A comparative study of compaction properties of binary and bilayer tablets

Chuan-Yu Wu , Jonathan P.K. Seville

1
Centre for Formulation Engineering, Department of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
A B S T R A C T A R T I C L E I N F O
Available online 22 April 2008
Keywords:
Binary mixture
Layered tablet
Delamination
Diametrical compression
Crush strength
Fracture
Bi-layer tablets have been developed to achieve controlled delivery of different drugs with pre-dened
release proles. However, the production of such tablets has been facing great difculties as the layered
tablets are prone to fracture. In this paper, the compaction behaviour of binary mixtures and bilayer tablets of
two common pharmaceutical excipients, Microcrystalline cellulose and lactose, is investigated. The effects of
compositions and compaction pressure on the compaction behaviour of binary matrix mixtures and bilayer
tablets are also explored. The delamination phenomena during the manufacturing of bilayer tablets and
fracture patterns of tablets subjected to diametrical compression are examined using X-ray computed
tomography. The mechanical properties of binary and bilayer tablets of the same composition were also
determined and compared. It has been shown that for binary and bilayer tablets with the same composition,
the apparent crush strength of these binary and bilayer tablets measured from diametrical compression tests
were generally comparable for the powders considered in this study. It was also found that, using the same
compaction process, the relative densities of the tablets were generally different when different
compositions were used, especially when the maximum compression pressure is relatively low.
2008 Elsevier B.V. All rights reserved.
1. Introduction
Pharmaceutical tablets are the dominant dosage form for drug
delivery, occupying two-thirds of the global market. Generally, they
are produced by compressing dry powder blends consisting of a
number of components with different functionalities in a die. It is
technically difcult to ensure that a tablet possesses both a certain
mechanical strength and a lowpacking density, so that it is sufciently
strong to maintain its integrity during handling and transport and also
weak enough to satisfy the dispersion and dissolution requirements.
In addition, layered tablets, such as bi-layered tablets [14], and even
triple-layered tablets [57], have been developed to achieve con-
trolled drug delivery with pre-dened release proles for different
active ingredients. However, the production of such tablets has proved
challenges as the layered tablets are prone to fracture by delamina-
tion, normally along the interfaces between different layers, because
of their inherent binding weakness [1]. Understanding and predicting
the mechanical strength of these tablets is of commercial signicance
since tablet failures due to weak mechanical strength can lead to
enormous nancial losses especially when costly drugs are involved.
This is a particularly challenging task due to the complexity and
diversity of pharmaceutical blends.
The mechanical strength of a cylindrical pharmaceutical tablet can
be characterized by the measurement of tensile strength, which is
generally determined using the diametrical compression test as
introduced by Fell and Newton [8]. In this test, the tablet is placed
between two platens and compressed diametrically until it breaks/
crushes. According to this method, the tensile strength can be
calculated from the crushing load and the dimensions of the tablet.
This procedure has been used to determine the tensile strength of
matrix tablets made of various components and has hence been
employed to explore the dependence of tensile strength on the
properties of constituent components, such as tablets porosity,
particle shape and size, effective contact surface area [9,10].
Since thorough understanding the dependence of the tensile
strength of binary tablets on their constituents is vital to full
understanding of how the properties of constituent components can
contribute to the tensile strength of real multi-component tablets,
there has recently been an increased interest in the study of tensile
strength of binary tablets [1114]. Chan et al. [11] developed a model
for tensile strength of binary mixtures by modifying the theory for
tensile strength of ne powder developed by Cheng [15] and
introducing the concepts of reference state and a reduced tensile
strength. The model took account of the effects of particle size and the
composition of binary mixtures by assuming that the tensile strength
is proportional to the total contact area between particles of different
sizes along the split plane. However, it is very difcult to apply the
model in practice, as some parameters in the equations are hardly
accessible, in particular the parameter describing intrinsic interaction
between particles of different materials. Bangudu and Pilpel [12]
measured the tensile strength of tablets of paracetamol and Avicel
powders and mixtures of these components and the inuence of the
Powder Technology 189 (2009) 285294
Corresponding author. Tel.: +44 121 4145365; fax: +44 121 4145324.
