Improving Powder Flow Properties of a Cohesive Lactose

Monohydrate Powder by Intensive Mechanical Dry Coating

QI ZHOU,1 BRIAN ARMSTRONG,2 IAN LARSON,1 PETER J. STEWART,1 DAVID A.V. MORTON1
1
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University,
381 Royal Parade, Parkville, Vic. 3052, Australia
2
Freeman Technology, Malvern, Worcestershire, UK

Received 13 February 2009; revised 29 May 2009; accepted 29 June 2009

Published online 30 September 2009 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21885

ABSTRACT: The objective of this study was to improve the cohesive lactose powder
flowability. A cohesive lactose monohydrate powder was processed in either a tumbling
blender or an intensive mechanical processor with either magnesium stearate or fumed
silica. No substantial changes in particle size were detected by laser diffraction following
either treatment. The untreated lactose sample exhibited very poor powder flow. Only
limited improvements in powder flowability were indicated after the tumbling blending,
intensive mechanical processing with the fumed silica or without additives. However,
the intensive mechanical processing of the lactose sample with magnesium stearate
demonstrated exceptionally large increases in both poured and tapped density as well as
notable improvements in all powder flowability indicators examined. Our findings
support the use of intensive mechanical processing technique as an effective method
to coat cohesive pharmaceutical powders with selected additives, modify the surface
nature of the particles, reduce the interparticle cohesive forces and hence improve
powder flowability. The subtle differences in powder flow behaviour of lactose samples
between the untreated and tumbling blended powders with magnesium stearate were
only detected by the powder rheometer using its dynamic mode, indicating its potential
advantages over traditional powder flow characterisation approaches. ß 2009 Wiley-Liss,
Inc. and the American Pharmacists Association J Pharm Sci 99:969–981, 2010
Keywords: powder flow properties; cohesive pharmaceutical powder; lactose mono-
hydrate; magnesium stearate; fumed silica; intensive mechanical dry coating; powder
rheometry

INTRODUCTION powder flow behaviour remains a relatively

Particulate handling plays a fundamental
part in almost every industrial manufacturing
operation.1 Notably, powder flowability is highly
influential and often the major issue with parti-
culate handling and processing. Given this
importance, it is perhaps initially surprising that
Correspondence to: David A.V. Morton (Telephone: 61-3-
9903-9523; Fax: 61-3-9903-9583;
E-mail: david.morton@pharm.monash.edu.au)
Journal of Pharmaceutical Sciences, Vol. 99, 969–981 (2010)
ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association
poorly understood phenomenon.2 Indeed the
processing of fine pharmaceutical particulates
can be notoriously complex and challenging.
As widely observed, powders uniquely exhibit
mixtures of features otherwise associated with
either solids, gases or liquids in that, unlike
simple states of matter, powders can be made to
deform, they can be compressed and they can also
be made to flow.1,3 The significance of assessing
powder flow has been recognised by the recent
introduction and harmonisation of powder flow
characterisation in US and European Pharma-
copoeias as outlined recently by Copley.4

