 min. 8 hrs.
tablets and capsules are commonly taken only once or Small 4500 5-7.5 2-6 hrs. 4-9 hrs.
twice daily, compared to their counterpart conventional intestine
forms which may have to be taken three or four times Large 0.5-0.1 6.8 2-6 hrs. 3 hrs. to 3
daily to achieve the same therapeutic effect. Typically, intestine days

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

Drug levels in the blood with Conventional drug delivery system 6

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: Drug levels in the blood with Controlled drug delivery system
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 a) Traditional drug delivery systems and
membrane of the small intestine possesses about 5 b) Controlled drug delivery systems.
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 delivery systems were introduced three decades ago.
length of 0.5-1.5 mm. Absorption of material occurs by These delivery systems have a number of
facilitate diffusion, osmosis, and active transport. advantages over traditional systems such as
The small intestine is the largest section of the digestive improved efficiency, reduced toxicity, and improved
tube and it is arbitrarily divided in three parts. patient convenience. The main goal of controlled
Duodenum (20-30 cm), Jejunum (2-5 m) and ileum (3-5 drug delivery systems is to improve the
m). The duodenum has a pH of 5 to 6 and the lower effectiveness of drug therapies.
ileum approaches a pH of 8.
• Ideally a sustained release oral dosage form is
• Conventional drug therapy requires periodic doses designed to release rapidly some pre determined
of therapeutic agents. These agents are formulated fraction of the total dose in to GI tract. This fraction
to produce maximum stability, activity and (loading dose) is an amount of drug, which will
bioavailability. For most drugs, conventional produce the desired pharmacological response as
methods of drug administration are effective, but promptly as possible and the remaining fraction of
some drugs are unstable or toxic and have narrow the total dose (maintenance dose) is then release at a
therapeutic ranges. Some drugs also possess constant rate. The rate of the drug absorption from
solubility problems. the entire maintenance dose into the body should
• In such cases, a method of continuous equal to the rate of the drug removal from the body
administration of therapeutic agent is desirable to by all the processes over the time.
maintain fixed plasma levels as shown in Figure. • 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.

