Powder Technology 236 (2013) 30–36

Contents lists available at SciVerse ScienceDirect

Powder Technology
journal homepage: www.elsevier.com/locate/powtec

Mechanistic characterization of bilayer tablet formulations

Ilgaz Akseli a,⁎, Admassu Abebe b, Omar Sprockel b, Alberto M. Cuitiño a,⁎⁎
a
Dept. of Mechanical and Aerospace Engineering, Rutgers University, Piscataway, NJ 08854, USA
b
Bristol-Myers-Squibb Company, Drug Product and Science Technology, New Brunswick, NJ, USA

a r t i c l e i n f o a b s t r a c t

Available online 29 May 2012 The interest in bilayer tablet as an oral immediate-release/controlled-release system has substantially increased
in the past decade. However, during the production of such tablets, lack of sufficient bonding and adhesion at
Keywords: interfaces between adjacent layers is compromising the mechanical integrity and performance of the final
Bilayer tablet solid dosage form. In this study, bilayer tablets of the widely used excipient microcrystalline cellulose in the
Axial tensile strength form of Avicel 102 and pregelatinized starch were formed with different pre-compression (2 kN, 4 kN, 6 kN,
Bilayer interface
8 kN) and final compression (6 kN, 10 kN, 14 kN, 18 kN) forces to quantitatively characterize the strength (σ)
Bonding
Delamination
of the interface and the compacted adjacent layers. Bilayer tablets were axially debonded (i.e., separation of ad-
jacent layers that are subjected to axial loading) until fracture and axial tensile strength values were determined.
It was observed that when the first layer was compressed to a low porosity, the bonding with the second layer
became difficult and it was not possible to produce intact bilayer tablets (σlayer > σinterface). It has been demon-
strated that the material response of the constrained MCC particles to an applied initial compression force within
the initial compacted layer have a detrimental effect on the resistance to fracture of a bilayer tablet. The mech-
anism of failure at the interface or at the individual layers was also studied. Different fracture patterns, namely,
clear layer break, half–half break, cap-shape break, and clear interface break were observed as a function of
various initial and final compression forces. X-ray micro-computed tomography (μCT) was utilized to examine
the influence of localized density distribution on the delamination (layer separation) phenomena of bilayer
tablets. It has been shown that once the magnitude of the applied final layer compaction stress greatly exceeds
the initial layer compaction stress, the tablet catastrophically fails at the initial layer not at the interface
(σlayer b σinterface). The results of this study point out that the measurement of the interfacial strength provides
insight into some of the major complications of bilayer tablets.
© 2012 Elsevier B.V. All rights reserved.

1. Introduction proper characterization of the interface of bilayer tablets in represen-

Solid oral dosage forms are the preferred route for many drugs and
are still the most widely used formulations for new and existing
complex-configuration dosage forms such as controlled-release (CR)
[1–7], osmotic pumps [8] and dry-coated tablets (i.e. tablet within a
tablet) [9,10]. In the past decade or so, it is observed that the interest
in bilayer tablets as an oral immediate-release/controlled-release
system has substantially increased. However, during the production
of such tablets, lack of sufficient bonding/adhesion at interfaces be-
tween the adjacent layers is compromising the mechanical integrity
and performance of the final solid dosage form. A path forward to
reduce the incidence of these issues in the production of bilayer tab-
lets is to establish a rational strategy for the selection of compatible
product formulations and process conditions. This approach requires
⁎ Corresponding author. Tel.: + 1 203 791 6703.
⁎⁎ Corresponding author. Tel.: + 1 732 445 4210.
E-mail addresses: ilgaz.akseli@boehringer-ingelheim.com (I. Akseli),
cuitino@gmail.com (A.M. Cuitiño).
tative pharmaceutical formulations.