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010 969

970 ZHOU ET AL.
Perhaps the most important concept to appre-
ciate in this context is that powder flow behaviour
is an inherently complex multidimensional phe-
nomenon, as it depends on the state (or condition-
ing) of the powder as well as the environment
surrounding the powder.2 For example, the state
of the powder flow is strongly dependent on the
consolidation history and degree of aeration of
the powder or the geometry of the hopper/vessel
that powder is required to flow from.5 Hence, the
aspect of flowability to be understood will vary,
depending on whether the process objective is, for
example, control flow from a hopper, fill a tablet
die, flow into a mixer or mill, fluidise in a coater,
empty a sachet, or re-suspend a powder from an
inhaler.
The challenge of designing an optimum flow
‘quality’ is especially severe for cohesive powders
containing fine particulates, typically below
50 mm as the increased dominance of interparticle
forces at reduced particle sizes makes powders
increasingly cohesive.6,7 As a consequence, such
powders will exhibit poor flowability when gravi-
tational, mechanical and hydrodynamic forces are
applied. Unfortunately, many solid-based dosage
forms not only require satisfactory control of
powder conveying, but also require the powder to
be in a finely divided form. Thus, there is a broad
desire in pharmaceutical production to under-
stand, characterise and control fine-particulate
cohesive powder behaviour, especially in the
context of regulators seeking quality-by-design
and process analytical technology approaches to
processing.4
Several recent studies have examined issues of
fine-particulate cohesive pharmaceutical powder
flowability on tabletting8,9 and powder inhala-
tion.10,11 For example, the influence of particle
size distributions on powder flow has been
demonstrated recently.8
Clearly, the nature and extent of interparticle
forces provide a pivotal influence in flowability,
and for a given particle size, size distribution,
and shape (often inherent properties that are
difficult to change for a given system), particulate
surface properties become the dominant factor
determining bulk powder flow behaviours.
Consequently, there is considerable interest in
examining practical methods to modify the
surfaces of fine pharmaceutical powders in order
to improve powder flowability.7,12–14
Improvement in powder flow properties of
cohesive powders is often sought with the use of
flow-aid additives (lubricants or glidants). The
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
most commonly used flow aids are submicron
inorganic oxides, such as fumed silicas (FSs),
which reduce particle–particle adhesion and
friction, and are often termed antiblocking glidant
agents. Alternatively, fatty acid salts such as
magnesium stearate (MgSt) are well known and
proposed to behave as boundary lubricants. A
good boundary layer lubricant is said to be capable
of strong adsorption onto a surface to give a close
packed-oriented monolayer, with polar groups
strongly hydrogen bonded to the respective
surface. The fundamental principles of the
improvement of powder flowability by coating or
surface layering are not well understood. Further-
more, improving the flow of pharmaceutical
powders at or below about 20 mm to a manu-
facturing-satisfactory level remains a challenge.
Recently, it has been suggested that intensive
mechanical dry-coating approaches (previously
these have been referred to under a general term
‘mechanofusion’) provide a technique to give a
more uniform and hence more effective coating
than using conventional blending particularly for
cohesive powders.7
In this study, we report our initial investigation
aiming to optimise and assess the flow behaviour
of a model milled pharmaceutical powder,
a-lactose monohydrate with median particle
diameter approximately 20 mm, which appears
to be a relatively cohesive powder15 and is widely
used in pharmaceutical applications. This study
investigates a form of mechanofusion coproces-
sing of a model cohesive pharmaceutical powder,
comparing the outcomes of this approach
with conventional blending, and comparing tradi-
tional glidants and boundary lubricants flow-aid
additives. To support this comparison of coating
methods and different type of additives, we
describe both traditional and more recently
developed methodologies in our aim to character-
ise the complex nature of powder flow behaviour.
MATERIALS AND METHODS
Materials
a-Lactose monohydrate samples (Pharmatose1
450M) were kindly donated by DMV International
(Veghel, the Netherlands). Magnesium stearate
NF (MgSt) was supplied by Mallinckrodt Baker,
Inc. (Phillipsburg, NJ). FS, CAB-O-SIL1 M-5, was
supplied by Cabot Corporation (Boston, MA), and
propan-2-ol from Honeywell Burdick & Jackson
DOI 10.1002/jps
 IMPROVING COHESIVE LACTOSE POWDER FLOWABILITY
(Muskegon, MI). All samples were used as
received.
Intensive Mechanical Dry Coating
Processing of lactose samples with MgSt or FS
was carried out in a Nobilta-130 unit (Hosokawa
Micron Corporation, Osaka, Japan) mechano-
fusion system. Lactose samples (approximately
100 g) were combined with 1% (w/w) of either
additive or with no additives and poured into a
sealed process cell.
As the name ‘mechanofusion’ suggests, this dry
coating process is designed to mechanically coat
an additive material onto a host material.16
The Nobilta mechanofusion processor com-
prises a cylindrical vessel with a rotating axial
