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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.

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)

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.

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

<325

mesh,

1.2

mm,

SSA

5.055 m

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.

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.

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

4.68) than SiO

(2.0

0.68) and is thus much

more hydrophobic than SiO

. The contact angle of

physical mixtures, containing up to 20% PVP, is only

slightly higher than that of SiO

(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

0.848, suggesting the coverage of

a majority of SiO

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

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

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.

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

1.2 GPa) wrapping the

hard SiO

core (E

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

cores

touch each other and deform elastically until the

system reaches force equilibrium (Fig. 3c). The strain

of SiO

particles needs not to be high at this point

because of the high-elastic modulus of SiO

. Under

the peak compaction pressure, the powder bed is

consisted of two interwoven continuous three-dimen-

sional networks of SiO

and PVP. During the

decompression process, where compaction pressure

decreases from a peak value to zero, SiO

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

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

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.

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

as expected from the much

higher elastic modulus of SiO

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

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

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

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.

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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