Bilayer tablets have some key advantages compared to conventional
(immediate-release) monolayer tablets. For instance, such tablets are
commonly used to avoid chemical incompatibilities of formulation
components by physical separation, and release profiles may be modi-
fied by combining layers with various release patterns, or by combining
slow-release with immediate-release layers [9]. Despite its various
functional advantages, a number of issues associated with the mechan-
ics and manufacturing of bilayer tablets have been reported in the
recent years. Some of the major complications of bilayer tablets include
insufficient hardness [4], inaccurate individual mass control [11], cross
contamination between the layers [4,8,9], elastic mismatch between
adjacent layers [7], reduced yield and their tendency to delaminate
at the non-planer interface between the adjacent compacted layers
(i.e. layer-separation) [4] during the various stages of production down-
stream of the compaction process. The fracture of bilayer tablets is often
the result of an interfacial crack driven by residual stresses in the tablet
propagating a finite distance within the tablet and leads to capping and
lamination which may not always be immediately apparent after
compaction [6,7]. It is known that occurrence of the fracture/crack at

0032-5910/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.powtec.2012.05.048
 I. Akseli et al. / Powder Technology 236 (2013) 30–36
the interface causes a reduction in the overall elastic stiffness (Young's
modulus) and layered tablets become fragile and develop a tendency
to fail. The cause of the fracture/crack at the interface causes a reduction
in the overall elastic stiffness (Young's modulus) and layered tablets
become fragile and develop a tendency to fail. Therefore, while the ther-
apeutic (chemical/pharmaceutical) functions of bilayer tablets are
crucial, they need to have a certain degree of mechanical strength and
ruggedness to survive normal processing, handling, packaging and
shipping stresses. Understanding what influences the stress state and
mechanical properties of a bilayer tablet and developing specialized
techniques for measuring those properties could then assist in the un-
derstanding of how, and why, defects such as capping, delamination,
and cracking, which are significant practical problems for the pharma-
ceutical industry, occur.
The objectives of this paper were three-fold: (i) to explore the
effect of tableting conditions on the interfacial and individual layer
strengths of bilayer tablets; (ii) to assess different fracture patterns re-
lated to the mechanical and fracture surface properties of compacted
adjacent layers; and (iii) to determine the influence of layer sequence
on the mechanical performance of bilayer tablets. In this reported
study, bilayer tablets of microcrystalline cellulose (MCC) in the form
of Avicel 102 and pregelatinized starch were formed with different
pre-compression and compression conditions to quantitatively char-
acterize the strength (σ) of the interface and the adjacent compacted
layers. A semi-automatic axial tensile strength tester was built and
used for bilayer tablet strength characterization. Bilayer tablets of
MCC–MCC and MCC–starch were axially debonded until fracture and
the corresponding axial tensile strength values were determined. It
was observed that when the first layer was compressed to a low
porosity, the bonding with the second layer became difficult and it
was impossible to produce intact bilayer tablets (σlayer > σinterface). In
the current study, we shall demonstrate that the material response
of the constrained particles to an applied initial compression force
within the initial compacted layer have a detrimental effect on the
resistance to fracture of a bilayer tablet. Moreover, we shall show
that once the magnitude of the applied final layer compaction stress
greatly exceeds the initial layer compaction stress, the tablet cata-
strophically fails at the initial layer not at the interface (σlayer b σinterface).
In addition and most notably, the mechanism of failure at the interface
or at the individual layers provides insight into some of the major
complications of bilayer tablets that arise during the various stages of
production downstream of the compaction process.
2. Materials and methods
2.1. Materials
In studying the effect of material properties on bilayer integrity,
two materials were selected to exemplify the extreme deformation
characteristics seen with pharmaceutical materials: plastic and visco-
Fig. 1. A close-up image of the bilayer tablet tensile tester equipped with 100 lb mini-load cells. Inset depicts the examined bilayer tablets glued to the holders.
31
elastic. The pool of pharmaceutically acceptable materials is severely
limited due to their use in patients. Out of this limited pool we further
restricted our selection criteria to diluents, which typically comprise
the largest excipient fraction of any composition. Of these diluents,
microcrystalline cellulose MCC (Lot # P208819508, Avicel PH102, FMC
Biopolymer, Newark, DE) was selected as it is a purely plastic material
and pregelatinized starch (Lot #7D30574, Starch 1500, Colorcon, West
Point, PA) was selected as it is mostly a visco-elastic material. These
two materials cover the spectrum of deformation behavior seen with
pharmaceutical materials. The true densities of powders were mea-
sured by helium pycnometry (AccuPyc 1330, Micromeritics Instrument
Corp., Norcross, GA) in triplicate using fresh samples each time. For MCC
and pregelatinized starch, densities are 1.567 g/cm3 and 1.488 g/cm 3,
respectively.
