Journal of Controlled Release 97 (2004) 393 – 405

www.elsevier.com/locate/jconrel

Review
A flexible technology for modified release of drugs:
multi layered tablets
Shajahan Abdul, S.S. Poddar *
Department of Pharmaceutics, Principal K.M. Kundnani College of Pharmacy, Plot No. 47, R.G.Thadani Marg, Worliseafce,
Mumbai-400018, India

Received 2 January 2004; accepted 30 March 2004

Abstract

Modified release dosage forms offer definite advantages over conventional release formulation of the same drug.
Hydrophilic polymers are mainly used for preparation of matrix type controlled delivery systems. The system usually provides
nonlinear release profile. The multi-layered matrix system overcomes inherent disadvantages of non-linearity associated with
diffusion controlled matrix devices by providing additional release surface with time to compensate for the decreasing release
rate. This technology also demonstrates a wide flexibility for various applications. In this article, we review system design,
various constructions and formulation parameters of modified release dosage forms.
D 2004 Elsevier B.V. All rights reserved.

Keywords: Multi-layered tablets; Linear release; Time programmed release; Layered matrix system; Bimodal release

1. Introduction controlled by ion exchange mechanism, systems using

Oral ingestion has long been the most convenient
and commonly employed route of drug delivery due to
its ease of administration, least aseptic constraints and
flexibility in the design of the dosage form. It is well
known that modified release dosage forms may offer
one or more advantages over immediate release for-
mulations of the same drug. There are many ways to
design modified release dosage forms for oral admin-
istration; from film coated pellets, tablets or capsules
to more sophisticated and complicated delivery sys-
tems such as osmotically driven systems, systems
* Corresponding author. Tel.: +91-22-24938618, 24937204;
fax: +91-22-24932808.
E-mail address: ssp306@rediffmail.com (S.S. Poddar).
three dimensional printing technology and systems
using electrostatic deposition technology. The design
of modified release drug product is usually intended to
optimize a therapeutic regimen by providing slow and
continuous delivery of drug over the entire dosing
interval whilst also providing greater patient compli-
ance and convenience [1 – 3]. The most common
controlled delivery system has been the matrix type
such as tablets and granules where the drug is uni-
formly dissolved or dispersed throughout the polymer,
because of its effectiveness, low cost, ease of manu-
facturing and prolonged delivery time period [4,5].
Hydrophilic polymers are becoming more popular in
formulating oral controlled release tablets. It is well
documented that the dissolution curve of drug release
from a hydrophilic matrix shows a typical time depen-

0168-3659/$ - see front matter D 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jconrel.2004.03.034
394 S. Abdul, S.S. Poddar / Journal of Controlled Release 97 (2004) 393–405

dent profile [6 –11]. The release of a dissolved drug
inherently follows near first-order diffusion with an
initially high release rate, due to the dissolution of the
drug present at the surface of the matrix, followed by a
rapidly declining drug release rate (Fig. 1). The en-
hanced release rate observed at the beginning for a
short time of the release process is known as burst
effect and is many a times undesirable since it may
have negative therapeutic consequences (e.g. toxicity
due to increase of the concentration of the delivered
substance beyond the acceptable higher limits espe-
cially on repeated administration). After this burst
effect, hydration and consequent swelling and/or ero-
sion of retard polymer occurs. These phenomena
control the release process but, with time, the diffusion
path-length increases and a saturation effect is attained,

