Druglactose binding aspects in adhesive mixtures: Controlling performance in dry

powder inhaler formulations by altering lactose carrier surfaces

Qi (Tony) Zhou, David A.V. Morton

Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), 381 Royal Parade, Parkville, VIC 3052, Australia
a b s t r a c t a r t i c l e i n f o
Article history:
Received 10 February 2011
Accepted 7 July 2011
Available online 18 July 2011
Keywords:
Dry powder inhaler
Lactose carrier
Adhesive mixture
Aerosol performance
Force control agents
Cohesiveadhesive balance
Surface modication
Mechanical dry powder coating
Surface coating characterization
For dry powder inhaler formulations, micronized drug powders are commonly mixed with coarse lactose
carriers to facilitate powder handling during the manufacturing and powder aerosol delivery during patient
use. The performance of such dry powder inhaler formulations strongly depends on the balance of cohesive
and adhesive forces experienced by the drug particles under stresses induced in the ow environment during
aerosolization. Surface modication with appropriate additives has been proposed as a practical and efcient
way to alter the inter-particulate forces, thus potentially controlling the formulation performance, and this
strategy has been employed in a number of different ways with varying degrees of success. This paper reviews
the main strategies and methodologies published on surface coating of lactose carriers, and considers their
effectiveness and impact on the performance of dry powder inhaler formulations.
2011 Elsevier B.V. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
2. Engineering of surface morphological properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
2.1. Smooth lactose carrier surfaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
2.2. Rough lactose carrier surfaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
3. Surface coating of lactose carrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
3.1. Solvent-based coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
3.2. Mechanical dry coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
3.2.1. Mechanofusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
3.2.2. Theta-composer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
3.3. Other coating strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
3.4. Characterization of the coating quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
1. Introduction
The performance of dry powder inhaler (DPI) formulations can be
a strong function of the balance of cohesive and adhesive forces
experienced by the drug particles [1]. In this article we consider the
most common DPI formulation approach, consisting of an adhesive
mixture of micronized drug with lactose carriers acting as a ow and
uidization aid. However it has been shown that in some formulations,
a further excipient additive (for example, additional ne lactose or
magnesium stearate) where included, can act as a de-agglomeration
facilitator or force control agent [2].
Lactose has been adopted as the safe excipient of choice for
pulmonary delivery [3]. The form of lactose used in such formulations
Advanced Drug Delivery Reviews 64 (2012) 275284
This review is part of the Advanced Drug Delivery Reviews theme issue on Lactose
as a Carrier for Inhalation Drug Delivery.
Corresponding author. Tel.: +61 3 99039523; fax: 61 3 99039583.
E-mail address: david.morton@monash.edu (D.A.V. Morton).
0169-409X/$ see front matter 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.07.002
Contents lists available at ScienceDirect
Advanced Drug Delivery Reviews
j our nal homepage: www. el sevi er. com/ l ocat e/ addr
should be well controlled, and generally contains a large size fraction
(in the order of approximately 40 to 200 m) and a ne size fraction
(in the order of approximately 1 to 40 m). The large size fraction acts
as a carrier to aid in a range of processes such as powder ow and
uidization as well as acting as a diluent to help in dose metering. The
ne size faction of lactose has been empirically observed to boost the
apparent de-agglomeration efciency of the micronized drug, as it is
released from the powder mass (although its mechanism of action is
not clear [4]).
As a result, micronized drug exists in an environment with a
number of possible contact neighbors, including other drug particles,
ne lactose particles or coarse lactose particles. Powders are largely
aggregated and can exist in a huge variety of agglomerates of varying
sizes, structures and compositions. Despite this highly complex
multi-particulate nightmare [5], it has been rather simplistically
assumed that aerosolization of the drug would generally be improved
by simply reducing the forces between drug and carrier [6]. In practice
the situation is not so simple, and apparent stronger bonds between
particles can surprisingly yield improved ne particle delivery
efciency [7]. The anomalies in these cases can be attributed to the
complexities of de-agglomeration mechanisms within different de-
vices. For good control over DPI product performance, a fundamental
understanding is required of the formulation, of the device, of the
patient behavior and of the environment, including the complex inter-
relationships between each [7].
To simplify this highly complex scenario it may be helpful to break
the aerosolization process from a DPI to occur into two denable
stages or processes, namely: uidization of the powder bed, followed
by drug detachment from its neighbors into respirable sizes [8], and
where both of these stages are inuenced by the adhesion/cohesion of
the powder.
Many attempts have been made to engineer particles and surfaces
with low adhesion/cohesion properties, and hence to control the
forces between particles, including between micronized drug parti-
cles and between drug and excipient carriers [8,9]. Several philoso-
phies have been investigated. These include the creation of particles
(drug or carrier) with highly crystalline, low surface energy and
atomically smoothed surfaces, which provide a surface of consistent
low energy, and remove the stickiness associated with amorphous
and associated forms of disordered material [10,11]. The removal of
surface cracks or faults on larger lactose particles is perceived to
remove areas which provide shelter into which ne particles become
trapped [12]. In contrast, creating very rough surfaces with features of
dimensions smaller than the nest constituent particles, may reduce
the surface contact area, therefore, inherently reduce particulate
interactions [13]. Such features are often also associated with low
density porous particles [14].