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

These are spatial delivery, which is related to the 5. Site-Specific and Receptor Release:
control over the location of drug release and In the case of site-specific release, the target is a certain
temporal drug delivery, in which the drug is organ or tissue, while for receptor release, the target is
delivered over an extended period of time during the particular receptor for a drug within an organ or
treatment. tissue. Both of these systems satisfy the spatial aspects of
drug delivery.
The conventional dosage forms are immediate release
type. Non-immediate release delivery systems may be Extended Release: 9-11
divided conveniently into following categories:7 Extended release drug delivery system is designed to
1) Delayed Release achieve a prolonged therapeutic effect by continuously
2) Sustained Release releasing medication over an extended period of time
3) Controlled Release after administration of a single dose.
4) Prolonged Release The smaller doses which are given after loading dose are
5) Site-specific and Receptor release called maintenance dose. Maintainance dose is achived
by extended release of the drug.
1. Delayed Release:
Delayed release systems are those systems that use Advantages:
repetitive, intermittent dosing of a drug from one or • The frequency of drug administration is reduced.
more immediate release units incorporated into a single • Patient compliance can be improved, and drug
dosage form. Delayed release dosage form does not administration can be made more convenient as
produce or maintain uniform drug blood levels within well.
the therapeutic range. • The blood level oscillation occurs by multiple
dosing of conventional dosage forms is reduced,
2. Sustained Release system: because a more even blood level is maintained.
It includes any drug delivery system that achieves slow • Minimizing drug accumulation with chronic dosing.
release of drug over an extended period of time. • Total amount of drug administered can be reduced,
thus maximizing availability with a minimum dose.
3. Controlled Release system: • In addition, better control of drug absorption can be
If the system is successful at maintaining constant drug attained, since the high blood level peaks that may
level in the blood or target tissues, it is considered as a be observed after administration of a dose.
controlled release system. Drug delivery systems from • The safety margin of high-potency drugs can be
which therapeutic agents may be automatically delivered increased, and the incidence of both local and
at predetermined rates over a long period of time are systemic adverse side effects can be reduced in
called as controlled drug delivery systems. 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 In a hydrophilic matrix, there are two competing
from a matrix system can be controlled are mechanisms involved in the drug release: Fickian
• The amount of drug in the matrix, diffusional release and relaxation release. Diffusion is
• The porosity of the release unit, The length of the not the only pathway by which a drug is released from
pores in the release unit the matrix; the erosion of the matrix following polymer
• The solubility of the drug (which regulates the relaxation contributes to the overall release. The relative
concentration gradient). The contribution of each component to the total release is
characteristics of the pore system can be affected by, 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 diffusion & dissolution mechanisms. Here the drug is
of drug release is controlled by the erosion of a matrix in dispersed in a polymer, but instead of an insoluble or
which drug is dispersed. non-erodable polymer, swelling of the polymer occurs.
This allows for the entrance of the water, which causes
The matrix is normally a tablet, i.e. the matrix is formed dissolution of the drug & diffusion out of the swollen
by a tabletting operation and the system can be described matrix. In these type of systems the release rate is highly
as a continuous liberation of matrix material (both drug dependant on the polymer swelling-rate and drug
and excipients) from the surface of the tablet, i.e. surface solubility. Mainly used excipients for these type of drug
erosion. 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. Fig. 8: Fronts in a swellable HPMC matrix
Drug can not only diffuses out of dosage form; as
described in previous matrix system, but matrix itself Drug release is controlled by the interaction between
also under goes dissolution process. The complexity of water, polymer and drug. The delivery kinetics depends
the system arises from the fact that as the polymer on the drug gradient in the gel layer. Therefore, drug
dissolves the diffusional path length for the drug may concentration and thickness of the gel layer governs the
change. This usually results in a moving boundary drug flux. Drug concentration in the gel depends on drug
diffusion system. Zero-order release is possible only if loading and solubility. Gel-layer thickness depends on
surface erosion occurs and surface area does not change the relative contributions of solvent penetration, chain
with time. 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 Drug selection for oral controlled release drug
than chain disentanglement, and a rapid build- up of delivery systems
gel-layer thickness occurs. However, when the solvent The biopharmaceutical evaluation of a drug for potential
penetrates slowly, owing to an increase in the use in controlled release drug delivery system requires
diffusional distance, little change in gel thickness is knowledge on the absorption mechanism of the drug
observed since penetration and disentanglement rates are form the G.I. tract, the general absorbability, the drug’s
similar. Thus gel-layer thickness dynamics in swellable molecular weight, solubility at different pH and apparent
matrix tablets exhibit three distinct patterns. The partition coefficient.14, 15
thickness increases when solvent penetration is the
fastest mechanism, and it remains constant when the Table: 3 Physicochemical Parameters for drug selection
disentanglement and water penetration occur at a similar Parameter Preferred value
Molecular weight/ size < 1000 daltons
rate. Finally, the gel-layer thickness decreases when Solubility > 0.1 mg/ml for pH 1 to pH 7.8
the entire polymer has undergone the glassy–rubbery Apparent partition coefficient High
transition. In conclusion, the central element of the Absorption mechanism Diffusion
release mechanism is a gel-layer forming around the General absorbability From all GI segments
matrix in response to water penetration. Phenomena that Release Should not be influenced by pH
and enzymes
govern gel-layer formation, and consequently drug-
release rate, are water penetration, polymer swelling,
The pharmacokinetic evaluation requires knowledge on a
drug dissolution and diffusion, and matrix erosion.
drug’s elimination half-life, total clearance, absolute
Drug release is controlled by drug diffusion through the
bioavailability, possible first- pass effect, and the desired
gel layer, which can dissolve and/or erode.
steady concentrations for peak.
E) Osmotic controlled release systems: Table: 4. Pharmacokinetic parameters for drug selection
Drug delivery from these systems to a large extent is Parameter Comment
independent of the physiological factors of the GI tract Elimination half life Preferably between 0.5 and 8 h
and it can be utilized for systemic as well as targeted Total clearance Should not be dose dependent
delivery of drugs. 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
The osmotic pump is similar to a reservoir device but Intrinsic absorption rate Must be greater than release rate
contains an osmotic agent (e.g., the active agent in salt Therapeutic The lower Css av and smaller Vd, the
form) which acts to imbibe water from the surrounding concentration Css av loss among of drug required
medium via a semi-permeable membrane. Such a device, Toxic concentration Apart the values of MTC and MEC,
safer the dosage form. Also suitable for
called the 'elementary osmotic pump', has been drugs with very short half-life.
described by Theeuwes. Pressure is generated within the
device which forces the active agent out of the device via Basic kinetics of controlled drug delivery:
an orifice. The internal volume of the device remains To influence of drug properties and the route of
constant, and there is an excess of solid (saturated administration on controlled drug delivery, following
solution) in the device, then the release rate remains mechanisms need a fair mention,
constant delivering a volume equal to the volume of 1. Behavior of drug within its delivery systems
solvent uptake. 2. Behavior of the drug and its delivery system jointly in
the body.
The release of drug(s) from osmotic systems is governed
by various formulation factors such as solubility and For conventional systems, the rate-limiting step in drug
osmotic pressure of the core component(s), size of the availability is usually absorption of drug across a
delivery orifice and nature of the rate controlling biological membrane such as the gastro intestinal wall.
membrane. 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
Fig. 9: Osmosis Pump separate feed frame with individual weight control. Ro-