shaft with a series of alternating angled paddles
extending from the shaft. These paddles extend
along the length of the axial shaft, and extend out
to within approximately 1 mm of the vessel wall.
Consequently, as the shaft rotates, the blades
continuously sweep close to the vessel wall,
ensuring all the powder is in constant and violent
motion. Due to the high rotational speed of the
paddles, the powder is propelled towards the wall,
and as a result the mixture experiences very high
shear forces at the paddle face, and compressive
stresses between wall and paddle. The energy is
intended to be sufficient to break up agglomerates
of guest and host particles, but due to the fixed
geometry, and control of speed, it is believed that
the size reduction of host primary particles can be
minimised. In the case of additives such as MgSt,
the energy applied may be sufficient to locally
soften, distort, fragment and wrap the particles of
coating material around the host particles to form
a coating. There are some attempts which try to
simulate or model the coating process of mechan-
ofusion but the true mechanism is still not well
understood.17,18
In these experiments, the mechanofusion pro-
cess was carried out by slowly ramping up the
paddle speed to 5000 rpm over a period of 1 min
and maintained at that speed for 10 min. Cold
tap water (20
28C) circulation was applied
using an incorporated water jacket to maintain
the vessel temperature at 22
28C during the
mechanofusion process.
Conventional Blending
Blending of lactose with the same content of MgSt
or FS as in the mechanofusion studies was also
DOI 10.1002/jps
971
carried out using a conventional tumbling
Turbula1 T2F mixer (Glen Mills, Inc., Clifton,
NJ). Lactose samples (approximately 20 g) and
additives were weighed into a glass container, the
container was approximately a quarter full. The
container was then fixed in the mixer and tumbled
for 30 min at 72 rpm. This was considered a
lengthy mixing process in order to maximise
any coating effects.
Scanning Electron Microscopy
Morphological properties of lactose samples were
investigated using a scanning electron microscope
(SEM) (PhenomTM, FEI Company, Hillsboro, OR).
Each sample was slowly poured onto double-
side carbon black tape which was mounted on a
sample holder, and excess powder not adhered to
the tape was gently shaken off. Samples were
sputter coated with gold using an electrical
potential of 2.0 kV at 25 mA (SCD005, BAL-TEC
AG, Balzers, Germany). SEM micrographs were
taken using in-built image capture software.
Powder Densities and Carr Index
The poured density (rp) was measured by pouring
samples slowly into a 10 mL calibrated measuring
cylinder through a funnel at a fixed height
above the cylinder. The tapped density (rt) was
determined after 1250 taps using an automatic
tapper (AUTOTAPTM, Quantachrome Instru-
ments, Boynton Beach, FL). The tapper operated
with a 3.18 mm vertical travel at a tapping speed
of 260 tap/min. Four replicates were carried out
for each measurement and results averaged.
The Carr index (CI)19 and Hausner ratio (HR)20
were calculated from poured density and tapped
density using Eqs. (1) and (2), respectively,
rt  rp
CI ¼ (1)
rt
rt
HR ¼ (2)
rp
Particle Size Analysis
Particle size distributions of both original and
processed powder samples were measured by
laser diffraction (Mastersizer1 S, Malvern Instru-
ments, Worcestershire, UK) using the 300 RF lens
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
972 ZHOU ET AL.
equipped with a small volume sample presenta-
tion unit (capacity 150 mL). Approximately
500 mg of lactose powder was sonicated in
20 mL of propan-2-ol in a water bath for 3 min
prior to measurement (as previously validated).21
Particle size analysis of each sample was calcu-
lated with the reference refractive index of lactose
(1.533) and propan-2-ol (1.378).21 The volume
median diameter (VMD), d10 (diameter at 10%
undersize), d90 (diameter at 90% undersize) and
span (the difference between the diameter at 90%
undersize and the diameter at 10% undersize,
divided by the VMD) were calculated from four
replicates of each sample.
Angle of Repose
The angle of repose (AOR) was measured as an
indicator of powder flow. The measurement
was carried out according to USP guidance
(USP 31-NF 26). A sample of approximately 50 g
was continuously fed through a sieve (850 mm
aperture size) and a glass funnel (diameter ¼
10 cm; length ¼ 10 cm; stem diameter ¼ 1 cm), to
form a balanced cone on the top of circular flat
surface (diameter ¼ 5 cm) of a cylindrical stand.
The height of the glass funnel was adjusted to
stay 2 cm above the top of the cone in order to
standardise the impact of falling powder on the
tip of the cone. The AOR was defined as the
angle between the sides of the cone formed and
the horizontal:
2h
tan a ¼
R
Figure 1. Diagram of the powder rheometer in the operation modes of (a) dynamic
mode, (b) compressibility mode and (c) shear mode.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
where a is the AOR, h is the height and R is the
diameter of the formed cone. Four readings for
each sample were obtained and results were
averaged.
Powder Rheometry and Interparticle Interaction
Powder flow behaviours, represented by their
rheological and shear properties, were charac-
terised using the Freeman FT4 powder rheometer
(Freeman Technology, Worcestershire, UK).
Briefly, the FT4 powder rheometer enables
measuring their dynamic, shear and bulk proper-
ties in one system using a range of attachments