Fig. 1. Effect of the application of polymeric layers (barriers) on the release of drug from a matrix core.
 S. Abdul, S.S. Poddar / Journal of Controlled Release 97 (2004) 393–405
resulting in a progressively slow release rate during the
end of dissolution span [6 – 11]. To overcome this
undesirable behavior, many authors [12 –19] evaluated
a number of variables able to affect the release patterns
in polymeric matrix devices such as physio-chemical
properties (solubility, viscosity, etc.); content of drugs
and polymers; drug/polymer weight ratio; administra-
tion form and dosage and manufacturing process to
achieve a constant rate release. Over the years consid-
erable efforts have been expended in the development
of new drug delivery concepts in order to achieve zero-
order or near zero-order release, since constant rate
delivery is the primary goal of controlled release
systems, especially for drugs with a narrow therapeutic
index. Examples of altering the kinetics of drug release
from the more commonly inherent non-linear behavior
to linear included the use of geometry factors (solid
units having spherical, cylindrical, conical, biconcave,
biconvex, donut shapes, hemisphere with cavity, core-
in-cup, circular sectioned cylinder, rings, oval bi-dose
divisible tablets, etc.), films, erosion/dissolution con-
trolled and swelling controlled mechanisms, non-uni-
form drug loading and matrix-membrane combination
[20 – 33]. Various matrix geometries have been recom-
mended over the last two decades to achieve an almost
constant release rate of the drug with time. One of
these techniques relies on the use of multi-layered
matrix tablets as drug delivery devices.
Multi-layered matrix tablet is a drug delivery de-
vice, which comprises a matrix core containing the
active solute and one, or more barriers (modulating
layers) incorporated during the tabletting process. The
modulating layers delay the interaction of active solute
with dissolution medium, by limiting the surface
available for the solute release and at the same time
controlling solvent penetration rate [34 – 36]. In this
device, the coat layers prevent the water penetration,
through the protected core for some duration. This
results in reduced hydration rate and controlled area
for solute release at the core. Thus burst effect can be
smoothened and the release can be maintained at a
relatively constant level during the barrier layers’
swelling and erosion process (Fig. 1). After this phase,
during the subsequent portion of the dissolution pro-
cess, these swollen barriers are erosion dominated and
the surface available for drug release slowly increases.
In this way the decrease of delivery rate due to the
increase of diffusion path-length (saturation effect) is
395
counterbalanced by the simultaneous increase of the
area available for drug release [35]. By this way,
combining a time-dependent control of the hydration
rate of the device with the reduction of tablet surface
exposed to the dissolution medium, it is feasible to
achieve a linear release profile. It is also possible to
obtain various dissolution patterns such as multi mod-
al, pulsatile or delayed delivery, extended release
(characterized by reasonably constant rate) for differ-
ent drugs by varying the formulations of layers. In all
the applications, the multi-layered system should
swell, gel and finally erode completely, leaving negli-
gible residue in the gastro-intestinal tract [36]. The
system is a unique drug delivery device, which over-
comes the major disadvantage of non-linear release
associated with most diffusion controlled matrix devi-
ces. This system also has the advantage of being
compatible with conventional manufacturing methods.
2. System design
Generally the drug release mechanism from hy-
drophilic, swellable matrices is a coupling of poly-
mer macromolecular relaxation and drug diffusion
[11,14]. Both the phenomena depend initially on the
rate at which water may enter the device. Multi-
layered design is based on the following aspects: (1)
matrix hydration rate and consequent swelling and/or
lowering of diffusion rate; (2) modulation of the
surface of matrix through which the drug can be
delivered. These principles are more effective in the
initial phase of the dissolution process and less
pronounced as swelling proceeds, leading to linear-
ization of the release profile. To achieve similar
objective, coating of the matrix tablets selectively
on various sides with an inert impermeable film have
been attempted [37,38]. The coating was applied
extemporaneously on the tablet faces and/or on the
sidewall in order to obtain different coating combi-
nations as schematically represented in Fig. 2. Their
release performance was tested in vitro. From Fig. 3,
it may become clear that, as the extent of coating is
increased, the release is slowed and the release
kinetics approached zero-order. The release rate
was mainly driven by the surface geometry of the
system (coated –uncoated surface ratio) [39]. From
these observations it is confirmed that, during disso-
396 S. Abdul, S.S. Poddar / Journal of Controlled Release 97 (2004) 393–405