2.2. Methods
Bilayer tablets were compacted by uni-axial compression on a
Piccola bilayer tablet press (SMI, Inc, Lebanon, NJ). In this bilayer
compaction press, the bottom punch is stationary while the top
punch is moving. A flat-faced punch with a diameter of 10 mm is
used. There is no requirement for punch lubrication on this tablet
press. In order to study the effect of pre-compression and compres-
sion forces on the mechanical integrity of bilayer tablets, different
compaction configurations were considered. In the first configuration
(MCC with MCC), the first layer was formed by compressing the MCC
at 2 kN, 4 kN, 6 kN and 8 kN pre-compression forces (compression
force in (kN) can be converted to compression pressure (MPa) by
force / area for a known tablet diameter). The second layer was then
formed and bonded by compressing the MCC powder at 6 kN,
10 kN, 14 kN, and 18 kN compression forces. In the second configura-
tion (MCC with starch), the first layer was produced by compressing
MCC and the second layer was formed by compressing the starch
powder on to the MCC layer with the same compression settings
reported above. The initial and final layers were carefully marked
after the compaction process. The compression dwell time is set to
153 ms (i.e., turret speed of 10 rpm) to enable the formation of
uniformly-bonded compacts. A set of 10 bilayer tablets was tested
for each compaction configuration and the mean average values of
these tablets were used. The thickness and diameter of the tablets
were measured by a digital caliper (±0.01 mm, Starrett B5000BZ-
40/1000, Athol, MA) and the mass was recorded by an electronic bal-
ance (±0.1 mg, Fisher Scientific XD-800, Pittsburgh, PA) immediately
after compaction. This study focused on the measurement of the axial
tensile strength at room conditions; no systematic study for the effect
of temperature and humidity on the strength of the bilayer tablets
was conducted. All measurements were conducted at ambient condi-
tions of 24 ± 2 °C and 35 ± 5% RH. All the bilayer tablets were stored
in sealed vials after manufacturing for a day. The examined bilayer
tablets were then individually glued to two tablet holders (Fig. 1)
32 I. Akseli et al. / Powder Technology 236 (2013) 30–36
using a cyanoacrylate-based fast-acting super glue and left for an
hour to ensure a good adhesion. An optical microscope was also
used to investigate the migration of glue (not reported in this paper)
and it was ensured that no glue migrated into the examined bilayer
tablets. Tablet holders were connected to the moveable ultra precision
100 lb mini-load cells (MDB 100, Transducer Techniques). Constant
displacement of the load cell was employed (0.005 mm/s) and the
resulting tensile force (i.e., the force needed to debond the bilayer
tablet) was determined (Fig. 2). In this configuration one of the load
cells was stationary while the other was moving. The applied displace-
ment was continued until the tablet catastrophically fractured (Fig. 1).
To account for the compliance of the equipment, the two holders
were adhered to each other with no tablet being present. A tensile
stress was then imposed up to the value of the highest fracture force
obtained from the compacts. The force–displacement curve was then
subtracted from the measured force–displacement curves obtained
from the samples. Fracture forces recorded and measured diameters
of the tablets were then used to calculate the tensile strength (σt) of
the tablets using
4F
σt ¼
πϕ2
where F is the force to fracture the compact and ϕ is the diameter of
the compact.
2.2.1. X-ray micro-computed tomography
X-ray micro-computed tomography is a volumetric imaging tech-
nique which permits noninvasive determination of the density of a
material in space on the principle of attenuation when X-rays pass
through it [12,15]. The specimen is placed on a rotating stage between
a micro-focal mono-energetic source and a charge couple detector
(CCD) array based detector. A phosphor plate between the specimen
and the detector is used to intensify the image. Most modern industrial
μCT systems are capable of attaining resolutions of less than 50 μm.
Projection images (radiographs) of the object are obtained in slices at
specified angular rotational steps; from which horizontal slices are
reconstructed utilizing Fourier based filtered back projection (FBP)
algorithms. The attenuation values calculated as a function of space
obey Beer–Lambert's Law:
I ¼ I o expð−μxÞ
where Io is the incident X-ray intensity, I is the measured X-ray intensity,
μ is the linear attenuation coefficient (cm− 1) and x is the sample length.
Upon normalizing the mass density, the mass attenuation coefficient
(μ/ρ) is found to be constant for most materials over a range of energies,
leaving the attenuation values (CT or HU) as a function of density and
path alone. By means of calibration, it is quantitatively possible to deter-
mine the density of the sample as a function of space at a sufficiently
Fig. 2. Force–displacement curve obtained during the fracture of an examined MCC
(compressed to 8 kN)–MCC (compressed to 6 kN) bilayer tablet.