while axial and rotational forces are measured. A
number of control/measurement modes are avail-
able including position, velocity, force and torque.
A more detailed description of the testing proce-
dures can be found elsewhere.22 In this study,
three modes (dynamic, compressibility and shear
modes) of the FT4 powder rheometer were used to
evaluate the powder flow properties and the
interparticle interactions.
In the dynamic mode, a blade with a diameter
of 23.5 mm was traversed through the 25 mL
samples in a 25 mm diameter glass vessel with a
blade tip speed of 100 mm/s and a helix angle of
58 (Fig. 1a). The energy required to move the
blade through the powder during an upward
traverse was defined as specific energy (SE). A
higher SE value generally represents poorer
powder flow.22 The conditioning cycles in which
a blade moves upwards to lift the samples with a
gentle shear were used to minimise or standardise
(3)
DOI 10.1002/jps
 IMPROVING COHESIVE LACTOSE POWDER FLOWABILITY
the influence of the stress history on the
measurement.
In the compressibility mode, a piston replaced
the blade and compressed the sample powders
under normal stress of 1, 2, 4, 6, 8, 10, 12 and
15 kPa (Fig. 1b). The compressibility is defined as
the change (in percentage) of the volume for the
sample powder under a given normal stress.
In the shear mode, a shear head was attached to
the powder rheometer and shear stress was
measured with respect to the normal stress for
a given consolidating stress (Fig. 1c). A fuller
description of the principles of shear cell testing
was described by Schwedes.23 For this applica-
tion, a consolidating stress of 9 kPa was applied to
the powder bed prior to each test. Shear tests were
then carried out at normal stresses of 7, 6, 5, 4 and
3 kPa. The shear stress at each normal stress was
recorded and yield loci were plotted. The cohesion
of each sample was evaluated as the shear stress
at zero normal stress by extrapolating the yield
loci. A higher cohesion value corresponds to
higher cohesive interparticle forces and hence
a more cohesive powder. From the yield loci,
standard Mohrs circle constructions provide
the unconfined yield strength (sc) and major
principle stress (s1). Flow function (ff) is defined
as the ratio of major principle stress to the
unconfined yield strength and used as an indi-
cator of powder flowability, that is, ff < 1, ‘Not
flowing’; 1 < ff < 2, ‘Very cohesive’; 2 < ff < 4,
‘Cohesive’; 4 < ff < 10, ‘Easy flowing’ and ff > 10,
‘Free-flowing’.24
Statistical Analysis
The statistical analysis of data derived from
different batches of lactose samples was carried
out using one-way analysis of variance (ANOVA)
with Tukey’s post hoc analysis at a p-value
of 0.05 (SPSS, Version 15.0.0, SPSS, Inc.,
Chicago, IL).
RESULTS
Scanning Electron Microscopy
Representative SEM micrographs of lactose
samples are shown in Figures 2 and 3. For the
untreated and mixed batches, fine particles less
than 10 mm tended to form agglomerates or be
adhered to the surface of larger particles. In
contrast, for the mechanofused batches, more
DOI 10.1002/jps
973
particles are present as nonagglomerated primary
particles (Fig. 2). At the higher magnification of
3500, it is quite clear that the untreated batch
exhibits flat smooth surfaces and sharp edges
(Fig. 3a). For the mechanofused sample without
additives, particle edges are rounded and surfaces
are pitted and rougher than the untreated
particles. For the batch mixed with FS (Fig. 3d),
some fine aggregates of FS particles are distrib-
uted discretely on the smooth lactose surface.
However, the batch mechanofused with FS
demonstrates rough surfaces similar to the batch
mechanofused without additives but with some
evidence of FS on the surface. For the batch mixed
with MgSt (Fig. 3b), flake-shaped MgSt particles
adhered to the lactose surface, which indicates
that the tumbling mixing process was unable to
provide sufficient shear and energy to extensively
delaminate and spread MgSt onto lactose sur-
faces. In contrast, the lactose particles mechan-
ofused with MgSt (Fig. 3c) have no visible MgSt
flake-shape particles. The rounded edges observed
on these particles can be attributed to either
attrition/corrasion during the intensive high-
shear and compressive processing or an effect of
the coating material covering the sharp edges, or a
combination of both effects. An undulating sur-
face, which was obviously different in textures to
the flat surfaces of the untreated batch and
rough surfaces of that mechanofused without
additives (or with FS), covers almost the whole
of the lactose particles mechanofused with
MgSt. This indicates that MgSt not only coats
the surface of lactose particles via intensive
mechanical dry coating, but also alters the
corrasion process during the process. Our earlier
studies employing elemental analysis was
unable to detect magnesium on the particle
surfaces after dry coating with MgSt due to
the thin film of the coating, hence with a very
low level of magnesium. SEM micrographs
also showed that lactose powders were better
dispersed after mechanofusion treatment as
reflected by a greater proportion of nonagglo-
merated particles. Repeated imaging of many
samples confirmed that these differences were not
due to sample preparation.
Particle Size Distributions
Particle size distributions of untreated and
processed lactose samples are shown in Table 1
and Figure 4. The VMD of MgSt was 7.9
0.7 mm.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
974 ZHOU ET AL.