Lactose monohydrate is regarded as a material that is prone to
highly variable and relatively sticky surface areas: such areas have
been termed active sites [15]. As noted earlier, one form of active
site is a physical surface feature larger than the drug particles that
provides shelter to trap ner particles, and reduce the probability of
their liberation during product use. An alternative formof active site is
an area which has a raised surface energy, related to polar or
dispersive forces, enhanced van der Waals forces, surface disorder,
moisture, charge, chemical contamination or other physico-chemical
surface features. This denition has resulted in numerous studies that
approached the perceived problem attempting to coat the lactose
carrier surfaces by using appropriate additives (also termed Force
Control Agents or FCAs) to reduce the force holding drug particles, and
mask any active sites, believing it would enhance drug particle
aerosolization efciency. The choice of FCAs is limited by toxicological
concerns, and this precluded the use of some materials like inorganic
oxides (i.e. colloidal silica) the traditional anti-adherents [16].
We have examined in this paper, the strategies and practical
methods that have been used in lactose surface treatment including a
focus on coating and a current perspective on implications for the dry
powder inhaler formulations based on such an adhesive mixture.
2. Engineering of surface morphological properties
Surface morphology is believed to affect particle adhesion by
increasing or reducing contact area. Thereby, modifying surface
morphological properties may be an effective way to alter cohesion/
adhesion, thus, inuencing aerosol performance. However, such
effects of surface roughness on the ne particle fraction are not rmly
established [8]. Indeed, it is notable that both smoothing lactose
surfaces and creating rough lactose surfaces have been reported to
result in an increase in the ne particle fraction (FPF) delivered by the
respective DPI as discussed in the following Sections 2.1 and 2.2.
2.1. Smooth lactose carrier surfaces
Lactose carriers have been crystallized from carbopol gel which
resulted in a smoother surface and better measured dispersion of drug
from a DPI [17]. The surface roughness was in this case quantied
using a parameter of surface factor measured by optical microscopy.
The FPF of salbutamol sulfate aerosolized by a Rotahaler device from
the binary mixture increased from 14.7% with the control lactose to
21.5% with the re-crystallized lactose at 60 l/min. Surface treatments
with ethanol also smoothed the lactose carrier surface and improve
the drug deposition [18,19]. Coating of lactose powders with lactose
aqueous solution and hydroxypropyl methylcellulose (HPMC, as a
binder) using a Wurster uidized bed was demonstrated to increase
the smoothness of the particle surface [20]. The arithmetic mean
roughness (Ra) value measured by atomic force microscopy (AFM)
decreased from 0.95 m to 0.61 m and the specic area decreased
from 0.148 m
2
/g to 0.125 m
2
/g after surface coating for 180 min. The
aerosol performance of salbutamol sulfate from the binary mixtures
was improved with an increase of respirable particle percent (RP)
from 14.6% to 34.9%. But it is also interesting to note that after surface
coating for 240 min, the Ra value of the lactose was further decreased
to 0.48 m, but RP of the DPI formulation decreased to 31.7%.
Reducing the surface roughness, to produce a smooth surface can
be argued to allow an increased surface contact area, for example, for
two at surfaces in contact. So although it may reduce the areas such
as crevices, hollows and other traps for particles to sit within, and
reducing so called surface active sites, there is also a potential for
reduced ease of particle release from the smoothed surface.
2.2. Rough lactose carrier surfaces
In contrast, a uid-bed has also been used for coating coarse
lactose carriers with ne lactose, resulting in an increased surface
roughness of lactose carriers [13]. Hence different uid bed coating
conditions used appear to have resulted in different effects on the
surface morphology of the coated lactose particles. In this study, the
Ra value of the lactose surface measured by atomic force microscopy
(AFM) increased from 159 nm for the untreated lactose to 216 nm for
the coated lactose while the FPF increased from 16.4% to 18.9% from a
Rotahaler after surface coating. Such improvement was relatively
small, and was attributed to the reduced contact area by introducing
microscopic asperities that is smaller than drug particles on the carrier
surface (Fig. 1) [21].
These conicting observations may be explained by the different
characterization tools/parameters used, as well as the signicant
complexity and limited understanding of the relationship between
lactose surface morphology and the aerosol performance. Furthermore,
the cohesionadhesion forces are dependent on many surface property
variables, not only simple surface morphology [8]. Surface engineering
often alters not only the morphology but also changes other surface
properties such as surface crystallinity or surface chemistry during the
276 Q.(T.) Zhou, D.A.V. Morton / Advanced Drug Delivery Reviews 64 (2012) 275284
process. Such changes in other properties rather than morphology may
have greater impact onthe aerosol performance thanmorphology itself,
and other variables as discussed elsewhere in this review, including
effect of device geometry, air ow, and nature of the drug particles will
contribute to the behavior.