Fig. 3. Effect of the initial and final compression forces on the axial tensile strength
values of the MCC–MCC tablets. 6 kN, 10 kN, 14 kN, and 18 kN final compression forces
are represented by a diamond (♦) shape, square (■) shape, triangular (▲) shape, and
cross (x) shape, respectively. The estimated interfacial strength is shown by a hollow
ð1Þ circle (○) shape. The axial tensile strength of the monolayer MCC tablet is represented
by a filled circle (●) shape. A dashed oval shape depicts the bilayer tablets that failed at
the initial layer.
high resolution. The individual slices can be stacked up and a 3D volu-
metric reconstruction of the specimen can be obtained using standard
interpolation techniques such as marching cubes or adaptive rendering
[15].
In this reported study, X-ray μCT measurements were carried out
on a high resolution SkyScan-1172 XRCT (SkyScan, Kontich, Belgium).
The X-ray source was operated at a voltage (U) of 50 kV and a current
(I) of 100 μA. The total sample rotation was set at 180° with an inter-
val of 0.6° (i.e., the tablet was scanned every 0.6°). The spatial resolu-
tion was 14.8 μm/pixel for the tablet considered (i.e., 14.8 μm
resolution size in the three directions after image reconstruction).
Magnified transmitted projection pictures were detected by a two-
dimensional X-ray CCD camera with a 1024 × 1024 pixel resolution
and 12-bit dynamic range sensor. To minimize the beam hardening
artifacts, an aluminum–copper plate with a 0.5 mm thickness was
placed over the X-ray source to filter the low energy X-rays. Depending
ð2Þ
on the sample length the typical image acquisition times were in
the range of 20–25 min. The reconstruction was carried out with the
NRecon software (Skyscan, Kontich, Belgium). Quantitative parameters
such as thresholding were analyzed using the CT-analyser (CTAn) soft-
ware (Skyscan, Kontich, Belgium). 3D model rendering and viewing
were performed using the associate program CT-Volume (CTVol) soft-
ware (Skyscan, Kontich, Belgium). ImageJ software which is a public
domain Java-based image processing program was employed to analyze
all the images (http://www.nih.gov).
2.2.2. Image processing
Due to the large volume of data and size of individual image data set,
images were resized to reduce computer storage space and improve
computational efficiency. Matlab 7.12a (The Mathworks, Natick, MA,
USA) software was utilized for the following image processing steps.
In the first step, individual images were read into 2D matrices and
then stacked up to render a 3D volume. Further reduction in data was
achieved by cropping individual slices to eliminate most empty voxels.
Since, in practice, the X-ray source is non-monoenergetic, despite the
use of an aluminum–copper filter, it was observed that few beam hard-
ening artifacts of relatively lower grayscale values remain. To prevent
their contribution to the calculations, artifacts were eliminated by
assigning a zero value for all voxels with values below a cutoff. The
choice of this cutoff value was made, visually, by selecting the gray-
scale value at which almost all the artifacts just vanish.
 I. Akseli et al. / Powder Technology 236 (2013) 30–36
Fig. 4. Effect of the initial and final compression forces on the axial tensile strength
values of the MCC–starch tablets. 10 kN, 14 kN, and 18 kN final compression forces
are represented by a diamond (♦) shape, square (■) shape, and triangular (▲) shape,
respectively. Failure patterns are shown in brackets as the number of tablets that failed
as clear-layer, cap-shape, half–half and interface break.
3. Results and discussion
MCC–MCC and MCC–starch bilayer tablets were produced with
different compression force configurations for axial tensile strength
measurements (Fig. 1). Figs. 3 and 4 depict the effective axial tensile
strength values of the examined MCC–MCC and MCC–starch bilayer
tablets as a function of initial (Fi) and final (Ff) compression forces,
respectively. Each data point is corresponding to the mean average
axial tensile strength values of 10 tablets. The standard deviation
values of each data set are less than ±0.18 MPa. For both bilayer sys-
tems (i.e., MCC–MCC and MCC–starch), in the range of the process
Fig. 5. Images of the MCC–MCC bilayer tablets compressed to an initial compression force of 2 kN (a), 4 kN (b), 6 kN (c), and 8 kN (d) and a final compression force of 18 kN.
