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Transforming Powder Mechanical Properties by Core/Shell
Structure: Compressible Sand
LIMIN SHI, CHANGQUAN CALVIN SUN
Pharmaceutical Materials Science and Engineering Laboratory, Department of Pharmaceutics, College of Pharmacy, University of
Minnesota, 9-127B Weaver-Densford Hall, 308 Harvard street S.E., Minneapolis, Minnesota 55455
Received 24 February 2010; accepted 10 March 2010
Published online 23 April 2010 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.22172
ABSTRACT:
Some active pharmaceutical ingredients possess poor mechanical properties and
are not suitable for tableting. Using fine sand (silicon dioxide), we show that a core/shell
structure, where a core particle (sand) is coated with a thin layer of polyvinylpyrrolidone
(PVP), can profoundly improve powder compaction properties. Sand coated with 5% PVP could
be compressed into intact tablets. Under a given compaction pressure, tablet tensile strength
increases dramatically with the amount of coating. This is in sharp contrast to poor compaction
properties of physical mixtures, where intact tablets cannot be made when PVP content is 20% or
less. The profoundly improved tabletability of core/shell particles is attributed to the formation
of a continuous three-dimensional bonding network in the tablet.
ß
2010 Wiley-Liss, Inc. and the
American Pharmacists Association J Pharm Sci 99:4458–4462, 2010
Keywords:
core/shell particles; tabletability; percolation; silica; PVP; particle engineering
Control of powder mechanical properties for desired
functionalities is an on-going central challenge in
materials science and engineering. This is especially
important in delivering drugs with the tablet
dosage form because mechanical properties dictate
the success or failure of tableting.
1–3
Some active
pharmaceutical ingredients (APIs), including aceta-
minophen, phenacitin, and ascorbic acid, possess poor
mechanical properties and are not suitable for direct
tableting.
4–7
Tableting problems caused by poor
mechanical properties of the APIs have been tradi-
tionally dealt with by using excipients to correct
deficiencies in tableting properties of API. This
approach however is not always effective when the
tablet contains more than 20% API that is poorly
compressible. The use of a large amount of excipients
may also lead to unexpected drug instability, larger
tablet size, and increased manufacturing costs. More
recently, crystal engineering has emerged as a
promising approach (e.g., by forming salts, hydrates,
and cocrystals), to prepare functional pharmaceutical
materials with improved mechanical properties.
8–14
This approach, although useful, is not ideal because
deficient mechanical properties are typically revealed
during an advanced stage of drug development. At
this point, it is time and resource prohibitive to
Correspondence to:
Changquan Calvin Sun (Telephone: 612-
624-3722; Fax: 612-626-2125; E-mail: sunx0053@umn.edu)
Journal of Pharmaceutical Sciences, Vol. 99, 4458–4462 (2010)
ß
2010 Wiley-Liss, Inc. and the American Pharmacists Association
change the solid form for the sake of improved
tableting performance. Moreover, it is not always
possible to obtain a new solid form with satisfactory
mechanical properties because of the finite number of
solid forms for each API. Consequently, formulation
scientists are often forced to struggle with challenges
from poor API mechanical properties, a leading cause
of failure in development and manufacturing of tablet
products.
15
Recently, core/shell particles have received signifi-
cant attention due to their versatile functionalities
and potential industrial applications.
16–18
Here, we
show that the formation of polymer-coated API core/
shell particles can profoundly improve powder
tableting performance. Because of the availability
of many pharmaceutically acceptable polymers for
forming the shell and the many mature coating
techniques to prepare core/shell particles, this novel
engineering strategy can be a universal solution to
most tableting problems related to the poor mechan-
ical properties of API. This strategy is highly effective
and its implementation is not restricted to an early
stage of development, which is a problem for crystal
structure engineering. In this study, we selected fine
sand (SiO
2
,
<325
mesh,
d
50
¼
1.2
mm,
SSA
¼
5.055 m
2
/
g; Sigma–Aldrich Inc, St. Louis, MO) as a model
compound because of its extremely poor tableting
performance.
Polyvinylpyrrolidone (PVP, K30, ISP Technologies
Inc. Wayne, NJ) was employed for forming the shell.
Distilled water and acetone (AR-ACS reagent grade;
4458
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 11, NOVEMBER 2010
TRANSFORMING POWDER MECHANICAL PROPERTIES
4459
Mallickrodt Baker Inc, Phillipsburg, NJ) were used
as solvent and anti-solvent, respectively. Precisely
weighed fine sand was added to an appropriate
volume of PVP aqueous solution (10% w/w) to form a
suspension, which was stirred by a magnetic stirring
bar. Acetone, six times the volume of water, was
then added to the suspension drop-wise using a
peristaltic pump. The precipitant was filtered and
washed with acetone for five times and then dried
overnight at 608C in a vacuum oven. Residual solvent
was negligible (<0.3% by thermogravimetry). A
material testing machine (model 1485; Zwick/Roell,
Kennesaw, GA) equipped with a 200 kN load cell was
used to prepare tablets at a loading rate of 1 mm/s.