Figure 2. SEM micrographs of lactose samples: (a) untreated, (b) mixed with MgSt,
(c) mechanofused with MgSt, (d) mixed with FS, (e) mechanofused with FS, (f) mechano-
fused without additive, at magnification of 750.

The VMD values of all untreated and processed
lactose samples are significantly greater than that
of MgSt ( p < 0.001). There are no significant
differences in VMD values between untreated and
corresponding batches mechanofused either with
MgSt or FS ( p > 0.05). The slight reduction in
VMD values after mixing with MgSt or FS is due
to the presence of smaller discrete MgSt or FS
particles or agglomerates whose VMD values are
much less than those of lactose samples.

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 IMPROVING COHESIVE LACTOSE POWDER FLOWABILITY 975

Figure 3. SEM micrographs of lactose samples: (a) untreated, (b) mixed with MgSt,
(c) mechanofused with MgSt, (d) mixed with FS, (e) mechanofused with FS, (f) mechano-
fused without additive, at magnification of 3500.

Angle of Repose AOR is found after mechanofusion without

The AOR values of untreated and processed
lactose samples are listed in Table 1, and
representative images of the measurements are
provided in Figure 5. A significant decrease in
additives, with MgSt and with FS as well as after
the tumbling mixing with FS ( p < 0.001). In
contrast, no significant differences are found
between the AOR of untreated and batches mixed
with MgSt ( p > 0.05). The batch mechanofused

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976 ZHOU ET AL.

(0.04)
(0.03)
(0.04)
(0.03)
(0.02)
(0.07)
HR
1.99
1.75
1.60
1.88
1.40
1.73
(0.01)
(0.01)
(0.02)
(0.01)
(0.01)
(0.02)
CI
0.50
0.43
0.37
0.47
0.29
0.42
(0.01)
(0.01)
(0.01)
(0.01)
(0.01)
(0.01)
rt (g/mL)
0.69
0.68
0.74
0.66
1.01
0.63

Figure 4. Particle size distributions of lactose and

(0.01)
(0.01)
(0.01)
(0.01)
(0.01)
(0.02)

MgSt samples measured by laser diffraction.

rp (g/mL)
0.34
0.39
0.46
0.35
0.72
0.37

with MgSt achieves the lowest AOR among all the

Table 1. Some Bulk Properties of Lactose Samples (Standard Deviations Are in Parentheses, n ¼ 4)

samples, followed by the batch mechanofused

(0.9)
(1.1)
(0.8)
(1.1)
(1.0)
(0.4)
AOR (8)

with FS, the batch mixed with FS and the batch

mechanofused without additives.
64.6
48.7
46.5
63.9
38.4
54.1
(0.1)
(0.1)
(0.1)
(0.1)
(0.1)
(0.1)

Powder Densities and Derived Indices

Span
2.2
2.6
2.4
2.5
2.2
2.5

The density, CI and HR results are also listed in

Table 1. The poured density values of untreated
samples were not significantly different from
Particle Size Distribution

(0.2)
(0.4)
(0.9)
(0.5)
(0.8)
(0.9)
d90 (mm)

those of the batch mixed with MgSt as well

as the batch mechanofused without additives
44.9
44.9
47.8
43.7
47.8
46.3

( p > 0.05) but were significantly lower than

the batch mixed with FS ( p < 0.05). Significant
VMD (mm)

increases in poured density value were also

(0.3)
(0.3)
(0.6)
(0.4)
(0.3)
(0.5)

observed after the mechanofusion with both MgSt

19.1
16.7
18.8
16.7
20.3
18.0

and FS ( p < 0.001). The greatest change in poured

density, with an increase of 111.8%, was found
after mechanofusion with MgSt compared with a
34.2% increase after mechanofusion with FS. For
d10 (mm)
(0.1)
(0.1)
(0.1)
(0.1)
(0.1)
(0.1)