33
conditions considered, as the final compression force increases the
axial tensile strength increases irrespective of the initial compression
force applied (Figs. 3 and 4). For instance, the axial strength values of
the MCC–MCC bilayer tablets formed by 2 kN initial and 10 kN final
compression forces are significantly higher (approximately twice)
than that of the tablets manufactured using 2 kN initial and 6 kN
final compression forces. In contrast, this is not the case for the initial
compression force. As the initial compression force increases from
2 kN to 4 kN, the axial strength of the bilayer tablet increases, how-
ever additional increase in the initial compression force (i.e., 4 kN to
6 kN and 6 kN to 8 kN) drastically decreases the axial tensile strength
of the tablet. The maximal axial tensile strengths for both bilayer
systems can be obtained by compressing the first layer with 4 kN
compression force (Figs. 3 and 4). Additional increase in the initial
compression force (i.e., 6 kN and 8 kN) creates a larger particle defor-
mation on the surface of the initial layer which leads to a relatively
smooth in other words ‘shiny’ surface and consequently results in
the decrease of the interfacial strength. The deformability capacity of
the particles on the initial layer as well as the surface is significantly
reduced for further elastic or plastic deformation. It is also known
that surfaces that are in contact with the punch faces are generally
harder than the surfaces in contact with the die [13]. Thus, the initial
layer surface in contact with the punch surface becomes more rigid
after relatively high compression forces are applied compared to rela-
tively low compression forces (i.e., 2 kN and 4 kN) which facilitate less
mechanical interlocking and particle bonding.
For cases of 2 kN and 4 kN initially compacted MCC–MCC bilayer
tablets, it was observed that once the final layer compression force
reached 18 kN, tablets failed in the initial layer rather than in the
interface (Fig. 5) (σlayer b σinterface), indicating a change of the mode
of failure from the inter-layer (σinterface) to the intra-layer (σlayer)
mode. This is only observed for the 2–18 kN and 4–18 kN compacted
bilayer tablets. In order to better understand and quantify the bound-
aries between the different regimes, we developed an estimate of the
34 I. Akseli et al. / Powder Technology 236 (2013) 30–36
interlayer (interfacial) strength for the two cases where the failure
did not occur at the interface, these are: 2–18 kN and 4–18 kN. The
estimates were obtained by utilizing the data for all other cases
where failure occurred at the interface. The procedure is as follows:
since the results for the cases 6 kN, 10 kN, and 14 kN can be described
reasonably well by a bilinear function with a positive slope up to 4 kN
followed by a negative slope thereafter (dashed-lines in Fig. 3),
we consider that the 18 kN case has the same trend, i.e. a bilayer
response characterized by a positive slope up to 4 kN followed by a
negative slope beyond that point. We estimate the positive slope for
the 18 kN case as the average of the positive slopes for the cases of
6 kN, 10 kN and 14 kN. Similarly, we determine the negative slope
for the 18 kN case as the average of the negative slopes. We construct
the bilinear function for the 18 kN case utilizing the strength value of
8–18 kN as the anchor point resulting in the graph depicted with a
dashed-line in Fig. 3. Based on this approximation we estimate the
interfacial strength for cases 2–18 kN and 4–18 kN indicated with
the open circles in Fig. 3. Note that the estimates can be considered
as a lower bound due to the increase in the slopes with compaction
force.
Additionally, we determine the intralayer strength for the same
material at 6 kN, 10 kN, 14 kN, and 18 kN by consolidating single
layer tablets. These single-layer values can be used as an upper
bound estimate of the intra-layer strength of the bottom layer of the
bilayer tablet due to additional frictional effects associated with this
configuration. The estimates for the first layer strength are shown by
the solid lines in Fig. 3. This description is consistent with the observed
behavior where the σlayer > σinterface for all cases resulting in an inter-
face break for all cases, expect for the 2–18 kN and 4–18 kN tablets
where the axial tensile strength of the initial layer is 9.18 MPa and
9.43 MPa, respectively (about 20% less than that of the estimated
interfacial strength). This result reveals that since the estimated inter-
facial strength is significantly higher than that of the layer, a layer
break occurs. This is a particularly notable result since this type of
performance map can help formulation and process scientists to pre-
dict their formulations and process parameters during bilayer tablet
development.