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 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. impressed on the surfaces of the multi-layer tablets.
Ideally, a slight compression of each layer and individual • Analytical work may be simplified by separating of
layer ejection permits weight checking for control the layers prior to assay.
purposes. They have the appearance of a sandwich
because the edges of each layer are exposed. 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:
Fig. 10: General Concept of Bilayer Tablets • Dusty fines must be limited. Fines smaller than 100
meshes should be kept at a minimum.
Advantages: • Maximum granule size should be less than 16
• Physical/chemical separation : meshes for a smooth, uniform scrape-off at the die.
It is possible to avoid the incompatibility in between • Low moisture is essential if incompatibles are used.
active-excipients and excipient-excipient by mean of • Weak granules that break down easily must be
physical separation. avoided. Excessive amounts of lubrication,
especially metallic stearates, should be avoided for
• Multiple release profile: better adhesion of the layers.
Bilayer tablets are able to provide multiple release • Formulation of multilayer tablets is more
kinetics of same/different Drugs of same or different demanding than that of single-layer tablets. For this
physico-chemical property by application of multiple reason, selection of additives is critical.
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. • A tablet multilayer press is simply a tablet press that
has been modified so that it has two die-filling and
• Immediate release ( disintegrating monolith): compression cycles for each revolution of the press.
Bilayer tablet can deliver the initial fast release required In short, each punch compresses twice, once for the
to achieve peak plasma concentration. first layer of a two-layer tablet and a second time for
the second layer.
• Delay release ( Erodible and swelling monolith):
• There are two types of layer presses presently in
Delay release can also be achived by bilayer tablet by
use-one in which each layer can be ejected from the
applying either erodible or swelling mechanism from
press separately for the purpose of weight checking,
which the drug were continuously released throughout
and the second in which the first layer is compressed
the GIT.
so hard that the second layer will not bond to it, or
For synergetic therapeutic effect: will bond so poorly that upon ejection the layers are
In the management of disease condition where easily separated for weighing. Once the proper
synergetic therapeutic effect from two or more drugs is weight adjustments have been made by adjusting the
essential and that are not compatible with each other in die fill, the pressure is adjust to the proper tablet
such condition bilayer tablet is the only option. hardness and bonding of the layers.
• Layers may be colored differently to identify the • Once hazard of layer tablet production is the lack of
product. proper bonding of layers. This can result in a lot of