the tapped density values, it is interesting to note

2.9
1.8
2.1
2.2
2.5
1.9

that very slight reductions were found for both

samples mixed with MgSt or FS, compared to the
original material. The tapped density values of
Mechanofused without additives

the batch mechanofused with FS increased

slightly from 0.69 to 0.74 g/mL. However, the
Mechanofused with MgSt

batch mechanofused with MgSt achieved a

Mechanofused with FS

marked increase of 46.4% in tapped density

compared with untreated powder.
Mixed with MgSt

Consistent with the patterns in the density

Mixed with FS

changes, limited changes were shown in the CI

and HR values after mixing with MgSt or FS and
Untreated

after mechanofusion without additives ( p < 0.05).

In contrast, substantial decreases in the CI and
HR values were observed after mechanofusion

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 IMPROVING COHESIVE LACTOSE POWDER FLOWABILITY 977

Figure 5. Representative images of AOR measurement for lactose samples:

(a) untreated; (b) mixed with MgSt; (c) mechanofused with MgSt; (d) mixed with FS;
(e) mechanofused with FS and (f) mechanofused without additives.

with both materials ( p < 0.001). The batch
mechanofused with MgSt obtained the best
flowability as indicated by CI and HR values.
Remarkable reductions of 42.0% and 29.6% in CI
and HR values, respectively, were achieved after
mechanofusion with MgSt compared with the
untreated sample.
Powder Rheological Properties and
Interparticle Interaction
Since the mechanofused lactose samples with
MgSt showed much greater improvement in
powder flow than those processed without addi-
tives and with FS, lactose samples mixed and
mechanofused with MgSt were selected for
rheological and shear evaluation. Selected result-
ing properties of these powders are shown in
Table 2. There are substantial differences in SE
( p < 0.001), cohesion, s1 and sc values between
untreated and mechanofused batches. The aver-
age SE value decreased from 7.04 mJ/g for the
untreated batch to 3.92 mJ/g for the mechan-
ofused batch. The cohesion of the mechanofused
lactose powder was as low as 0.47 kPa compared to
1.88 kPa for the untreated sample. However,
there were no apparent differences in all rheo-
logical values except SE value ( p < 0.05) between
untreated batch and that mixed with MgSt.
The compressibility results at different normal
stresses are shown in Figure 6. At each normal
stress, the untreated sample showed the greatest
compressibility value followed by the mixed batch.
The mechanofused batch had the lowest compres-
sibility, which was in accord with the CI and HR
results. The compressibility values increased with
an increase in normal stress for all three lactose

Table 2. Some Rheological and Shear Properties of Untreated, Mixed and

Mechanofused Lactose Samples With MgSt

SE (mJ/g)a Cohesion (kPa) s1 (kPa) sc (kPa) ff

Untreated 7.04 (0.92) 1.88 17.71 6.60 2.68
Mixed 5.12 (0.97) 1.97 17.02 6.81 2.50
Mechanofused 3.92 (0.12) 0.47 14.31 1.42 10.68
a
Standard deviations are in parentheses, n ¼ 4.