Fig. 2. Schematic representation of the matrix tablet (a) and of the four partially coated designs (b, c, d and e).
lution, although the matrix swells, the coating con-
siderably reduces the drug-releasing surface com-
pared with the uncoated matrix and also hinted
towards the ability of coating design to modulate
both release extent and kinetics. The casting of
impermeable membrane on a portion of the matrix
tablet is a manual process [37,38]. To overcome this
drawback, which does not allow for the automatic
production of the system, different approaches were
tried. In particular, the application of polymeric
swellable and erodible barrier layers, instead of
impermeable film, was evaluated taking into account
that former should exhibit properties of drug imper-
meability similar to those offered by the latter. The
development of the barrier formulation was carried
out through two different approaches [35]. The first
was based on the use of inert insoluble polymer
(ethyl cellulose) and the second was based on the
use of hydrophilic swellable polymer (Hydroxy pro-
pyl methyl cellulose). The in vitro release perfor-
Fig. 3. Release profiles of the uncoated matrix (a) and of the four
partially coated designs (a, ; b, x; c, ; d, w ; e, ) [35].
mance of such layered tablets and their morpholog-
ical behavior were examined and compared to that of
partial film coated system [35]. The partial film
coating does not swell and maintains its original size
and shape and offer consistent release retardation for
the whole duration of dissolution process. On the
contrary, the barrier made of an inert polymer tends
to crack and detach itself from the core within hours
after water immersion. This effect is due to core
volume expansion upon water immersion, by poly-
mer swelling. This stresses the outer barrier layer,
which does not expand to accommodate the swelling
of the core. The swellable barriers show a more
homogenous system in which both the barrier and
the core may swell simultaneously without any inter-
nal stress during the dissolution process [35]. The
barriers can be applied using a multi-layer compres-
sion process. The easiest example was represented by
either double layer (Fig. 2b) or three layer tablets
(Fig. 2c) in which only one layer contains the active
ingredient (active core), while one or two other layers
are barrier layers. A considerable time has been
devoted to the optimization of suitable barrier for-
mulations that could be applied on the core directly
during the tabletting process. The performance of the
final barrier formulation was evaluated using many
active cores, compositions [40] proving the efficiency
and flexibility of the multi-layered concept, particu-
larly in controlling the release of drugs of high
solubility [41 – 45]. Based on these new develop-
ments, a product was launched in 1992 in the US.
It is DILACOR XR of Rhone Poulene-Rorer, a
device for the 24-h extended release of Diltiazem
Hydrochloride a drug of high solubility.
The multi-layer design allows for the production
of different tablet designs by varying the geometry
of the device or modulating layers characterized by
 S. Abdul, S.S. Poddar / Journal of Controlled Release 97 (2004) 393–405
specific release properties to achieve various disso-
lution patterns (not limited to a constant release)
such as delayed, pulsatile or multi modal delivery
profiles. The section below deals with various tablet
possibilities based on this proposed design.
3. Different designs
3.1. Zero order sustained release
This system as has been described in the previous
section, comprises either a hydrophilic or hydropho-
bic intermediate layer containing the active drug(s)
and one or two barrier layers which are press coated to
the faces of the tablet core, leaving the sides of the
core exposed. Many authors have evaluated this
design, to approach zero-order sustained release
[46 – 49]. The widely used barrier polymers for sus-
taining the drug delivery are either hydrophilic and/or
hydrophobic materials. In general linear release pro-
files can be obtained by applying hydrophilic barrier
layers (H) on both the faces of a hydrophobic matrix
tablet (M) or by applying a hydrophilic barrier layer
on one face and hydrophobic barrier layer (L) on the
other face of the matrix tablet. However, net formu-
lation and variables within the matrix and barrier
layers need to be controlled rather carefully in order
to achieve zero-order drug release from hydrophobic
Fig. 4. Invitro release profiles of different matrix designs: (5)
uncoated single hydrophobic layer matrix M; (o) Layered matrix
HMH; (
) Layered matrix HML; (D) Layered matrix LML
containing Pseudoephedrine hydrochloride [48].
397
Fig. 5. Simulated plasma levels for different dose fractions com-
binations for a quick/slow Geometric device [7].
matrix tablet coated with hydrophobic barrier layers
on both the faces (Fig. 4) [48 –51].
3.2. Quick/slow delivery system
During the early stage of formulation develop-
ment, the question of interest is ‘‘what in vitro release
characteristics will achieve the in vivo target?’’ To