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

100,000 tablets ending up as 200,000 layers after • Very short first layer dwell time due to the small
several days if the layers are not sufficiently bonded. compression roller, possibly resulting in poor de-
• In a two layer tablet press, two hoppers above the aeration, capping and hardness problems. This may
rotary die table feed granulated material to two be corrected by reducing the turret-rotation speed (to
separate feed frames without intermixing. extend the dwell time) but with the consequence of
Continues, gentle circulation of the material through lower tablet output.
the hoppers and feed frames assures uniform filling • Very difficult first-layer tablet sampling and sample
without segregation of particle sizes that would transport to a test unit for in-line quality control and
otherwise carry over to the second layer and affect weight recalibration.
layer weight, tablet hardness, and, in the case of • To eliminate these limitations, a double-sided tablet
differently colored granulations, the press with three press is preferred over a single-sided press. A
hoppers for the tree granulations instead of two. double-sided press offers an individual fill station,
precompression and main compression for each
Limitations of the single-sided press: layer. In fact, the bi-layer tablet will go through 4
• The simplest design is a single-sided press with both compression stages before being ejected from the
chambers of the double feeder separated from each press.
other. Each chamber is gravity or forced-fed with a
different powder, thus producing the two individual Limitations of “compression force” - controlled tablet
layers of the tablet. When the die passes under the presses
feeder, it is at first loaded with the first-layer • Separation of the two individual layers is the
powder followed by the second-layer powder. Then consequence of insufficient bonding between the
the entire tablet is compressed in one or two steps two layers during final compression of the bi-layer
(two=pre- and main compression). tablet. Correct bonding is only obtained when the
• The two layers in the die mix slightly at their first layer is compressed at a low compression force
interface and in most cases bond sufficiently so that so that this layer can still interact with the second
no layer-separation occurs when the tablet is layer during final compression of the tablet.
produced. This is the simplest way of producing a Bonding is severely restricted if the first layer is
bi-layer tablet. The limitations of such single-sided compressed at a too-high compression force. The
press are: low compression force required when compressing
• No weight monitoring/control of the individual the first layer unfortunately reduces the accuracy of
layers the weight monitoring/control of the first layer in
• No distinct visual separation between the two layers the case of tablet presses with “compression force
• The fact that it is not possible to monitor and control measurement”.
the weight of the individual layers raises the • Most double-sided tablet presses with automated
question whether we can consider this production production control use compression force to monitor
GMP? Individual layer-weight control on a single- and control tablet weight. The effective peak
sided press requires some form of measurement of compression force exerted on each individual tablet
the first layer. The first control loop indirectly or layer is measured by the control system at main-
monitors weight and controls the fill depth of the compression of that layer.
first layer. The second loop indirectly monitors the
Release Patten of bilayer tablets having immediately
total tablet weight, but adjust only second-layer fill
release part and extended release part.
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:
Fig. 11: Release pattern of bilayer Tablet
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 Research Journal of Pharmaceutical Dosage Forms and Technology. 10(4): October- December, 2018

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
Fig. 12: Compression cycle of bi-layer tablet
serves as an important tool. Hence the problem like poor
Steps of compression of bi-layer tablet: patient compliance, multiple dosing, see-saw
1. Filling of first layer. fluctuations can be easily minimized.
2. Compression of first layer.
3. Ejection of upper punch. REFERENCES:
4. Filling of second layer. 1. Chien YW. Oral drug delivery systems in novel drug delivery
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6. Ejection of bi-layer tablet. 2. Qiu Y, Zhang G. Research and development aspects of oral
controlled release dosage forms. Handbook of pharmaceutical
controlled release technology.1st Indian Ed. Replika press. New
York. 2005; 465-503.
3. Chien YW. Oral drug delivery systems in novel drug delivery
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6. Agarwal G, Kaushik A. Pharmaceutical Technology-II. 1stEd.
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Fig. 13: Bilayer Rotary Machine (2):12-24.
11. Patel H, Panchal DR, Patel U,et al. Matrix type drug delivery
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CONCLUSION: 12. Jamini M, Kothari A. Sustained release matrix type drug delivery
The most widely used measure of the margin of a drug’s system: A review. JDDT. 2012;2(6):142-8.
safety is its therapeutic index, that is, the median toxic 13. Liberman H, Lachman L. The theory and practice of industrial
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very small. They are used in the treatment of chronic methacrylic and acrylic acid polymers on the release performance
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require greater adjustment of the dosage by the physician Journal of Pharmaceutical Science; 2004; 93, 2319-2331.
15. M E Aulton; “Pharmaceutics” The Science of dosage form
than that provided by extended-release products. design; Churchill Livingstone; 2nd edition; 2002; 414-418.
Modified-release products including extended-release, 16. Asgar A, Sharma SN. Evaluation of oral sustained release
prolonged-release, controlled-release, controlled- formulation. The Eastern Pharmacist 1991, pg. no. 69-74.
delivery, slow-release and sustained-release. These
preparations, by definition, have a reduced rate of release

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