Prior to each compaction, tablet die and punches
were lubricated with a suspension of magnesium
stearate in ethanol (5% w/v) and air dried. The peak
compaction pressure was varied from 50 to 400 MPa
to prepare tablets (8 mm in diameter, approximately
200 mg). The loading platen was withdrawn imme-
diately after the peak pressure is reached at the
same rate. Elastic recovery was determined from
the in die thickness at peak pressure and after
pressure removal.
19
Tablets were relaxed in a
desiccator for at least 8 h before the measurement
of their diametrical breaking strength using a texture
analyzer (TA-XT2i; Texture Technologies Corp.,
Scarsdale, NY) equipped with a 30 kg load cell, which
was used to calculate tensile strength.
20
Static water
contact angle was measured using the sessile drop
technique on a contact angle goniometer (Model G10,
Kruss, Hamburg, Germany) at room temperature.
Sample surface for contact angle measurement was
prepared by: (1) first placing powder on a double-sided
adhesive tape attached to a glass slide; and (2)
covering the powder with a glass slide and compres-
sing it by hand to form a visually dense and flat
surface.
PVP exhibits a much higher water contact angle
(71.4
Æ
4.68) than SiO
2
(2.0
Æ
0.68) and is thus much
more hydrophobic than SiO
2
. The contact angle of
physical mixtures, containing up to 20% PVP, is only
slightly higher than that of SiO
2
(Fig. 1). On the other
hand, core/shell powders exhibit a significantly higher
contact angle than the corresponding physical mixtures
(Fig. 1). With only 5% PVP, the contact angle of core/
shell powders is 36.3
Æ
0.848, suggesting the coverage of
a majority of SiO
2
surface by PVP. The contact angle of
core/shell particles rapidly approaches that of pure PVP
with increasing PVP content. In particular, the water
contact angle is 70.4
Æ
2.78 when the PVP level is 20%.
These results confirm that the powder surface proper-
ties have been significantly modified and are consistent
with the expected behavior of core/shell structure.
21–23
The presence of a polymer layer on silica surface is also
confirmed by SEM—Energy Dispersive Spectroscopy
technique.
DOI 10.1002/jps
Figure 1.
Effect of PVP content on water contact angle of
(a) core/shell powders and (b) physical mixtures.
Intact tablets without capping or lamination
could not be formed under any pressure for PVP/
SiO
2
physical mixtures containing 20% or less PVP
(prepared by bottle mixing). These results confirm the
commonly observed ineffectiveness of adding tablet
binder to improve tableting performance of a poorly
compressible drug, a standard practice in pharma-
ceutical industry. Intact tablets could be made from
the physical mixture only if 40% or more PVP is
present. However, 60% or more PVP is required for
achieving acceptable tablet strength of 2 MPa, a
criterion for acceptable tabletability.
24
In contrast, intact tablets could be made from core/
shell powders containing only 5% PVP (Fig. 2a). The
tabletability of core/shell powders increases sharply
with increasing PVP content (Fig. 2a). Strong tablets
(>2 MPa) could be made from the core/shell powder
containing 15% PVP (Fig. 2a and b).
The key feature responsible for the superior
tableting performance of core/shell powders is the
surface layer of soft PVP (E
¼
1.2 GPa) wrapping the
hard SiO
2
core (E
¼
70 GPa; Fig. 3b).
25,26
The thick-
ness of the shell is proportional to amount of PVP
and is calculated to be 16 nm for 10% PVP. During
compression, local stress at the contact points exceeds
the yield strength of PVP and plastic deformation of
PVP takes place. The plastic deformation of PVP
continues and at some point, neighboring SiO
2
cores
touch each other and deform elastically until the
system reaches force equilibrium (Fig. 3c). The strain
of SiO
2
particles needs not to be high at this point
because of the high-elastic modulus of SiO
2
. Under
the peak compaction pressure, the powder bed is
consisted of two interwoven continuous three-dimen-
sional networks of SiO
2
and PVP. During the
decompression process, where compaction pressure
decreases from a peak value to zero, SiO
2
particles
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 11, NOVEMBER 2010
4460
SHI AND SUN
Figure 2.
Tableting properties of core/shell powders in
comparison to physical mixtures. a: Tensile strength of
tablets, compressed at 250 MPa, as a function of PVP con-
tent. b: Tablet tensile strength as a function of compaction
pressure. Physical mixtures containing 15% PVP do not
form intact tablets under any pressure. The dashed line
indicates the desired minimum tablet strength.
undergo elastic recovery. However, the three-dimen-
sional bonding network of PVP is preserved because
PVP can undergo plastic deformation to accommodate
the recovery of SiO
2
particles (Fig. 3d). Therefore, an
intact dense tablet is obtained as a result (Fig. 3e).