answer, a simple simulation approach using tra-
ditional pharmacokinetic model is of sufficient so-
phistication to define an ideal range of formulation
characteristics. The objective of these simulation
exercises is to provide in vitro release targets to
maximize efficiency of development of a new system
bio-equivalent to SR form of model drug. This system
may be achieved by quick/slow delivery system
[52,53]. This is characterized by an initial rapid
release phase, followed by a period of constant slow
release (Fig. 5). This is achieved by the application of
immediate release layer to the conventional layered
matrix tablet. This system can produce a rapid rise in
plasma levels for those drugs that are needed to show
appearance promptly for the therapeutic effect, fol-
lowed by an extended release phase at a constant rate.
Collaborators Maggi et al. [53] have developed a
Naproxen quick/slow system. This new system was
more likely compared to a simple slow release sys-
tem, to prove its bioequivalence to Naprosyn SR,
which were used as the in vivo target with the premise
398 S. Abdul, S.S. Poddar / Journal of Controlled Release 97 (2004) 393–405
that these would be similar to those for the US
product, Naprelan of Elan Corporation PLC. Thus
these quick/slow drug delivery systems demonstrated
their versatility for those dosing regimens where a
simple constant rate of drug release does not entirely
satisfy the therapeutic objective [52 – 54].
3.3. Time-programmed delivery system (press coated
tablet)
Recently the concept of the Chronopharmacoki-
netics and Chronotherpay of drugs has been exten-
sively utilized in clinical therapy for improving the
drug efficacy and preventing the side effects and
drug tolerance [55 –57]. The maintenance of a con-
stant drug blood level in the body is not always
desirable for optimal therapy. For ideal therapeutic
efficacy a drug with optimum concentration should
be delivered only when and where it is needed.
Hence the drug release behavior should be controlled
by time in addition to rate. To avoid developing
tolerance and to follow the innate circadian rhythm,
a reasonable and generally accepted rationale is to
have a delivery system capable of releasing drugs, in
a pulsatile fashion rather than continuous, at prede-
termined time points and/or sites following suitable
administration like oral [58 – 61]. For this purpose,
different systems including the time clock system
Fig. 6. Geometric press coated tablets for the delayed release of drugs (courtesy: Conte and Maggi [7]).
have been developed using various techniques and
functional polymers or additives [62 – 65]. Press
coating technique is one candidate for such a novel
system that not only acts as a rate controlling system
but also delivers the drug in the gut when it is
required, which is in a time-controlled fashion. This
technique has many advantages because no special
coating solvents or equipments are needed for coat-
ing of tablets and manufacturing speed is also faster.
The system consists of a core (either conventional or
a modified release formulation), which is coated by
compression with different polymeric barriers (press-
coated systems) [66,67] (Fig. 6). This system deliv-
ers the drug from the core tablet after swelling/
eroding the hydrophilic or hydrophobic barrier of
the coating shell and may exhibit a pulsatile release
of the drug [68 – 71]. This outer shell may delay the
penetration of fluid, thereby inducing a long lag time
prior to the start of drug release. Once the solvent
penetrates into the interior core tablet, the core tablet
will dissolve and/or swell to break the outer shell
resulting in rapid drug release [71 –73]. This delay in
the start of release is not influenced by the core
composition and only depends on the shell formula-
tion. Moreover, except for time lag, the release
kinetics of the core is not significantly influenced
by the presence of erodible barrier. However, the
kinetics is strongly influenced by the presence of
 S. Abdul, S.S. Poddar / Journal of Controlled Release 97 (2004) 393–405
Fig. 7. Dissolution profile of Diltiazem hydrochloride from core
.
tablet (o) and two types of press coated tablets ( and D) [71].
gellable or expandable polymeric shell. This type of
coating hydrates and gels completely but does not
get removed from the surface of the core; the device
can be considered as a reservoir system [66,67]. The
net release pattern depends on the release kinetics of
.
Fig. 8. Release profiles of theophylline from investigated tablets ( ) Bimodal; (x) Single layered tablet; (5) Tri-layered tablet (modified from
Ref. [82]).
399
the core and penetration behavior of the swelled/
gelled coat.
Fig. 7 shows the dissolution profiles of core tablets
and two types of press coated tablets [71]. The press-
coated tablets displayed a timed-release function i.e. a
lag phase was observed in the dissolution profile and
the drug was released rapidly after the lag time.
3.4. Bimodal release profile
An oral controlled release system which releases
drug at zero-order rate is often considered an ideal
system for maintaining constant drug levels in plasma.