3. Surface coating of lactose carrier
3.1. Solvent-based coating
Another approach to engineer lactose surfaces is to coat with
appropriate additives so as to reduce the adhesion between drug
particles and lactose surfaces. In this way, both surface roughness and
chemistry may be altered. The additives used in this context have
been termed force control agents (FCAs). Such coating process can
be either solvent-based or solventless. Fluid-bed spray coating is a
common solvent-based approach in pharmaceutics for coating
particles. However, only a limited number of studies have employed
a uid-bed coating approach to coat lactose carriers for DPI use. This
may be due to several practical constraints when spray coating ne
lactose carrier powders whose particle sizes are usually smaller than
100 m in a uid bed. Coating such ne powders in this way is a
challenge as they tend to agglomerate or granulate in the uid bed
especially when an additive is presented, thus, the process conditions
should be very carefully chosen [22]. Another challenge for uid-bed
spray coating of lactose carrier for DPI formulations is the choice of
FCAs, including their solubility and solvent choice. The toxicology for
inhalation is a major consideration and limitation in selecting suitable
FCAs to be used, and further limited in terms of solubility for uid-bed
coating. It is interesting to note that coating lactose carrier with
lactose solution using a uid bed has been demonstrated to both
increase and decrease the surface roughness represented as Ra value
measured by AFM in two different studies [13,20], although the in
vitro performance of the DPI formulations in both studies improved
after surface coating. Given the different process conditions and
solution compositions used across these studies, it is not surprising to
observe the different effects on surface morphology and their impact
on the aerosol performance of DPI.
An alternative solvent-based coating technique has also been
employed to smooth the surface of lactose carrier for a DPI formulation
[23,24]. Atypical commercially available lactose with sizes around 90
150 m was wetted with ethanol/water (3:5, v/v) solution. Then the
wetted particles were dried under vacuum during high speed mixing.
Additives such as magnesium stearate (MgSt) or amino acids (0.25%,
w/w) were also added into the smoothing solvent as coating material.
Such additives were expected to coat the lactose particle surface
during the preparation. The results demonstrated that a smoothed
surface of lactose was created after processing with or without
additives. However, only the lactose particles processed with additives
showed signicant increases in FPF, notably from 13.2% for the
untreated lactose to 58.9% for the lactose processed with magnesium
stearate from a mixture of lactose and beclomethasone dipropionate
after aerosolization from a Pulvinal inhaler [25]. Apparently a greater
performance improving inuence may be obtained by the optimum
selection of FCA rather than smoothing the surface alone, however
further work will help to clarify how the relative increases in FPF can
be attributed to the changes in surface morphological properties or
attributed to the changes in surface chemical properties after coating,
or as combined.
3.2. Mechanical dry coating
Solvent-based coating provides disadvantages compared to a
solvent-less process: for example it is generally more complex,
requiring additional energy and time in adding/removing solvent,
plus associated environmental hazards and issues with possible
organic solvent emission and disposal. As such, mechanical dry
coating approaches may be practically a preferred alternative for the
surface modication of lactose carrier.
The use of mechanical methods for coating lactose carriers with
FCAs for DPI formulations can arguably be related to the problems
faced by tablet formulators knowing that when magnesiumstearate is
more intensely mixed into tablet powder blends, it may increasingly
coat the particles/granules and reduce cohesion such that the granules
will not adhere to each other under compression. Hence, efcient
mixing and coating has been a focus in use of lubricants as FCAs.
Magnesiumstearate use in DPI lactose carriers was outlined as early
as 1987 [26] in a patent application describing the use of magnesium
stearate wet granulated with lactose: however, this approach was
specied as to prevent adhesion of lactose to device mechanisms rather
than alter drug detachment. This was followed by patent applications
describing the use of magnesiumstearate blended with lactose carriers,
to attach to the lactose surface with motivation to either reduce drug
attachment force or alternatively to protect against moisture affects on
cohesion [27,28]. Further advances indicated that benet accrued with
use of a number of such FCAs. However, where the combination process
of FCA and lactose increased in intensity, particles could be co-milled,
which not only appeared to improve coating, but lactose nes were
simultaneously generated [29]. The difculty in mechanically coating
surfaces effectively was considered an important factor in explaining
this phenomenon. Conventional blending appears capable of delami-
nating MgSt onto coarse particles, but such coating layers appear
commonly to be non-continuous and non-uniform[30]. Furthermore, it
is suggested that conventional blending may not provide sufcient
energy and shear to uniformly coat ne cohesive particles even when
blending duration is extended to as long as several hours. It has been
noted that ineffective coating was observed after blending MgSt with a
ne lactose powder (volume median diameter, VMD, approximately
20 m) in a Turbular mixer for 30 min [31]. Co-milling has been
claimed in this context as a more effective way to coat smaller lactose
particles, that conventional blending could not achieve [32]. Co-milling
was arguedtobefurther improveduponbythe useof a selectedrange of
intensive mechanical dry coating processes [3234].
A range of intensive mechanical dry coating techniques is
available, including MechanoFusion processors, the Hybridizer,
the Magnetically Assisted Impaction Coater (MAIC) and the Theta-
Fig. 1. Effect of surface roughness of lactose carriers on particulate interactions between
micronized drug particles and lactose carrier surfaces: (a) smooth carrier surface;
(b) carrier surface with microscopic asperities that is smaller than drug particles;
(c) individual drug particles trapped in the carrier surface; (d) drug cluster trapped in
the carrier surface.