E-mail address: [email protected] (C.-Y. Wu).
1
Current address: School of Engineering, University of Warwick, Coventry CV4 7AL, UK.
0032-5910/$ see front matter 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.powtec.2008.04.026
Contents lists available at ScienceDirect
Powder Technology
j our nal homepage: www. el sevi er. com/ l ocat e/ powt ec
concentration of Avicel powder in the binary tablets were explored.
Kuentz and Leuenberger [13] investigated the tensile strength of
binary tablets comprising well- and poorly-compactable substances
and developed a model using percolation theory. For the cases in
which both components can contribute to the tensile strength of
binary tablets, a modied model was proposed by Ramirez et al. [14].
The development of predictive models, which can assess the
properties of the multi-components tablets based upon the knowl-
edge of material properties of the individual constituent substances, is
of great interest in pharmaceutical formulation design and develop-
ment. Wu et al. [16] developed a simple predictive model for the
tensile strength of binary tablets based upon RyshkewitchDuck-
worth equation and showed that the model can accurately predict the
tensile strength of binary tablets made of some commercial excipients.
The model was extended to predict the tensile strength of tablets
made of multi-components and was veried by experimental
measurements for the mixture of three and four powders [17].
Mohammed et al. [18] developed a simple model to predict the
required volume fraction of microcrystalline cellulose (MCC) to
produce a binary tablet of MCC and paracetamol. Michrafy et al. [19]
investigated the tensile strength of binary tablets using an extended
RyshkewitchDuckworth model in which the tensile strength at zero
porosity and binding capacity were given by linear and power laws.
For layered tablets, it is still unclear how their mechanical strength
can be measured and whether or not the diametrical compression test
can be directly used to determine their tensile strength due to their
heterogeneous structures, which may result in different stress distribu-
tions from those developed in matrix tablets. While fundamental
scientic investigations are awaited to address these issues, alternative
approaches have been reported in the literature. Dietrich et al. [20] used
a shear apparatus to measure the shear forces needed to separate the
layers in the radial direction and these shear forces were regarded as a
measure of adhesion strength. Podczeck et al. [21] measured the tensile
strength of bilayer compacts, which are rectangular beams consisting of
two layers of equal thickness, using three-point bending tests and found
that the value of tensile strength was either greater or lower than the
tensile strength of the beams of the same thickness composed of the
same materials, which cannot even be corrected by considering the
Fig. 1. Bilayer tablets made of 20%MCC+80%lactose (Mcc 1st) with different maximum compression forces.
286 C.-Y. Wu, J.P.K. Seville / Powder Technology 189 (2009) 285294
differences in the elasticity of the materials in layered compacts. They
anticipated that the way in which the failure of the beam crossed the
interface between different layers was an important factor in determin-
ing the tensile strength of bilayer compacts using this test. In this paper,
X-ray computed tomography (XRCT) is used to examine howthe failure
crosses the interface between different layers when bilayer tablets are
subjected to diametrical compression.
The purpose of this study is to examine how the individual
constituents contribute to the overall response of the mixtures of two
powders at two extreme mixing states: i) binary mixture, in which two
powders are mixed thoroughly and they interact with each other at a
particle/particle level; ii) bilayer structure, in which the two powders
only interact at their interface. Since it is still questionable if the
conventional diametrical compression test can be used to measure the
tensile strength of bilayer tablets, we introduce the term apparent
crush strength to represent the mechanical strength of bilayer tablets
measured by diametrical compression. We then investigate how the
mixing states in the tablets made of two different materials, i.e., binary
matrix and bilayer tablets, affect their apparent crush strength and how
the apparent crush strength of bilayer tablets compares with the tensile
strength of binary matrix tablets consisting of the same mixture.