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978 ZHOU ET AL.
Figure 6. Compressibility of untreated, mixed and
mechanofused lactose samples with MgSt at different
normal stresses measured by the powder rheometer in
its compressibility mode (error bars represent standard
deviations, n ¼ 4).
samples. However, for the mechanofused sample,
the increases in compressibility values were much
less than for the untreated and mixed samples.
For example, for the untreated sample, the
compressibility value increased from 18.6% to
42.2% over the normal stress range of 1–15 kPa. In
contrast, the compressibility value of the mecha-
nofused sample only increased from 6.8% to 11.6%
over the same range of normal stresses.
The shear stress results at different normal
stresses are shown in Figure 7. The untreated
batch demonstrated the highest shear stress
value at each normal stress. The yield locus of
the untreated lactose was very similar to that of
the mixed sample. However, for the mechanofused
batch, all shear stress values were much lower
than those of the untreated and mixed batches
Figure 7. Shear stress values of untreated, mixed
and mechanofused lactose samples with MgSt at dif-
ferent normal stresses measured by the powder
rheometer in its shear mode (error bars represent
standard deviations, n ¼ 4).
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
at all normal stresses ( p < 0.001). The ff values
indicated that the flowability of the lactose powder
was improved from the category of ‘Cohesive’ to
‘Free-flowing’ after mechanofusion with MgSt.
DISCUSSION
Laser diffraction particle sizing indicated that no
significant changes in particle size distributions
of lactose samples were detected after mecha-
nofusion without additives, with MgSt or with
FS (Fig. 3). These findings are in agreement
with other reports,25,26 and recently it has been
reported that the thickness of coating layer of
MgSt after mechanofusion is indicated as less
than 10 nm.27 These findings indicate that the
coating of MgSt on the surface of lactose particles
is too thin to be detected using the laser diffraction
technique, and hence the changes in the densities
and powder flow behaviour after coating were not
due to the change in particle size.
Powder densities and their derived parameters
such as CI and HR values are widely used to
evaluate powder flow, particularly for cohesive
poor-flowing powders.28–30 Generally, noncohe-
sive free-flowing powders will consolidate before
tapping due to the weak interparticle forces and
hence are not very compressible during the
consolidation process. In contrast, cohesive poor-
flowing powders are highly compressible due to
the high voidage from inefficient packing caused
by strong cohesive interparticle forces, and have
poor powder flow. During consolidation, this
structure of the cohesive powder bed can collapse
substantially which is manifested as a large
reduction in volume and a large increase in
density. In this study, the untreated lactose
powder exhibited a very high voidage powder
bed structure represented by the low poured
density. After mechanofusion with MgSt, the
poured density increased (by over 110%), the
absolute compressibility and the change in
compressibility with increasing normal stress
decreased, as did the shear stresses at different
normal stresses. All these changes can be ex-
plained by a substantial decrease in the strength
of the interparticle forces following mechanofu-
sion with MgSt and reflected by much lower
cohesion values. Further evidence of weaker
interparticle forces comes from the decreases in
CI and HR values, AOR and SE following
mechanofusion with MgSt. A previous study also
supported that the interparticle pull-off forces
DOI 10.1002/jps
 IMPROVING COHESIVE LACTOSE POWDER FLOWABILITY
were reduced after mechanofusion with addi-
tives such as MgSt measured by atomic force
microscopy.31
It is widely recognised that the formation of
delaminated MgSt thin films on host particle or
granule surfaces will reduce cohesive and friction
forces between particles or between particles and
walls.32 It provides dramatic improvements
in powder flow for the lactose powders when
mechanofused in this study. In contrast, low-
shear tumbling blending lactose powders with
MgSt here shows almost no improvement in
powder flow for the specific cohesive lactose
samples involved here. Previously, it has been
suggested that conventional blending of pharma-
ceutical powders with MgSt can result in
improved flow.8,33–35 But these studies generally
involved less-cohesive powders whose average
particle sizes were larger than 60 mm, which are
substantially different from the cohesive lactose
powder involved in this study whose median
particle size is approximately 20 mm. From the
SEM micrographs (Fig. 2a), it can be observed
that fine particles under 10 mm of untreated
lactose samples were generally not presented as
separate particles but as agglomerates due to
their strong cohesive interparticulate forces.
During tumbling blending, the shear and energy
are insufficient to break the agglomerates of
lactose, or delaminate the MgSt for the sub-
sequent coating onto individual particles. Conse-
quently, despite the presence of MgSt, and
prolonged mixing for 30 min, very limited flow
improvement was found. In contrast, during the
mechanofusion treatment, the observations here
support the concept that the process provides
sufficient shear or energy to break agglomerates
and coat individual particles. To support this
conclusion, recently reported surface chemistry
analysis of mechanofused lactose with MgSt has
provided evidence of nanometer scale thin-film
coating of MgSt on micrometer-sized lactose
particles. Results from X-ray photoelectron
spectroscopy and confocal Raman microscopy
have confirmed the formation of thin MgSt films
whose thickness is less than 10 nm on lactose
particle surfaces after mechanofusion using sub-
stantially equivalent process conditions as in this
study. This supports that the reduction in the
interparticle interactions can be attributed to both