277 Q.(T.) Zhou, D.A.V. Morton / Advanced Drug Delivery Reviews 64 (2012) 275284
composer. There are common principles to these different mechan-
ical dry coating processes: during the coating, smaller or softer guest
particles are coated onto the surface of larger host particles through
intensive mechanical forces. The interactions between the guest and
host particles during the process can be either physical or chemical
bonding, or both [35]. The different types of coating layers are shown
in Fig. 2. The coating layers may be either discrete or continuous. The
continuous layers may consist of a particle layer (monolayer or
multilayer) or a lmlayer, which appears to depend on the properties
of the material, the device design as well as operation conditions. In
principle, the guest particles are relatively smaller and softer than the
host particles in order to permit effective immobilization of the guest
particles on the host particle surfaces. The coating device should
provide enough strength and energy for the physical or chemical
bonding between the guest and the host particles, ensuring a
continuous layer can be formed. For the ne host particles with
relative small particle size less than 50 m, the strength of the process
should also be sufcient to overcome strong inter-particle attractive
forces so as to separate individual host particles from agglomerates in
order to expose all surfaces and to coat individual particle surface,
rather than to form coated agglomerates [31]. Dry coating processes
have been widely applied for applications in various areas such as
cosmetic, metallurgy, ceramics, cement, inks, foods and photography
[36]. They have also attracted intensive interest for its applications in
some pharmaceutical areas [37].
3.2.1. Mechanofusion
The term mechanofusion has been adopted as a generic term for
many intensive dry coating processes [35], and is used in this review
in this context, but the original term, MechanoFusion related to a
suite of process equipment developed by Hosokawa Micron, Japan,
largely applied to non-pharmaceutical applications. Various mechan-
ofusion processes have been reported as dry coating process for use in
formulating DPIs. Mechanofusion is reported as notably effective in
coating lactose carrier particles whose particle size is generally much
ner than the traditional 40 to 200 m, or for drug powders ner than
5 m, without the byproduct of co-milling such as size reduction, and
so is claimed as attractive as a single step dry coating process [38].
A typical mechanofusion system consists of outer cylinder vessel
and an inner raft with processor blades extended from the raft. The
vessel or the processor rotates at speeds between 500 and
10,000 rpm. In the context of mechanofusion processing, tip speed
may be a more appropriate descriptor of intensity/speed, as vessel
diameters may vary considerably. A gap of approximately 13 mm
between the vessel and the processor is designed to allowthe powder
to be compressed and sheared during the coating process. Conse-
quently, as the shaft or the vessel rotates, the processor continuously
sweeps close to the vessel wall, ensuring all the powder is in constant
and violent motion. Due to the high rotational speed of the processors,
the powder is propelled towards the wall, and as a result the mixture
experiences very high shear forces at the processor face, and
compressive stresses between wall and processor. The energy is
intended to be sufcient to break up agglomerates of guest and host
particles, but due to the xed geometry, and control of speed, it is
believed that energy input is controlled such that size reduction of
host primary particles can be minimized. In an earlier version
(Mechanofusion AMS, Hosokawa Micron, Japan), the inner raft
and processor are xed while the outer vessel rotates during the
processing [35] (Fig. 3). For more recent Hosokawa Micron designs,
the outer vessel is xed and the processor rotates for the coating
(Fig. 4) [39]. Various processors with different shapes and geometries
can be chosen according to the purpose and the nature of the coating
[40].
Begat et al. [33] applied such a mechanofusion process to coat both
drug particles of salbutamol sulfate and lactose carrier with three
FCAs, MgSt, leucine and lecithin. The lactose carrier used in this study
was a relative ne powder with VMD around 10 m rather than more
conventional coarse carriers with VMD ranging from 40 to 200 m. It
is interesting that the in vitro performance (reected by FPF of the
emitted dose) of the binary mixtures from a Monohaler device was
only improved for those containing the coated drug particles. The
reduction in adhesion forces between lactose carrier surface and drug
particles appeared to result in drug particles sticking together, as
measured by AFM and the cohesiveadhesive balance (CAB) ap-
proach. This work was extended for carrier-free high drug dose DPI
formulations [40,41].
Kumon et al. [34], also dry coated lactose carriers using a
mechanofusion process aiming to improve aerosolization. Lactose
carriers of Sorbolac 400 (VMD approximately 8 m), Pharmatose
325 M (VMD approximately 60 m) and Lactohale 100 (VMD
approximately 145 m) were coated with either MgSt or sucrose
stearate, or processed without any additives. The coating for the nest
lactose powder of Sorbolac 400 was reported to be unsuccessful as
attributed to the small particle size and the mechanofusion device
Fig. 2. Schematic of mechanical dry powder coating. Reprint from ref. [35] with
permission from Elsevier.
Fig. 3. Schematic of an early model of Mechanofusion AMS system.
Reprint from ref. [35] with permission from Elsevier.