2. Materials and methods
Two widely used pharmaceutical excipients were considered:
microcrystalline cellulose (MCC) (Avicel PH-102; FMC Corporation,
Brussels, Belgium), which is one of the most commonly used ller-
binders in pharmaceutical products, and lactose monohydrate
(Pharmatose 50 M, DMV International), widely used as a diluent and
also ow improvement agent in pharmaceutical tablet formulation.
All the powders were used as received and the mean particle sizes of
MCC and lactose are 110 m and 290 m, respectively. The true
densities of these powders were measured using a helium gas
displacement pycnometer (AccuPyc 1330, Micromeritics

, Bedford-
shire, UK). The measured true densities are 1.5900.003 g/cm
3
for
MCC and 1.5390.001 g/cm
3
for lactose, respectively. Single-compo-
nent matrix tablets of MCC and lactose were produced by compressing
800 mg of the powders inside a 13 mm evacuable pellet die (Specac
Ltd, Kent, UK) using an universal materials testing machine. No
lubricant was used in any tablets produced in this study and all the
tablets were produced using single ended compression with a moving
top punch. The compression and decompression speeds were
identical at 0.083 mm/s and the maximum compression forces were
Fig. 2. Bilayer tablets made of 20%MCC+80%lactose (lactose 1st) with different maximum compression forces.
287 C.-Y. Wu, J.P.K. Seville / Powder Technology 189 (2009) 285294
specied in the range of 3 kN to 18 kN, so that tablets with different
relative densities (dened as the ratio of tablet packing density to true
density) can be produced and tested. All the experiments reported
here were run in triplicate.
The tablet weight was measured using an electronic balance and
the diameter and the thickness were measured with digital callipers.
From these measurements, the volume and packing density of the
tablets were determined. The relative density (D) was calculated by
dividing the packing density by the true density. The tensile strength
of the tablet was determined from diametrical compression tests,
which were performed using an universal materials testing machine
with an 1 kN load cell in order to measure the maximal diametrical
crushing force (F) accurately. Together with the measured diameter
and thickness of the tablets, the tensile strength (
t
) is then calculated
as follows [8]
r
t

2F
pdt
1
where d and t are the diameter and thickness of the tablet,
respectively.
For binary tablets, two mixtures of MCC and lactose at two
different mass fractions (80% MCC+20% lactose; 20% MCC+80%
lactose) were prepared. The powder mixtures of 100 g were mixed
in a Turbula T2F Shaker Mixer (Basel, Switzerland) at 23 rpmfor 30 min.
Using the helium pycnometer, the measured true densities are 1.553
0.001 g/cm
3
for the mixture of 80% MCC+20% lactose and 1.542
0.001 g/cm
3
for 20% MCC+80% lactose, respectively. The true density of
these mixtures can also be determined according to the rule of mixing
[17], i.e.,
1
q
m

n
1
q
1

n
2
q
2
2
where
m
,
1
and
2
are the true densities of the mixture, the
constituent powders 1 and 2, respectively.
1
and
2
are the weight
fractions of the constituent powders 1 and 2. Using Eq. (2), the
calculated true densities for the mixtures of 80% MCC+20% lactose and
20% MCC+80% lactose are 1.579 g/cm
3
and 1.549 g/cm
3
, respectively. It
is clear that the measured and calculated true densities are com-
parable. For consistency with the studies on bilayer tablets, only the
calculated true densities were used in determining the relative
densities of the binary tablets. The same approaches as those used
for the single-component matrix tablets were employed to produce
binary tablets of 800 mg and to determine their relative densities and
tensile strengths.
Bilayer tablets of 800 mg were produced using two combinations
of MCC and lactose with the same mass fractions (i.e., 80% MCC+20%
lactose; 20% MCC+80% lactose) as used for producing binary tablets.