This is based on the assumption that drug absorption
occurs rapidly and uniformly through the entire GI
tract, so that the rate of elimination dictates the rate at
which the drug must release from the dosage form.
However, for many drugs, absorption is moderately
slow in the stomach, rapid in the proximal intestine, and
declining sharply in the distal segment of the intestine.
400 S. Abdul, S.S. Poddar / Journal of Controlled Release 97 (2004) 393–405
This means that to maintain constant drug absorption,
the delivery system should release drug in such a way
that it is able to compensate for the changing drug
absorption pattern in the GI tract by increasing or
reducing drug release rate to adjust the regional flux.
Thus, a release system with variable rate of release may
indeed be more desirable than a constant zero-order
release system. The bimodal release system provides
such a variable rate release. Bimodal release is charac-
terized by an initial rapid release, followed by a period
of slow and constant release, and again a second phase
of rapid drug release (i.e. sigmoidal release profile)
[74]. Such bimodal release system can offer two major
advantages over other systems: (1) it produces rapid
drug release during the initial and later phase to
compensate for the relatively slow absorption in the
stomach and large intestine; (2) it can be used to design
programmed pulse release oral drug delivery systems
for the therapeutic agents that perform more effectively
when drug levels at the site of action undergo periodic
changes. To obtain bimodal drug release patterns,
Collaborators, Shah et al. [75,76] used hydroxypropyl-
methylcellulose based matrix tablets. Collaborators,
Marvola et al. [77 –79] developed core-in-cup tablets.
Collaborators, Conte et al. [80,81] developed three
layer GeomatrixR tablets. Recently Collaborators,
Streubel et al. [82] developed layered matrix tablets.
Fig. 8 shows that in bimodal delivery system an
additional layer, i.e. fourth, containing initial dose
rapidly disintegrates to produce quick onset of disso-
lution, promoting greater concentration gradient to
compensate for poor absorpitivity in stomach. The
release from the SR portion-containing drug is con-
trolled by barrier layers to achieve constant rate release.
The appearance of the pH 7.4 in the GIT is the initiator
for the second rapid drug release towards promoting the
absorption in large intestine. Thus, although the in vitro
release profile is stepped, the in vivo picture, though
dependent on GIT transits and pH values, would be
smoother due to improved absorption in stomach as
well as large intestine [82].
4. Influence of process and formulation
parameters
Since the incorporation of initial dose layer (as in
the case of bimodal delivery system and quick/slow
delivery system) affected neither the intermediate
slow nor the second rapid phase or constant phase,
this layer is not necessary to be considered in the
formulation process. Therefore multi-layered tablet
consisting of a core and one or more barrier layers
and/or a core and outer shell (in the case of press-
coated tablet) should be taken into account while
determining the parameters involved in the process-
ing. The following factors should be considered for
the process and formulation [83,84].
4.1. Granulation-layer containing therapeutics
The following factors are to be considered while
making granulation of active substances: granulation
liquid percentage, massing step time, outlet air target
temperature during the drying step and milling screen
apertures as well as the interaction between the
amount of granulation liquid and the outlet tempera-
ture [85]. While considering the impact of these
factors on the final product quality, the responses
are classified into four categories: (i) granulation
physical characteristics (e.g., flowability, bulk density,
ability to settle, particle size distribution), (ii) exten-
sometric responses (e.g. cohesion index, lubrication
index, ejection strength, plasticity, elasticity), (iii)
Tablet characteristics (eg. Thickness, weight variation,
hardness, friability) and (iv) analytical results (e.g.
content uniformity, dissolution profile). Wehrle et al.
[85] reported that granulation liquid percentage and
milling screen aperture were considered as significant
factors affecting the granulometric fractions. The bulk
density increased with increase in amount of granu-
lation liquid. The ability to settle was also affected by
the granulation liquid. But the extensometric
responses, tablet characteristics, and analytical results
did not vary according to factor variations. The
authors also have recommended the Table 1 given
below for setting the above factors [86]. A balance
between the advantage and disadvantage permits
confirmation of nominal manufacturing process and
also validating of granulation process.
4.2. Compression process
The critical parameters in the compression pro-
cess are turntable speed and compression forces
corresponding to first, second and main layers. The
 S. Abdul, S.S. Poddar / Journal of Controlled Release 97 (2004) 393–405 401