278 Q.(T.) Zhou, D.A.V. Morton / Advanced Drug Delivery Reviews 64 (2012) 275284
used. The larger lactose particles were rounded and the surfaces were
smoothed after the mechanofusion process. The in vitro results froma
Jethaler device demonstrated that the mechanofused batches pro-
cessed with MgSt achieved the highest FPF value of 42.4% compared to
20.8% for the untreated batch, with a drug concentration of 2% w/w in
the mixture. The mechanofused batches without additives exhibited a
poorer performance (FPF of 13.2% with 2% drug). Such improvement
was explained by the increase in similarity of surface properties of
electron donation between drug and carrier surfaces after
mechanofusion.
However, it is interesting to note that in this study, the dispersive
energy of the lactose carriers, measured by inverse gas chromatog-
raphy (IGC) was increased after the mechanofusion with MgSt, which
in principle should strengthen the adhesion forces between drug
particle and lactose surfaces. In a further study, Kumon et al. [42] also
demonstrated that the width of the distribution of adhesive forces
between drug particle and carrier surfaces was reduced after
mechanofusion. It was proposed that the improvement in DPI
performance after this mechanofusion processing was due to both
the increase in surface energy and the reduction in range of adhesive
forces on the lactose surfaces. However, such observations of
increased surface energy could also be due to the limitation of the
innite dilution method used for the IGC surface energy measure-
ment. For IGC surface energy measurement at innite dilution, only
very small proportions of the surface, namely the highest energy sites,
are examined. Thus, the surface energy values measured at innite
dilution may not represent the properties of the majority of the
surfaces [43,44]. It was also shown that the surface dispersive energy
of a mixed salbutamol sulfate powder with MgSt decreased when the
IGC measurement was extended to a higher coverage on the sample
surfaces at nite dilution [45]. In a more recent study, the surface
energy of the mechanofused ne lactose powder with MgSt was
measured using IGC under nite dilution conditions. The results here
instead indicated substantial reductions in dispersive energy for the
majority of the lactose surfaces after mechanofusion, although a high
dispersive energy was demonstrated at innite dilution [46]. This
indicates that the mechanofusion processing may create a very small
proportion of lactose surface area with a high energy, possibly due to
the intensive interactions during the surface processing. However, the
mechanofusion appears to decrease the energy of the majority of the
host particle surface area by covering most high-energy sites with the
lower surface energy coating material. These IGC data at nite dilution
are also in good agreement with the observations that the cohesive
forces are substantially reduced and the powder owability is
substantially improved for ne particles after mechanofusion treat-
ment [47].
Zhou et al. [47] showed that the owability of a ne lactose
powder, Pharmatose 450M (VMD approximately 20 m), improved
from poor ow to free-owing characteristics after mechanofu-
sion with 1% w/wMgSt. There was no apparent change in particle size
while the particles were rounded and the surfaces were smoothed,
which was in good agreement with previous observations (Fig. 5)
[34]. These modications in particle shape and morphology may be
due to the attrition or plastic deformation occurring as a result of high
shear and interaction process [48]. Interestingly, the improvement in
ow after dry coating with MgSt was greater than with standard
glidant, fumed silica, for this ne milled lactose powder. A near
complete nano-scale ultra-thin layer of MgSt was demonstrated as
formed on the lactose particle surface after dry coating using XPS and
ToF-SIMS (see Section 3.4) [49,50]. Such a coating layer is claimed to
reduce the attractive forces between particles and, thus, decrease the
powder cohesion improving the powder ow. It is also shown that the
improvement in powder ow after surface coating is mainly
attributed to the modication of surface chemical properties rather
than the changes of surface morphological properties [51]. A further
study demonstrated that the dry coating process with MgSt not only
improved the powder owability but also the uidization (as
measured by a Freeman FT4 powder rheometer, Freeman Technology,
UK) and de-agglomeration (measured by real-time laser diffraction)
behavior of model ne milled lactose powders [39]. The uidization
and de-agglomeration behavior of the coated powders appeared more
consistent under the varying air ow rates, indicating the aerosoli-
zation is less dependent on the air ow and therefore, giving a more
stable performance. The aerosolization performances of a range of
micronized drug powders froma Monohaler were also indicated to be
improved signicantly after the mechanofusion with 5% MgSt [40].
The dispersion behaviors of coated drug particles from the binary DPI
formulations containing similar mechanofused ne lactose carriers
have been reported [38], indicating that coated ne lactose powders
with free-owing characteristics are promising candidates acting as
carriers for DPI formulation, given that a free-owing carrier with
relative smaller sizes is perceived as desirable for a binary DPI
formulation [18].
3.2.2. Theta-composer
The Theta-composer is an alternative type of mechanical dry
coating technique. It consists of a faster (approximate 5003000 rpm)
inner elliptical rotor and a slower outer elliptical vessel (approximate
30 rpm) [35]. The rotor and the vessel rotate in the opposite
directions, forcing host and guest particles mixtures pass the small
clearance between the vessel and the rotor by high shear and
compression stresses (Fig. 6). Hence the process may provide similar
outcomes to the mechanofusion style approach described above.