The rst layer of powder was manually poured into the 13 mm
evacuable pellet die and was gently tapped with a plunger so that a
at surface was created. Then the other powder was poured into the
die to create the second layer. The layered powder bed was then
compressed to a specied maximum compression force ranging from
3 kN to 18 kN followed by decompression, at the same speed of
0.083 mm/s. For each combination, the sequence to create the two
layers was altered, i.e., the powders used to formthe rst (bottom) and
second (top) layers were swapped, so that the effect of this on the
properties of the tablets can be investigated. Since Eq. (2) is
independent of the mixing state [17], it can also be used to determine
the true densities of the powder combinations. The packing density
was determined using the same method as single-component and
binary tablets. The diametric compression test was employed to
measure the apparent crush strength of bilayer tablets for the purpose
of comparative studies, bearing in mind the reservations expressed
above about the links between the results of this test and the true
tensile strength for bilayer tablets.
In order to explore the delamination mechanisms during manu-
facture of these tablets, bilayer tablets of different compositions and
compressed at different maximum compression pressure were
examined using XRCT, which has been widely used to visualize the
cracks or voids inside a sample [22,23]. In addition, the fracture
patterns of tablets crushed in the diametrical compression tests were
also examined using XRCT, aiming to investigate how the materials in
the matrix and bilayer tablets were fractured and how the failure
crossed the interface between the different layers. In this study, a
desktop high-resolution micro-CT system (Skyscan 1072, SkyScan,
Aartselaar, Belgium) was used to visualise the fracture patterns. Using
Fig. 4. X-ray tomographic images of a binary matrix tablet crushed by diametrical
compression showing the cross sections (a) parallel and (b) orthogonal to the crushing
axis.
Fig. 3. Fracturepatterns of binarymatrixtablets crushedbydiametrical compression, a) intact
binary tablet; b)d), binary tablets made with different maximum compression forces.
288 C.-Y. Wu, J.P.K. Seville / Powder Technology 189 (2009) 285294
this system, a spatial resolution of 10 m was achieved for the tablets
considered.
3. Results and discussion
3.1. Delamination phenomena for bilayer tablets
During the formation of the bilayer tablets of 20%MCC+80%lactose
with MCC as the bottom layer (MCC 1st), it was found that, at high
maximum compression forces (i.e., 18 kN), some tablets delaminate,
i.e., break into two layers. A typical photograph of delaminated tablets
is shown in Fig. 1a. Using XRCT, a detailed examination of the internal
microstructure of the bilayer tablets with this composition at different
maximum compression forces reveals that cracks are induced even at
a maximumcompression force as lowas 9 kN (Fig. 1b), although these
cracks do not form a continuous fracture surface that results in the
delamination as shown in Fig. 1a. At even lower maximum compres-
sion forces (say 3 kN), no cracks are detected (Fig. 1c), and nor is
delamination observed. It is also clear from Fig. 1b that the cracks are
not induced along the interface between the two materials, indicating
that delamination can occur outside the material interface in bilayer
tablets. Fig. 2 shows the X-ray tomographic images of the cross
sections parallel to the compression loading axis for bilayer tablets
with the same compositions but where the bottom layer is lactose
(lactose 1st). It can be seen that, at high maximumcompression forces,
cracks form an essentially continuous surface across the tablet
(Fig. 2a), implying that delamination is possible. Cracks can also be
clearly identied for the bilayer tablets produced at intermediate
values of maximum compression force (Fig. 2b). No visible crack is
detected by XRCT for the bilayer tablets produced at relatively low
maximum compression force (Fig. 2c). Similar phenomena are also
observed for the bilayer tablets made of 80%MCC+20%lactose.
3.2. Fracture patterns of tablets subjected to diametrical compression
When a matrix tablet is compressed diametrically, the loaded
diameter of the tablet experiences a transverse tensile stress as given
by Eq. (1), which is either uniform along the length of the diameter
Fig. 5. Fracture patterns for crushed bilayer tablets made of 80%MCC+20%lactose (MCC 1st) with different maximum compression forces.