Table 1 added to the outer shell polymer to prevent the

Recommendation for process setting: granulation penetration of dissolution medium into the pores in
Process Recommended Advantages Disadvantages the outer shell. For example, Magnesium stearate
variable setting
(MgSt) calcium stearate (CaSt) were added to the
Granulation 11% Decrease: Decrease: final Hydroxy propyl methyl cellulose acetate succinate
liquid massing load bulk density
(HPMCAS) polymer to increase the lag time [72]. Eiji
and drying
duration Fukui et al. [72] reported that the drug release in
Increase: Increase: gastric fluid was completely suppressed until 15 h in
massing wet ability tablets containing MgSt irrespective of compression
density and to settle force and for those containing CaSt, it was necessary to
particle size
increase the compression force to more than the range
>63 Am
Massing 1 min Decrease: Decrease: applied, to suppress until 12 h. In the intestinal fluid
time massing crushing the lag time was not prolonged to more than 2 h by
product strength addition of MgSt. In contrast lag time could be
temperature prolonged by CaSt as long as 9 h by increasing the
Drying 36 jC Decrease: Increase:
compression force. The above results suggested that
temperature drying time crushing
and drying strength press coated tablets intended for colon targeting main-
product ly depends on compression force when poor wettabil-
temperature ity additives used.
Increase:
drying yield
4.3. Hardness of compressed tablet
and final yield
Screen size 1.25 mm Decrease: Increase:
sizing duration particle size Hardness of tablet is expressed in terms of tensile
and particle >1.0 mm strength. The tensile strength of the tablet is calculated
size >500 by the formula, according to Fell and Newton [88]:
and >250 Am
Increase: final r ¼ 2P=pDt
yield
where r = tensile strength (kg/cm2), D = tablet diame-
ter (cm), t = tablet thickness (cm), P = force applied to
tablet crushing strength response improves when the fracture (kg).
turret compression speed on the main compression The porosity of the tablets decreased with increas-
force is increased. But these parameters (within a ing compression load indicated by the rise in tensile
particular range) do not influence the content unifor- strength. But since the compression force (particular
mity and the release performances in multi-layered, range) does not influence the release rate, generally in
press coated and, bimodal delivery systems [35,69,82]. layered construction, the hardness of the tablet has
But in the case of press coated tablet intended for minor significance in the formulation [35,69,82].
distant destination (e.g. colon targeting) the release
rate and lag time are dependent on the compression 4.4. Adhesion strength
force. The release rate of drug decreases and the lag
time increases with increasing compression force till a This factor should be considered in the process of
critical point. After this point increasing compression complex layer tablets (Smatrix tablets), which have
force does not provide further reduction in porosity. layers that are shaped individually. The individual
There is necessity of increasing the lag time more than shaping of layer is achieved by geometry and direc-
10 h in the gastric fluid under some physiological tions of one pre-compressed layer (‘‘core tablet’’) that
conditions [87] and also there is need for suppression is made available as a central layer in the tablet. Upper
of release in the intestinal fluid for more than 3 h in and lower layers are pressed onto the central layer in
order to obtain colon targeting. To achieve these the second step [89,90]. Adhesion strength should
certain additives, which have poor wettability, are have to be considered here because of (i) the outer
402 S. Abdul, S.S. Poddar / Journal of Controlled Release 97 (2004) 393–405