Iida et al. have reported the use of Theta-composer for coating
lactose (Pharmatose 200M, VMD approximately 70 m) with sucrose
tristearate for DPI formulations [52]. The surfaces of the lactose
particles were smoother after the processing indicated as a decrease
in measured surface area. The respirable particle percentage (RP)
values of the resulting formulations containing salbutamol sulfate
froma Jethaler increased from17.4% for the untreated lactose batch to
46.8% for the lactose processed with 10% w/w sucrose tristearate as a
Fig. 4. MechanofusionAMS Mini systems with (a) Nobilta and (b) Nanocular processors.
Reprint from ref. [40] with permission from Elsevier.
279 Q.(T.) Zhou, D.A.V. Morton / Advanced Drug Delivery Reviews 64 (2012) 275284
FCA with an increase in sucrose tristearate concentration. A further
study concluded that the RP increased with an increase in processing
speed although the differences appeared unlikely to be signicant
[53]. Signicant increase of RP was also observed for the DPI formu-
lation containing micronized salbutamol sulfate and dry coated
lactose carrier with MgSt using a Theta-composer [54]. The coating
process with MgSt as a FCA was demonstrated to increase the contact
angle of lactose due to the hydrophobic nature of MgSt and hence may
Fig. 5. SEM micrographs of a) untreated; b) mixed with MgSt; c) mechanofused with MgSt; d) mixed with FS; e) mechanofused with FS; f) mechanofused without additives batches
of lactose samples at magnication of 3500.
Reprint from ref. [47] with permission from John Wiley and Sons.
280 Q.(T.) Zhou, D.A.V. Morton / Advanced Drug Delivery Reviews 64 (2012) 275284
reduce the inuence of high humidity on the aerosol performance
[54].
The effect of surface coating, but of a micronized drug, pranlukast
hydrate, with hydrophilic colloidal silica (AEROSIL200, VMD16 nm)
has been reported using a Theta-composer [55]. The RP increased
signicantly after the surface modication but only greater than the
spray dried batch at the silica concentration of 5%. The use of colloidal
silica for the inhalation, as alluded to earlier, may also bring the
concerns in lung toxicity [16].
Other mechanical dry coating techniques such as the Hybridizer
[56,57] and Magnetically Assisted Impaction Coater (MAIC) [58,59]
have also shown their ability to engineering particles for the featured
purposes, although reports of their use to engineer lactose carriers for
DPI were not found.
3.3. Other coating strategies
Alternative non-solvent based strategies to surface coating include
methods to condense material onto a surface from the vapor phase.
One of the more innovative approaches for surface treating ne
lactose particles, employed a plasma vapor deposition approach to
provide a siloxane surface coating from a plasma downstream reactor
[60]. But the use of Siloxane is likely to raise lung toxicity issues. Prior
to this, surface coating of particles has been suggested via the
condensation of the volatile amino acid, L-leucine, onto drug or carrier
particles [61,62].
3.4. Characterization of the coating quality
Appropriate characterization of the coating quality on the particle
surfaces formed froma suitable coating process is critical for the process
control, process optimization and understanding the inuences of
surface coating on the bulk powder behavior. Such characterization is a
major challenge especially when precise quantication of the coating
quality is required. This is mainly due to: (1) the coating could be a very
thin lm or layer (as thin as a few nano-meters) and (2) a thin coating
lm or layer is on the surface of complex-shaped micron-scale particle.
Thus, the appropriate characterization tools should not only have the
ability to accurately capture the information of the thin coating layer,
but also require the high spatial resolution as the subject particles are
relatively very small.
In early studies, energy dispersive X-ray (EDX) analysis was used
to characterize the distribution of lubricant on the particle surfaces
after traditional blending MgSt with coarse subject particles [63,64].
When combined with scanning electron microscopy (SEM), EDX can
provide qualitative chemical information of the particle surfaces [63].
Nevertheless, unpublished attempts to detect a thin layer of MgSt of
the mechanofused lactose samples using EDX have not been
successful and not reported due to the extremely low Mg content
on the mechanofused particle surfaces and the insensitivity of the
method used. In addition, EDX has a corresponding depth of
approximately 12 m [65]. As the coating layer is likely to be much
thinner than 1 m, the information detected will not only come from
the coating but also from the host particles beneath the coating layer.
Raman microscopy is another potential candidate for characteri-
zation of dry coating layers. With a mapping technique, both spectral
and spatial information of the measured sample can be obtained.
Therefore, this technique provides measurement on both the
chemical and morphological character of the target materials as
well as the distribution of such properties in two or three spatial
dimensions [66]. However, Raman microscopy usually has a relatively
low spatial resolution of a few micro-meters [67,68]. For the lactose
carrier particles with sizes smaller than 100 m, this spatial resolution
may not provide useful distribution information on the coating layers.
Furthermore, the irradiation depth of the Raman microscopy may also
be greater than 1 m.
Time-of-ight secondary ion mass spectrometry (ToF-SIMS) is an
analytical technique used to image and record organic and inorganic
mass spectral data of solid material surfaces. This is a highly sensitive
technique that provides chemical information regarding elemental,
isotopic and molecular structure from the upper surface struc-
ture [69,70]. The chemical information can be collected only from
the top one or two molecular layers of the particle surfaces [70].