289 C.-Y. Wu, J.P.K. Seville / Powder Technology 189 (2009) 285294
under conditions of ideal line loading if the contact area is very small
and can be treated as a point loading, or constant over most of the
loaded diameter in the centre, except for the regions near the loading
areas, for distributed loading over a nite contact area as generally
happens in laboratory testing [8]. Consequently, fracture usually
occurs along the loaded diameter as a result of the tensile stress acting
normal to that diameter. Fig. 3 shows the appearance of the tablet
surfaces after they are compressed diametrically until failure takes
place, illustrating fracture patterns of binary matrix tablets after the
diametrical compression tests. It is clear that the fracture is in the
normal tensile failure mode, with a crack along the loaded diameter,
which can result in the splitting of the tablets into two halves [8]. The
fracture patterns (crack distribution) inside the binary matrix tablets
were again examined using XRCT. Fig. 4 shows typical XRCT images of
the crushed tablets, in which Fig. 4a shows the cross section parallel to
the crushing axis while Fig. 4b shows the cross section orthogonal to
the crushing axis. It can be seen that there is a single fracture surface
that traverse the loaded diameter and goes fromthe top to the bottom
surfaces of the tablet. The kink of the fracture surface shown in Fig. 4b
is believed to be a consequence of the non-homogeneous structure of
compressed tablets.
The fracture patterns for bilayer tablets considered are shown in
Figs. 58. In these gures, only cross sections orthogonal to the
crushing axis are shown, while the appearance of the cracks in the
cross section parallel to the loading axis is similar to that shown in
Fig. 4a. Figs. 58 illustrate that the fracture patterns for bilayer tablets
depend upon the compositions and the manufacturing procedures.
For the tablets made of 80%MCC+20%lactose (Figs. 5 and 6), the
fracture surface is continuous and passes through the material
interface without deviation in direction. Horizontal branches of
crack near the material interface, which is localized in the tablet
centre, can clearly be seen inside the tablets made at high
compression forces (Figs. 5a and 6a,b). This is a different case from
that of the cracks leading to delamination as shown in Figs. 1 and 2,
which appear to initiate at the circumference of the tablets. It is likely
that the horizontal crack branches seen in Figs. 5 and 6 are a result of
the incompliance in elastic deformation of the two layers under
diametrical compression. For the tablets made of 20%MCC+80%
Fig. 6. Fracture patterns for crushed bilayer tablets made of 80%MCC+20%lactose (lactose 1st) with different maximum compression forces.
290 C.-Y. Wu, J.P.K. Seville / Powder Technology 189 (2009) 285294
lactose (Figs. 7 and 8), fracture appears to occur only in the layer of
lactose and no through-thickness fracture surface as shown in Figs. 5
and 6 is observed. Comparing Figs. 7 and 8, it is clear that more
signicant fracture is induced when MCC is the bottom layer (MCC
1st) than when it is compressed as the top layer (lactose 1st). This is
due to the difference in relative density of different layers caused by
non-uniform distribution of compression pressure during uni-axial
compressions [22].
3.3. Apparent crush strength of binary and bilayer tablets
The variation of tensile strength with relative density for single-
component MCC and lactose tablets is shown in Fig. 9. It can be seen
that, at the same relative density, MCC tablets have a much higher
tensile strength than lactose tablets. It is also clear that the logarithm
of the tensile strength is proportional to the relative density. This is
consistent with the results for a range of porous materials reported in
the literature [16,17,2430]. Ryshkewitch [24] and Duckworth [25]
proposed an empirical equation, which is generally referred to as the
RyshkewitchDuckworth equation, for the correlation of tensile
strength with the relative density:
ln
r
t
r4

k D 1 3
where D is the relative density of the powder compact,

is the
tensile strength of the materials with zero porosity (D=1) and k is a
material constant representing the bonding capacity. The parameters

and k can be determined by tting the experimental data.

According to the principle of least squares, the experimental data
presented in Fig. 9 were tted using Eq. (3), which leads to

=29.96 MPa and k=7.6 for the MCC powder, and

=2.80 MPa
and k=14.8 for the lactose powder. The tted lines are also super-
imposed in Fig. 9.