the chemical and physical changes on the particle
surfaces due to nanoscale coating with MgSt.
In this study, our characterisation work focused
on quantitative bulk properties assessments such
DOI 10.1002/jps
979
as specific interparticle cohesion measurement of
the powder. These findings indicate that coating
quality of fine cohesive powders with MgSt is very
process dependant, and the mechanofusion treat-
ment appears substantially more efficient than
other traditional processes for such materials.
Although this study did not focus on any specific
pharmaceutical applications, it should be noted
that the coating with MgSt on separate host
particles may reduce the tensile strength of any
compacts when they are compressed due to the
reduction of strength of interparticle interactions.
While exhibiting substantially poorer flowabil-
ity compared with the batches mechanofused with
MgSt, it was noted that the batch mechanofused
without additives showed a limited improvement
over the untreated lactose samples. From the
SEM micrographs, it was observed that the sharp
edges and angles of the untreated samples were
rounded and the surfaces rougher after mechan-
ofusion without additives. This is most likely due
to the high-shear compression and corrasion
during the process. Since particle shape has been
reported to have significant influence in powder
flow behaviours,36,37 these limited improvements
in powder flowability may be due to the modifica-
tions in particle shape induced by the mechan-
ofusion processing.
Another interesting finding in this study is that
mixing with the traditional glidant, FS, only
shows a limited improvement in powder flow of
the cohesive lactose sample used here, when
added at levels indicated to be effective in the
literature.38 Previous work with polymer particles
has shown mechanofusion to be essential for
significant flowability improvement by addition of
glidants.39 Surprisingly, in our present work,
even lactose samples mechanofused with FS ex-
hibited substantially less improvement in powder
flow than mechanofusion with MgSt, which to
authors’ knowledge is the first report of this
phenomenon for pharmaceutical powders. Thus,
the use of glidants to improve powder flow is not
superior to boundary lubricants for all powders at
all process conditions. The difference in powder
flowability between the batches mechanofused
with MgSt and FS probably arises from the dif-
ferent mechanisms of action between lubricants
and glidants, and their behaviours during the
mixing or corrasion processes. Evidence of such
findings is indicated by the contrasts in resulting
surface textures from the SEM observations.
As a glidant, FS has been described as having
two modes of action: (a) to modify the particle
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
980 ZHOU ET AL.
surface morphology and reduce the attractive
forces between particles by increasing their
contact distance; (b) to act as ball bearings which
can reduce the friction forces between particles
when they flow.40,41 It has been suggested that FS
may only discretely cover host particle surfaces
and tends to form nonuniform coating during the
intensive coating process since those nano-meter
size particles tend to form agglomerates.39,40 In
addition, the physical separation provided by
these nanoparticles may not be as effective as
the hydrophobic boundary provided by the fatty
acid. Also the intensive shear during the mechan-
ofusion process may press the FS particles
together or into host particle surfaces that weaken
the separation or ball bearing action during the
powder flow.16 To confirm this assumption,
further investigations on mechanisms and nature
of coating with different materials are warranted.
CONCLUSIONS
In this study, the flow characteristics of a cohesive
lactose monohydrate powder were modified fol-
lowing the processing with MgSt or FS using an
intensive mechanical dry-coating technique,
termed ‘mechanofusion’. The untreated lactose
sample, with primary particle size of around
20 mm, exhibited very poor powder flow which is
considered to be unsuitable for pharmaceutical
manufacturing operations. After mechanofusion
treatment with MgSt, substantial changes in
interparticle interactions in the powder bed were
achieved and the powder flow properties of the
processed lactose samples were all substantially
improved, and achieved a ‘fair’ flowability, or ‘free-
flowing’ nature (according to different terminol-
ogies used). In contrast to the mechanofusion
results, a traditional tumbling blending with
MgSt approach for this cohesive lactose powder
has shown no measurable improvement in most
powder flowability indicators (except SE value by
the powder rheometry in dynamic mode).
This study also reported a substantially greater
improvement in powder flowability for the
cohesive pharmaceutical powder when inten-
sively coated with a traditional lubricant, MgSt,
compared to coating with a traditional glidant, FS.
This is attributed to the different qualities of the
resulting coating with the different additive
materials. Consequently, further assessment of
such intensive mechanical dry-coating processing
is attractive to modify particle surface properties,
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
to control powder interparticle interactions and to
obtain improved and more consistent powder flow
characteristics of otherwise cohesive ‘problem’
pharmaceutical powders.
The ability of the powder rheometer to test
powders over a range of stress conditions has been
useful to characterise powder flow behaviours in
this study. The data measured by the powder
rheometer generally agree with the more tradi-
tional tests such as CI and AOR, but have
provided a greater level of differentiation, insight
and detail into the powder flow behaviours.
ACKNOWLEDGMENTS
Thanks to Hosokawa Micron Corporation for help
in mechanofusion operations. Q.Z. would like to
acknowledge the financial support from Faculty of
Pharmacy and Pharmaceutical Sciences, Monash
University, in the form of faculty scholarship.
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