Fig. 4 depicts the axial tensile strengths of the MCC–starch bilayer
systems. For these bilayer tablets, it was impossible to form intact
tablets with a final compression force of 6 kN irrespective of the initial
layer compression forces. These tablets were split apart along the
interface either during the decompression–ejection phase or during
post-compaction handling due to weak bonding between the adjacent
layers. X-ray micro-CT was utilized to visualize the internal structure
of these bilayer tablets (Fig. 6). The interfacial crack can be clearly
seen between the adjacent layers. This crack nucleation was caused
Fig. 6. X-ray micro-computed tomography cross-section images obtained after 2D reconstruction of the defective MCC–starch bilayer tablet compacted to an initial compression
force of 4 kN and a final compression force of 6 kN. The image is taken at mid-height of the tablet. An interfacial crack that weakens the bilayer system can be seen between the
adjacent layers.
by weak bonding between the MCC and the starch layer, thus making
it impossible to test these tablets. This could be attributed to the initial
compression process; the deformation within the MCC layer could re-
sult in the accumulation of stored elastic strain which will be released
upon removal of the rigid constraints (e.g., loaded-spring analogy).
This mechanism will act as a stress concentrator and hence will
cause a reduction in the strength of the interface. In addition, it is
known that the retardation of the particulate movement of the parti-
cles in contact with the die wall may cause the inherent bonding
mechanisms such as particle interlocking [14] to be reduced and
thus the energy required to be dissipated upon ejection may exceed
the adhesive bond energy between the adjacent layers. Thus, the
relaxation of the individual layers will not occur uniformly through
the whole bilayer tablet which results in mechanical property anisot-
ropy [7,15] in the tablet. For these tablets, we observed four different
fracture patterns namely; clear-layer break, cap-shape break, half–
half break and interface break (Fig. 7). In Fig. 4, we categorized these
tablets by their fracture patterns. In this graph, it is clear that for low
initial compression forces (2 kN and 4 kN) the bilayer system often
fails at the starch layer either as layer/cap-shape or half–half break.
Half–half break represents a fracture pattern where some part of the
starch layer is adhered to the MCC layer. In other words, during testing
when the cohesion force between starch particles is relatively less
than the adhesion forces at the MCC–starch interface, some part of
the starch layer adheres to the MCC layer (i.e., cross-contamination).
One of the reasons that we frequently observe this type of starch
layer adhesion at the middle part of the MCC layer rather than the
radial periphery is that during the bilayer compaction process the
consolidation of the second layer compacted on top of the first layer
is relatively higher at the middle region of the second layer than the
edges (i.e., nonuniform stress/density pattern). This is due to the un-
even stress concentration that is developed during bilayer compaction
that creates local high relative density regions resulting in internal
heterogeneous strain gradients. Thus, this high stress concentration
at the middle part compacts the material to a larger extent than that
at the edges and consequently increases the bond formation at the
middle part of the interface between adjacent layers. Die-wall friction
between the second layer and the die-wall also hinders the powder
movement downward resulting in a weaker compaction process at
the radial periphery of the bilayer tablet and consequently the middle
bottom region of the second layer compacted relatively higher than
that of the radial region. Before examining these bilayer tablets, we
utilized X-ray micro-CT to visualize the density distribution in com-
pacts. The 3D X-ray image of the bilayer tablet formed by 4 kN–
14 kN is shown in Fig. 8. As shown in Fig. 8, a localized high density
concentration can be seen at the initial layer edges, middle region of
 I. Akseli et al. / Powder Technology 236 (2013) 30–36 35

Fig. 7. Images of the MCC–starch bilayer tablets compressed to initial and final compression forces of 8 kN–18 kN (a) — interface break, 2 kN–18 kN (b) — half–half break, 4 kN–
10 kN (c) — clear-layer break, and 6 kN–14 kN (d) — cap-shape break.

the initial and bottom middle part of the second layer where low
density regions can be found at the top of the tablet and at the radial
periphery. This also confirms our experimental observations. The
difference in the intrinsic tensile strength of these two materials
(i.e., for the process conditions considered, the tensile strength of
the starch monolayer at an 18 kN compression force, 0.9 MPa, is a
magnitude order lower than that of the MCC tablets, 9.81 MPa), bond-
ing mismatch at the interface and the relatively higher tendency to
brittle fracture of the starch material than the MCC can be listed as
some of the reasons for this type of bilayer tablet failure. In Fig. 4, for
all final compression forces, as the initial compression force increases
the interface break increases and the clear starch layer break relatively
decreases. This is a similar observation that we have seen with the
MCC–MCC tablets. As the initial layer compaction increases bonding
at the interface between adjacent layers significantly decreases.