Wu et al. [16,17] have developed a predictive approach for the
tensile strength of powder mixtures, which is based on the
RyshkewitchDuckworth equation. Using parameters associated
Fig. 7. Fracture patterns for crushed bilayer tablets made of 20%MCC+80%lactose (MCC 1st) with different maximum compression forces.
291 C.-Y. Wu, J.P.K. Seville / Powder Technology 189 (2009) 285294
with the properties of individual components, the model gives the
tensile strength of mixtures as a function of the relative density as
ln r
tm
D
m
1
X
n
1
k
i
1
i
ln
X
n
1
r
i
4
1
i
!
4
where subscripts m and i denote the mixture and the individual
component i (=1,n), n is the number of total components and
i
represents the volume fraction of the constituent powder i. It has been
shown that Eq. (4) can well predict the tensile strength of binary
mixtures of MCC and starch, MCC and hydroxypropylmethyl cellulose
(HPMC) [16], MCC and lactose as reported in Tye et al. [30]; ternary
mixtures of MCC, HPMC and starch, and of MCC, HPMC and lactose;
and the four-component mixture of MCC, HPMC, starch and lactose
[17].
Fig. 10 shows the variation of apparent crush strength with relative
density for binary tablets consisting of MCC and lactose at two
different compositions. In this gure, the apparent crush strength for
bilayer tablets made of same combinations determined using the
diametrical compression test is also presented. It can be seen that, for
the tablets with higher concentration of MCC (i.e., 80%MCC+20%
lactose), the data for binary tablets, and bilayer tablets with either
MCC or lactose as the bottom layer (MCC 1st or lactose 1st) coalesce
into a single curve. For the tablets with lower concentration of MCC
(i.e., 20%MCC+80% lactose), the apparent crush strength for the binary
tablets and the bilayer tablets with MCC as the bottomlayer (MCC 1st)
Fig. 8. Fracture patterns for crushed bilayer tablet made of 20%MCC+80%lactose (lactose 1st) with different maximum compression forces.
Fig. 9. The variation of tensile strength with relative density for single-component MCC
and lactose tablets.
292 C.-Y. Wu, J.P.K. Seville / Powder Technology 189 (2009) 285294
are very close. Compared with these two cases, the bilayer tablets with
MCC as the top layer (Lactose 1st) have a noticeably higher apparent
crush strength. This is due to the fact that the thin MCC layer at the top
has been compressed to a higher density due to the pressure gradients
induced as a result of the die wall friction during single-ended uniaxial
compression [22] and this highly compressed MCC layer determines
the overall response during the diametrical compression of this type
of tablet. Consequently a higher crushing load is achieved and a higher
apparent crushing strength is obtained. In Fig. 10 the predictions given
by Eq. (4) are also superimposed. It is clear that Eq. (4) can well predict
the tensile strength for the binary tablets considered.
It is clear from Figs. 9 and 10 that the tensile strength of
pharmaceutical tablets depends strongly on the relative density or,
equivalently, the porosity. For a given compaction speed, different
relative densities can be obtained by varying the maximum compres-
sion pressure. Fig. 11 shows the variation of relative density with
maximum compression pressure for binary and bilayer tablets with
different compositions. It is clear that, for all cases considered, the
relative density increases with maximumcompression pressure but at
a decreasing rate. It is interesting to note that for the powder mixtures
with different compositions the relative densities of the binary and
bilayer tablets are essentially identical when the maximum compres-
sionpressure is high (say N120 MPa), while the difference between the
relative densities of powder compacts with different compositions
increases as the maximum compression pressure decreases. For a
given composition, the relative densities for binary and bilayer tablets
are very close at low maximum compression pressure, while at high
maximum compression pressure, the relative densities of bilayer
tablets are generally lower that those of binary mixtures.
4. Conclusions
The compaction behaviour of binary mixtures and bilayer tablets of
two common pharmaceutical excipients, MCC and lactose, was
experimentally investigated. The effects of compositions and compac-
tion pressure on the compaction behaviour of binary mixtures and
bilayer tablets were examined. X-raycomputedtomography was usedto
examine the delaminationand fracture patterns of the produced tablets.