Moreover, ToF-SIMS provides mapping of chemical compositions with
relatively higher spatial resolution of 20100 nm, compared with EDX
and Raman. Thus, ToF-SIMS is considered a promising technique to
probe the surface coating quality [71]. In pharmaceutical area, ToF-
SIMS has been used to characterize coating of tablets, granules or
pellets [68]. However, ToF-SIMS only provides qualitative or semi-
quantitative chemical information.
X-ray photoelectron spectroscopy (XPS) may also provide useful
chemical information regarding the surface as a result of coating. XPS
is a spectroscopic technique that measures the elemental composi-
tion, empirical formula, and to some extent chemical state and
electronic state of the elements that exist on the material surface [72].
With XPS the chemical information is obtained from the top layer
(typically 210 nm) of the material surface being analyzed. Thus, the
chemical information collected from XPS is only related to their
surface properties. Unlike ToF-SIMS, the results obtained fromXPS are
more quantitative as the composition ratio of each component on the
surface can be calculated from the ratio of each element. Therefore, it
has been popular in characterizing thin coating lms [7376].
There is a lack of literature regarding the appropriate character-
ization of the quality of the coating layers generated by mechanical
dry coating approach on ne pharmaceutical particles. Green et al.
[49] briey reported the examination of coating layers produced by
mechanofusion on micronized pharmaceutical drug and excipient
powders. The study conrmed the existence of the coating lm of
magnesium stearate on the ne particle surface by XPS and Raman
microscopy, but detailed information on coating was not investigated.
A series of recent studies reported successful characterization of
mechanical surface coating of MgSt on either the coated ne lactose or
the coated micronized drug particles [77,78]. XPS and ToF-SIMS were
employed to characterize the coverage of the coating both qualita-
tively and quantitatively. The results indicated that a near-complete
coverage of MgSt on the ne particles was achieved after the
mechanofusion processing for 10 min. Such MgSt coating layer was
suggested to be as thin as a few nano-meters [50]. Successful char-
acterization of coating quality facilitates the fundamental study of the
relationship between surface coating and their bulk behavior. The
results from the subsequent studies indicated the ow and aerosol-
ization behaviors of ne particles were strongly dependent on the
coating coverage [51].
4. Discussion
Drug aerosolization from a DPI is a more complex phenomenon
than a process simply dependent on the attachment forces of discrete
Fig. 6. Schematic of Theta-composer.
Reprint from ref. [35] with permission from Elsevier.
281 Q.(T.) Zhou, D.A.V. Morton / Advanced Drug Delivery Reviews 64 (2012) 275284
drug from a lactose surface. Two critical events may be considered to
explain observed effects. First, the powder should be uidized, re-
suspended and carried froman inhaler device by air ow, termed here
as entrainment into air ow [39]. Recent work illustrated the effect
of particle size and surface modication on the uidization of ne
lactose particles following mechanofusion with magnesium stearate
[39]. Particles as small as 10 m appeared to be easily uidized where
the cohesion was substantially reduced as a result of coating. A critical
size was identied where the lactose changes from free owing to
poorly owing reecting the balance of gravity forces compared to
cohesion forces. Hence it was suggested that these ne lactose
powders might be used as ne carriers, with increased surface area for
drug attachment. However, previous work alternatively argues a
benet of increasing cohesion rather than reducing it in a uidization
context, explained as a benet of the subsequent de-agglomeration
[79]. But increasing the cohesion of the powder may alternatively be
viewed as a risk-prone approach as it may consequently compromise
the ow and uidization of the powder, and make performance less
consistent especially with variable ows. Coating both drug and
lactose carriers may provide an alternative solution to facilitate both
uidization and de-agglomeration by reducing both cohesion and
adhesion in the mixture [33].
Secondly, the powder should be de-agglomerated into a suitable
ne particle form during the aerosolization, often previously termed
as dispersion (or probably more appropriate in this context, de-
agglomeration). Thus, the performance of a DPI depends on the
balanced effect of both cohesion between drug particles as well as
adhesion between drug particles and carrier surfaces. Single detach-
ment measurements are generally unrepresentative of the DPI
performance as particles will experience forces from multiple
surrounding particles in contact in a real system. It has been shown
that de-agglomeration efciency of drugs like salbutamol sulfate or
budesonide is not easily predicted from the attachment forces, and
formulation performance is also strongly dependant on specic
devices used [2,80]. The uidization and dispersion mechanisms
may be entirely different during the aerosolization of the powders for
each different inhaler device, where geometry will provide changes in
airows resulting in different experiences for each particulate entity:
leading to exposure to different potential de-agglomeration mecha-
nisms [81,82]. For example, it was shown that two different types of
surface-modied DPI formulations exhibited markedly different
performance in contrasting active and passive inhaler devices, with
formulation A performing much better in passive device while
formulation B performed similarly better in the active device. Such
differences in aerosol performance for two coated formulations were
in this case attributed to the difference in their ow properties,
examined using a high speed camera [7]. Thus, the observation
emphasizes that it is critical that the device should match the
formulation, which allows the dispersion forces generated by/through
the device to match with the requirements for efcient powder de-
agglomeration [6]. It should also be noted that although FPF is heavily
used for the evaluation of DPI performance, this single parameter may
not fully represent the safety and efcacy of the DPI formulations [83].