These data suggest that careful selection of an initial compression
force is crucial in obtaining a desirable bilayer tablet robustness. For
the MCC–starch bilayer tablets, layer sequence is also investigated.
As described in the tablet preparation section, the bilayer tablets of
starch–MCC were formed with the same initial and final compression
forces as described in the Materials and methods section. Fig. 9 depicts
the comparison of axial tensile strength values of the MCC–starch and
starch–MCC bilayer tablets. For the starch–MCC bilayer tablets, it is
possible to form compacts with 6 kN final compression force with
all initial compression forces considered. As seen in Fig. 9, the axial
tensile strength values of starch–MCC are significantly higher than
the MCC–starch bilayer tablets. It has been earlier suggested [16]
that both materials cohere by forming a similar type of inter-
particulate attraction forces. Therefore, the differences in distribution
of interparticulate attractions could be related to the way the mate-
rials behave when subjected to compression [16]. It has been known
that pregelatinized starch is considered as a visco-elastic material

Fig. 8. X-ray micro-computed tomography cross-section images obtained after 3D reconstruction of the MCC–starch bilayer tablet compacted to an initial compression force of 4 kN
and a final compression force of 14 kN. The image is taken at mid-height of the tablet.
36 I. Akseli et al. / Powder Technology 236 (2013) 30–36
Fig. 9. Comparison of the effect of layer sequence on the axial tensile strength values of
MCC–starch (solid lines) and starch–MCC tablets (dashed lines). 6 kN, 10 kN, 14 kN,
and 18 kN final compression forces are represented by a cross (x) shape, diamond
(♦) shape, square (■) shape, and triangular (▲) shape, respectively.
[17] and MCC is considered as a ductile material [18]. When the MCC
layer compacted first and starch second, MCC is known to consolidate
mainly by plastic deformation and the surface roughness of the MCC
layer that is in contact with the punch significantly reduces, thus
resulting in the decrease in inter-particular attraction between the
two different adjacent layers when the starch layer is compressed
as the final layer. Furthermore, nesting sites for the starch particles
decrease as the surface asperities on the MCC layer decrease, thus
the capacity of bond formation and the possibility of mechanical inter-
locking are significantly reduced. In addition, the MCC material is
known to be more compactable than the starch material [19], thus,
after the initial compression, the starch material is not rigid as the
MCC material and it is a compact made of deformable particles
which have the capacity for further elastic and/or plastic deformation
during the compression phase of the second layer and consequently
starch–MCC bilayer tablets result in relatively higher axial tensile
strength values than the MCC–starch tablets.
4. Conclusions and remarks
Mechanical failure of bilayer tablets can be broadly classified into
two different regimes, the first is characterized by the separation of
the top and bottom layers (inter-layer failure) and the second is
governed by the rupture within either the top or the bottom layer
(intra-layer failure). The dominance of the inter- or intra-failure
type is determined by a competition among mechanisms responsible
for developing strength in between the layers and within the layers.
In this study, we quantitatively assess the boundaries of these two re-
gimes attendant to the selected material combinations, formulation
and processing conditions. We have selected two well-characterized
pharmaceutical excipients with dissimilar elastic–plastic response, such
as MCC and starch, to manufacture mono-material and bi-material bilayer
tablets with different layer sequencing subjected to a consolidation pro-
cess with varying first-layer and final force. In order to characterize and
quantitatively map the effect of these parameters on the failure response,
we have developed a device/methodology for measuring the axial
strength of bilayer tablets, in which tensile normal stresses are applied
across the bilayer interface. This methodology contrasts with the current
standard diametrical-compression test (hardness) where tensile stresses
are applied in a plane normal to the interface, and therefore, limiting the
ability to record relevant information about layer-to-layer strength. This
methodology enables one to decipher the evolution of the inter- and
intra-failure strengths while providing quantitative information about
the relative importance of the material, formulation and process parame-
ters. Similar concepts can be utilized to study other relevant conditions
such as humidity, lubrication, shape and ejection forces among others.
Acknowledgments
The authors would like to acknowledge Bristol-Myers Squibb Co.
for their funding for this investigation. The authors would also like
to acknowledge Kyle Martin and Niranjan Kottala (BMS) for preparing
the tablets used in this study.