It has been found that, for the bilayer tablets with different composi-
tions, delamination or horizontal branches of cracks that may lead to
delamination occur when the tablet is compressed with a high
maximum compression force. Under the diametrical compression,
tensile failure is the dominant failure mode for all the tablets
investigated, and the fracture patterns depend upon the compositions
and the processing conditions. A single fracture surface passing through
the material interface undeviated was induced for bilayer tablets of 80%
MCC+20%lactose, while more complicated fracture patterns were
observed for the bilayer tablets of 20%MCC+80%lactose, for which the
failure was found to concentrate in the lactose layer. More severe
fracture was observedwhenthe lactose was compressed as the toplayer
than when lactose was the bottom layer. The mechanical properties of
binary and bilayer tablets of the same compositions were also
determined and compared. It has been shown that for binary and
bilayer tablets with the same compositions, the apparent crush
strengths measured from diametrical compression tests were generally
comparable for the powders considered in this study, although a
noticeably higher apparent crush strength were obtained for the bilayer
tablets of 20%MCC+80%lactose with MCC as the top layer, when
compared to the tablets made of the same compositions. It was also
foundthat, usingthesamecompactionprocess withthesamemaximum
compression pressure, the relative densities of the tablets were
generally different when different compositions were used.
References
[1] J. Inman, B.J. Briscoe, K.G. Pitt, Determination of the critical stress intensity factor
(K
IC
) for Microcrystalline Cellulose (MCC) using a developed tensile stress method
and its application to double-layer tablets, Proceedings of the 5th World Congress
on Particle Technology, Orlando, USA, 2005.
[2] H. Choi, C. Yong, C. Kim, Development of terfenadinepseudoephedrine double
layer tablet dissolution-equivalent to core tablet, Drug Dev. Ind. Pharm. 26 (2000)
605611.
[3] L. Maggi, E.O. Machiste, M.L. Torre, U. Conte, Formulation of biphasic release tablets
containing slightly soluble drugs, Euro. J. Pharm. BioPharm. 48 (1999) 3742.
[4] C.R. Park, D.L. Munday, Development and evaluation of a biphasic buccal adhesive
tablet for nicotine replacement therapy, Int. J. Pharm. 237 (2002) 215226.
[5] L. Yang, G. Venkatesh, R. Fassihi, Compaction simulator study of a novel triple-layer
tablet matrix for industrial tabletting, Int. J. Pharm. 152 (1997) 4552.
[6] U. Conte, L. Maggi, P. Columbo, A. La Manan, Multi-layered hydrophilic matrices as
constant release devices (Geomatrix

Systems), J. Control. Release 26 (1993)

3947.
[7] S. Abdul, S.S. Poddar, A exible technology for modied release of drugs: multi
layered tablets, J. Control. Release 97 (2004) 393405.
[8] J.T. Fell, J.M. Newton, Determination of tablet strength by the diametrical
compression test, J. Pharm. Sci. 59 (1970) 688691.
[9] I. Nikolakakis, N. Pilpel, Effects of particle shape and size on the tensile strengths of
powders, Powder Technol. 56 (1988) 95103.
[10] T. Sebhatu, G. Alderborn, Relationships between the effective interparticulate
contact area and the tensile strength of tablets of amorphous and crystalline
lactose of varying particle size, Eur. J. Pharm. Sci. 8 (1999) 235242.
[11] S.Y. Chan, N. Pilpel, D.C.-H. Cheng, The tensile strengths of single powders and
binary mixtures, Powder Technol. 34 (1983) 173189.
[12] A.B. Bangudu, N. Pilpel, Tensile strength of paracetamol and avicel powders and
their mixtures, J. Pharm. Pharmacol. 36 (1984) 717722.
[13] M. Kuentz, H. Leuenberger, A new theoretical approach to tablet strength of a
binary mixture consisting of a well and a poorly compactable substance, Eur. J.
Pharm. Biopharm. 49 (2000) 151159.
Fig. 11. The variation of relative density with maximumcompression pressure for binary
and bilayer tablets.