In the powder bed of physical mixtures, PVP
particles are distributed in a discrete state (Fig. 3f).
At a lower PVP concentration, tablet bonding network
is compromised because of the presence of pockets of
nonbonding SiO
2
particles, which form as macro
defects (Fig. 3g and h) and leads to the failure of
tablets, such as capping (Fig. 3i) or lamination
(Fig. 3j) after being ejected out of the die. Intact
tablets cannot be prepared until the PVP concentra-
tion reaches approximately 40%. The presence of a
critical concentration of PVP in tablet formation is
predictable based on the percolation theory. In this
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 11, NOVEMBER 2010
mixture system, tablet with appreciable strength can
be formed only when the bonding PVP particles form
a network that spans the entire tablet.
27
This
mechanism also explains why simply mixing a poorly
compressible API with a binder is inefficient to
improve powder tabletability. In contrast, the pre-
sence of PVP shell circumvents the need of bond
percolation and can readily form a continuous
bonding network in the entire tablet.
The proposed model in Figure 3 is supported by the
different elastic behavior of the physical mixture and
core/shell powders. Elastic recovery of PVP is slightly
higher than that of SiO
2
as expected from the much
higher elastic modulus of SiO
2
than that of PVP. For
both physical mixtures and core/shell powders, elastic
recovery increases slightly with increasing compac-
tion pressure (Fig. 4). Increasing amount of PVP
causes increased elastic recovery of physical mixtures
but opposite effect for core/shell powders (Fig. 4). This
observation, although not expected initially, can be
well explained using the model described in Figure 3.
For physical mixtures, the replacement of more silica
particles with PVP naturally leads to reduced
E
of the
tablet of composite powder and thus higher elastic
recovery under the same compaction pressure. For
core/shell powders, more PVP corresponds to thicker
polymer layer. Under sufficiently high compaction
pressure, plastic PVP are squeezed out of the contact
zone between adjacent particles and silica particles
will touch each other. More PVP will be surrounding
each silica–silica contact point when initial PVP layer
is thicker. Consequently, the apparent
E
of the tablet
is higher because of the larger silica-PVP contact
area. The larger contact area will also lead to lower
average stress at each contact point when the force is
the same. A result of the higher
E
and lower local
stress is a reduced elastic recovery with increasing
PVP (Fig. 4). For the same reason, elastic recovery of
core/shell powders is significantly lower than that of
physical mixtures (Fig. 4). For example, at 200 MPa
and 20% PVP, the elastic recoveries are 3.1% and
6.7% for core/shell powders and physical mixtures,
respectively. A lower elastic recovery improves
powder tabletability by alleviating the problems of
capping and lamination. The relative standard
deviation of the elastic recovery for core/shell powders
is also significantly lower than that of the correspond-
ing physical mixtures (Fig. 4). For example, at
200 MPa and 15% PVP, the relative standard devia-
tions of elastic recovery of core/shell powders and
physical mixtures are 3.50% and 6.49%, respectively.
This is again consistent with the more homogeneous
distribution of PVP in tablet made from the core/shell
powders. The proposed model also explains an early
observation where glass beads exhibited much
improved compaction properties after wet granula-
tion with polymers.
28
DOI 10.1002/jps
TRANSFORMING POWDER MECHANICAL PROPERTIES
4461
Figure 3.
Evolution of bonding network in a tablet by compaction for a core/shell
powder and a physical mixture. (a) Poorly compressible powder, (b) core/shell powder, (c)
core/shell powder under compaction pressure, (d) core/shell powder after decompression,
(e) intact tablet, (f) physical mixture, (g) physical mixture under compaction pressure,
(h) physical mixture after decompression, (i) capped tablet, and (j) laminated tablets. A
continuous three-dimensional bonding network is a prerequisite for tablets of high
strength.
In summary, we have demonstrated that a binder
shell can profoundly improve the tableting properties
of poorly compressible powders. This is understood
based on the reduced elastic recovery and the
generation of a three-dimensional bonding network
in the tablet by compaction. The strategy of engineer-
ing powder mechanical properties by forming a core/
shell structure holds promise to offer a universal
solution to common tableting problems that are
important to pharmaceutical and related industry.
ACKNOWLEDGMENTS
Parts of this work were carried out in the Institute of
Technology Characterization Facility, University of
Minnesota, a member of the NSF-funded Materials
Research Facilities Network (www.mrfn.org). We
thank Mr. Wieslaw J. Suszynski for technical assis-
tance with contact angle goniometry.
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