It provides no detail as to the size distribution of the aerosol belowthe
specied size cut, and this size distribution may well alter aerosol
transport and deposition behavior. Together with uniformity of
delivered dose, ne particle dose, and/or aerodynamic particle size
distributions, the performance of the DPI needs to be well character-
ized and appropriately correlated with their in vivo performance,
especially under realistic patient-use conditions such as varying air
ow rates [84].
Moreover, lactose carrier-based DPI formulations rarely exist as
traditional ordered mixtures: i.e. where it is assumed a simple
structure of ne drug stuck on the lactose surfaces, exists as
represented in Fig. 7. The reality is quite different, with formulations
having some drug adhered to large lactose, some to itself and some
attached to ne lactose [5]. Much of the ne material may not be
attached to a large carrier at all but form agglomerates (see Fig. 8 for
example). In the literature, micronized drug particles have been
demonstrated not to be adhered on the lactose carrier surface but
forming drug agglomerates in the case when the lactose carrier
surface was coated with FCAs [33]. This appears simply the effect that
the cohesive forces become dominant over the adhesive forces in a
drugcarrier mixture. Thus, it may be more meaningful to examine
the balance between cohesion and adhesion rather than a single
attachment force of drug particle from carrier surface [1].
What then are the implications of the substantial reduction of the
attachment force of drug to lactose in such circumstances? Clearly the
potential result can be the reduced function of the lactose as a carrier,
leading to good potential uidization but segregation problems. So,
how much of a real benet can be achieved with respect to drug
release from such mixtures by solely pursuing modifying the lactose
carrier surface? One study has indicated that at high drug to lactose
ratio, coating lactose too well may cause the formulation to segregate
[33]: the drug may behave during aerosolization in a manner similar
to the drug alone, and the lactose carrier may act not as a carrier, but
as a uidization aid only. A potential solution to this may be to coat the
drug instead [33], or even both drug and lactose [38], in order to
maximize the benet.
Fig. 7. Diagram of an idealized view of drug adhered to lactose carrier.
Fig. 8. SEM micrograph of a more realistic drug/lactose mixture containing micronized
salbutamol sulfate (2.5%, VMD 3 m), Sorbolac 400 (20%, VMD 7 m) and Inhalac
230 (77.5%, VMD 90 m), which was mixed for 60 min at 49 rpm using a Turbula
mixer (scale bar represents 300 m).
282 Q.(T.) Zhou, D.A.V. Morton / Advanced Drug Delivery Reviews 64 (2012) 275284
It is known that the storage of some DPI formulations under some
specic conditions (such as high relative humidity, RH) may inuence
their aerosol performance [8587]. The effect of storage on the reduction
of aerosol performance was shown to be less for a hydrophobic drug,
budesonide, than for a hydrophilic drug, salbutamol sulfate [88]. This can
be explained by the difference in surface interactions with moisture
during the storage for the powders with these different surface
hydrophobic/hydrophilic properties [88,89]. Blending DPI formulations
with MgSt was claimed to substantially improve the resistance to
exposure to elevated moisture conditions [28]. Giventhat surface coating
provides better coating coverage than traditional blending [31,50],
surface coating is promising as an approach to protect DPI formulations
frommoisture attack during the storage. Iida et al. also reported that the
surface coating of lactose carriers with MgSt achieved improved both
aerosol performance and reduced the inuence of storage at high RH on
the aerosol performance of the DPI formulation after being stored for
7 days. Such improvements in formulation stability during high RH
storage were attributed to the changes in surface hydrophobic/hydro-
philic properties after coating with MgSt, a hydrophobic material [54].
Stearate salts coatings have also been proposed as means for reducing
chemical interactions between drug and lactose carrier surfaces [90].
However, work on the long-term stability of such coatings has not been
extensively reported yet.
5. Conclusions
This paper provides a perspective on current reported attempts to
control of lactose cohesion (and adhesion) by surface modication.
Several methodologies have been discussed. Substantial reduction in a
drug attachment force to lactose has been shown after surface
modication. In addition, improvement in ne particle uidization
can also be achieved by reducing the cohesion via surface modica-
tion. Furthermore, Surface coating of lactose may also hide some of its
associated problems, especially relating to compatibility with mois-
ture, with drugs and related forms of stability. The philosophy of
providing an appropriate surface coating, on one or more components
of a DPI formulation appears to have strong merit, in providing a more
uniformand well suited surface energy for the process of efcient and
reproducible aerosolization.
However, converting these factors into product performance is
proving a far more complex issue given the performance of a DPI is not
solely dependent on the attachment force but dependent on the
combination effect of cohesion and adhesion, plus of the relationship
with the specic storage and aerosolization conditions provided by
the device, with the physic-chemical properties of excipient, with the
range of patient behaviors (especially the inhalation air ow prole),
and other inuences of the environment, including all the complex
inter-relationships between each. In each case, the potential for
successful outcomes appears to be dependent on a robust under-
standing of these factors, and their inter-relationship.
Acknowledgement
Qi (Tony) Zhou would like to acknowledge the nancial support of
Postgraduate Publications Award from Monash University.
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