Fig. 10. The variation of apparent crush strength with relative density for binary and
bilayer tablets.
293 C.-Y. Wu, J.P.K. Seville / Powder Technology 189 (2009) 285294
[14] N. Ramrez, L.M. Melgoza, M. Kuentz, H. Sandoval, I. Caraballo, Comparison of
different mathematical models for the tensile strengthrelative density proles of
binary tablets, Eur. J. Pharm. Sci. 22 (2004) 1923.
[15] D.C.-H. Cheng, The tensile strength of powders, Chem. Eng. Sci. 23 (1968)
14051420.
[16] C.Y. Wu, S.M. Best, A.C. Bentham, B.C. Hancock, W. Boneld, A simple predictive
model for the tensile strength of binary tablets, Eur. J. Pharm. Sci. 25 (2005)
331336.
[17] C.Y. Wu, S.M. Best, A.C. Bentham, B.C. Hancock, W. Boneld, Predicting the tensile
strength of compacted multi-component mixtures of pharmaceutical powders,
Pharm. Res. 23 (2006) 18981905.
[18] H. Mohammed, B.J. Briscoe, K.G. Pitt, A study on the coherence of compacted
binary composites of microcrystalline cellulose and paracetamol, Euro. J. Pharm.
BioPharm. 63 (2006) 1925.
[19] A. Michrafy, M. Michrafy, M.S. Kadiri, J.A. Dodds, Predictions of tensile strength of
binary tablets using linear and power law mixing rules, Int. J. Pharm. 333 (2007)
118126.
[20] P. Dietrich, A. Bauer-Brandl, R. Schubert, Inuence of tabletting forces and
lubricant concentration on the adhesion strength in complex layer tablets, Drug
Dev. Ind. Pharm. 26 (2000) 745754.
[21] F. Podczeck, K.R. Drake, J.M. Newton, I. Haririan, The strength of bilayer tablets, Eur.
J. Pharm. Sci. 29 (2006) 361366.
[22] C.Y. Wu, O. Ruddy, A.C. Bentham, B.C. Hancock, S.M. Best, J.A. Elliott, Modelling the
mechanical behaviour of pharmaceutical powders during compaction, Powder
Technol. 152 (2005) 107117.
[23] C.Y. Wu, A.C. Bentham, A. Mills, Analysis of failure mechanisms during powder
compaction, Mat. Sci. Forum 534536 (2007) 237240.
[24] E. Ryshkewitch, Compression strength of porous sintered alumina and zirconia,
J. Am. Ceram. Soc. 36 (1953) 6568.
[25] W. Duckworth, Discussion of Ryshkewitch paper, J. Am. Ceram. Soc. 36 (1953) 68.
[26] R. Steendam, C.F. Lerk, Poly(-lactic acid) as a direct compression excipient in
controlled release tablets: Part I. Compaction behaviour and release characteristics
of poly(-lactic acid) matrix tablets, Int. J. Pharm. 175 (1998) 3346.
[27] J.E. Barralet, T. Gaunt, A.J. Wright, I.R. Gibson, J.C. Knowles, Effect of porosity
reduction by compaction on compressive strength and microstructure of calcium
phosphate cement, J. Biomed. Mater. Res. 63 (2002) 19.
[28] U. Gbureck, O. Grolms, J.E. Barralet, L.M. Grover, R. Thull, Mechanical activation and
cement formation of -tricalcium phosphate, Biomaterials 24 (2003) 41234131.
[29] H.S. Shin, S.K. Lee, B.K. Lee, Aggregate and necking force in MnZn ferrite, Mater.
Lett. 57 (2003) 14671470.
[30] C.K. Tye, C. Sun, G.E. Amindon, Evaluation of the effects of tabletting speed on the
relationships between compaction pressure, tablet tensile strength, and tablet
solid fraction, J. Pharm. Sci. 94 (2005) 465472.
294 C.-Y. Wu, J.P.K. Seville / Powder Technology 189 (2009) 285294