References
[1] A. Nangia, T. Molloy, B.J. Fahie, S.K. Chopra, Novel regulated release system based
on geometric configuration, Proc Int Sym Control Release of Bioactive Mater, 22,
1995, pp. 294–295.
[2] N. Chidambaram, W. Porter, K. Flood, Y. Qiu, Formulation and characterization of new
layered diffusional matrices for zero-order sustained release, Journal of Controlled
Release 52 (1998) 149–158.
[3] U. Conte, L. Maggi, P. Columbo, A. La Manna, Multi-layered hydrophilic matrices
as constant release devices (Geomatrix Systems), Journal of Controlled Release
26 (1993) 39–47.
[4] S. Abdul, S.S. Poddar, A flexible technology for modified release of drugs: multi
layered tablets, Journal of Controlled Release 97 (2004) 393–405.
[5] F. Podczeck, K.R. Drake, J.M. Newton, I. Haririan, The strength of bi-layered tablet,
European Journal of Pharmaceutical Sciences 29 (2006) 361–366.
[6] S.J. Inman, B.J. Briscoe, K.G. Pitt, Topographic characterization of cellulose bilayered
tablets interfaces, Chemical Engineering Research and Design 85 (2007) 1005–1012.
[7] I. Akseli, D. Dey, C. Cetinkaya, Mechanical property characterization of bilayered
tablets using nondestructive air-coupled acoustics, AAPS PharmSciTech 11 (2010)
90–102.
[8] P.S.L. Wong, S.K. Gupta, B.E. Stewart, Osmotically controlled tablets, in: M.J.
Rathbone, J. Hadgraft, M.S. Roberts (Eds.), Modified-Release Drug Delivery Tech-
nology, Informa Healthcare, London, 2002, pp. 101–114.
[9] H.G. Zerbe, M. Krumme, Smartrix system: design characteristics and release prop-
erties of a novel erosion-controlled oral delivery system, in: M.J. Rathbone, J.
Hadgraft, M.S. Roberts (Eds.), Modified-Release Drug Delivery Technology,
Informa Healthcare, London, 2002, pp. 59–76.
[10] Y. Ozeki, M. Ando, Y. Watanabe, K. Danjo, Evaluation of novel one-step dry-coated
tablets as a platform for delayed-release tablets, Journal of Controlled Release 95
(2004) 51–60.
[11] S.A. Charman, W.N. Charman, Oral modified-release delivery systems, in: M.J.
Rathbone, J. Hadgraft, M.S. Roberts (Eds.), Modified-release Drug Delivery Technology,
Informa Healthcare, London, 2002, pp. 1–19.
[12] A.C. Kak, Computerized tomography with X-ray, emission and ultrasound sources,
Proceedings of the IEEE 67 (1979) 1245–1272.
[13] M.E. Aulton, Indentation hardness profiles across the faces of some compressed
tablets, Pharmaceutica Acta Helvetiae 56 (1981) 133–136.
[14] F. Podczeck, Particle–Particle Adhesion in Pharmaceutical Powder Handling,
Imperial College Press, London, 1998.
[15] I. Akseli, S. Iyer, P. Lee, A.M. Cuitino, A quantitative correlation of the effect of den-
sity distributions in roller-compacted ribbons on mechanical properties of tablets
using ultrasonics and X-ray tomography, AAPS PharmSciTech 2011 (12) (2011)
834–853.
[16] P.G. Karehill, C. Nyström, Studies on direct compression of tablets XXI. Investiga-
tion of bonding mechanisms of some directly compressed materials by strength
characterization in media with different dielectric constants (relative permittivity),
International Journal of Pharmaceutics 61 (1990) 251–260.
[17] S.T. David, L.L. Augsburger, Plastic flow during compression of directly compress-
ible fillers and its effect on tablet strength, Journal of Pharmaceutical Sciences 66
(1977) 155–159.
[18] J.E. Rees, P.J. Rue, Time-dependent deformation of some direct compression
excipients, Journal of Pharmacy and Pharmacology 30 (1978) 601–607.
[19] C.K. Tye, C. Sun, G.E. Amidon, Evaluation of the effects of tableting speed on the
relationships between compaction pressure, tablet tensile strength, and tablet
solid fraction, Journal of Pharmaceutical Sciences 94 (465–472) (2005) 2005.