layers control the rate of release from the central-layer
[91,92]; (ii) the central-layer is already a compressed
tablet, a fact that makes adhesion quite difficult to
achieve. The parameters setting to achieve high ad-
hesion strength in complex layer tablets are low
lubricant concentration and low compression force
for central-layer core tablets and finally high com-
pression force for complex layer tablets. But this
demand is limited to practical reasons: (i) lubricant
concentration has to be sufficient to avoid sticking;
(ii) compression force for central-layer tablets has to
be high enough to achieve sufficient crushing strength
and resistance to friability; (iii) compression force for
complex layer tabletting cannot be increased infinitely
because of (a) limitations of tablet process and tool-
ing; (b) the asymptotic approach toward a final
density of the tablet; [93] and (c) when the central-
layer tablet has been highly compressed, an increase
in compression force during the complex layer tablett-
ing can not reduce its volume further. Dietrich et al.
[94] reported that if large fraction of lubrication in the
central-layer has to be used, adhesion strength could
only by obtained with low compression forces during
central-layer tabletting. Furthermore, the positive ef-
fect on adhesion strength of higher compression
forces during complex layer tabletting increased with
central layer tablets that were tabletted with lower
compaction force at all lubricant fraction levels.
4.5. Polymer concentration in core
Generally, increasing polymer concentration de-
creases the dissolution rate of the tablet. The polymer
concentration in core usually does not influence the
release pattern of drug in the layered tablets. But this
factor plays important role in bimodal delivery system,
because certain polymers are destined to be dissolved at
a particular pH values in these cases. For example [82],
the effect of decreasing HPMCAS-MF amounts in the
inner layer of bimodal delivery system is not significant
in pH 1.2 but in pH 7.4, drug release increases with
decrease in the amount of polymers. At high pH values
a less dense polymer network dissolves more rapidly
than a tight structure, leading to increased drug release
rate. At low pH HPMCAS-MF is not soluble, thus there
is no effect on the breakdown of the polymer network.
Therefore, concentration of pH sensitive retard poly-
mers in the core should be controlled more closely.
4.6. Filler concentration in core
The amount of added fillers influence the rate of
release of drug from core. If the amount of filler is
increased, there is need to decrease the amount of
polymer (to keep the tablet at constant weight). This
leads to significant acceleration of drug release and
this is mainly due to water solubility of filler such as
lactose. Upon contact with the release medium, the
lactose dissolves and diffuses out of the device,
increasing the porosity of resulting polymer network.
5. Conclusions
Although the burst effect has been reported in
numerous publications in our field, much of research
has focused on methods to prevent this. One of the
techniques is multi-layered tablet system. This system
provides zero order or near zero order release. This
concept also demonstrates a wide technology for
various applications such as quick/slow, bimodal,
pulsatile delivery of active ingredients because it
allows the precise modulation of drug release process
even for drug characteristics by extreme physico-
chemical properties.
By considering various formulation parameters it is
possible to get the appropriate release kinetics. The
system has the advantages of relatively low cost and
potentially feasible to large scale production using
layered tablet process.
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