Influence of Particle Properties on Powder Bulk Behaviour and Processability

Umang V. Shaha, Vikram Kardeb, Chinmay Ghoroib, Jerry Y. Y. Henga*

a Surfaces and Particle Engineering Laboratory (SPEL), Department of Chemical Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.

b DryProTech Lab., Chemical Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar, Gujarat 382355, India

*Corresponding Author: jerry.heng@imperial.ac.ukPhone: +44-(0)207-594-0784. Fax: +44-(0)207-594-5700 Web: www.imperial.ac.uk/spel

- 1 -

Abstract

Understanding interparticle interactions in powder systems is crucial to pharmaceutical

powder processing. Nevertheless, there remains a great challenge in identifying the key

factors affecting interparticle interactions. Factors affecting interparticle interactions can be

classified in three different broad categories: powder properties, environmental conditions,

and powder processing methods and parameters. Although, each of these three categories

listed is known to affect interparticle interactions, the challenge remains in developing a

mechanistic understanding on how combination of these three categories affect interparticle

interactions. This review focuses on the recent advances on understanding the effect of

powder properties, particularly particle properties, its effect on interparticle interactions and

ultimately on powder bulk behaviour. Furthermore, this review also highlights how particle

properties are affected by the particle process route and parameters. Recent advances in

developing a particle processing route to prepare particles with desired properties allowing

desired interparticle interaction to deliver favoured powder bulk behaviour are also discussed.

Perspectives for the development of potential particle processing approaches to control

interparticle interaction are presented.

Key words: interparticle interactions, powder bulk behaviour, particle properties, powder

flow, surface properties, tailored surfaces

- 2 -

1. Introduction

Powder handling and processing operations are dependent on the physicochemical properties

of powder materials. Understanding these physicochemical properties of pharmaceutical

powder can aid the development strategies for efficient and cost effective powder processing

(Hou and Sun, 2008). Thus, the role of these properties of particulate pharmaceutical

materials on cohesion and adhesion and their effect on powder flow has attracted much

research interest over the past four decades (Feng et al., 2007; Ghoroi et al., 2013a; Kaerger

et al., 2004; Lam and Nakagawa, 1994; Podczeck and Mia, 1996; Podczeck and Révész,

1993; Ridgway and Morland, 1977). Powder cohesion or adhesion is reported to be

dependent on both the intrinsic material properties (surface functional end groups, surface

energy, elastic module and plasticity) (Castellanos, 2005; Fichtner et al., 2008) and particle

attributes (particle size, size distributions, shape and surface roughness) (Kaerger et al., 2004;

Kumar et al., 2013; Lam and Newton, 1992; Podczeck and Mia, 1996; Rasenack and Müller,

2002).

On the other hand, the particle properties are known to be affected by the processing routes

and processing conditions used for generating particles (Buckton, 2000, 1995; Heng et al.,

2006; Planins̄ek et al., 2010; Smith et al., 2000). Milling can cause particulate breakage

resulting in surface defects as well as surfaces with a heterogeneous surface energy landscape

and irregular particle shape, which affects interparticle interaction (Williams, 2015).

Similarly, in crystallisation, choice of solvent can result in different particle size, shape and

crystal habit (Bourne and Davey, 1976), which can ultimately affect interparticle interactions

and thereby the flow properties.

- 3 -

This review focuses on establishing linkages between particle processing approaches,

processing parameters and particulate bulk behaviour. Recent advances towards developing a

rational understanding of the role of particle properties on powder bulk behaviour is

discussed with an emphasis on reviewing the effects of particle bulk and surface properties on

powder flowability and compressibility. Finally the review also highlights opportunities to

employ the understanding of the role of particle processing methods on particle properties to

control powder bulk behaviour.

This review commences by providing an insight into different interparticle interaction

mechanisms and recent modelling approaches relevant for the prediction of interparticle

interactions. This is followed by discussion on modelling approaches, recent efforts on

developing mechanistic understanding on the role of particle properties, e.g. particle bulk

properties (solid state properties, particle size, shape, surface area), and surface properties

(surface roughness, and surface energetics) on bulk powder behaviour, i.e. powder

flowability, compressibility, are discussed in detail. Particle properties (both surface and

bulk) are known to be affected by particle processing methods and routes, and a review of the

role of particle processing methods (i.e. crystallisation, spray drying, milling, blending) and

processing parameters (i.e. processing temperature, humidity, milling intensity, crystallisation

solvents, etc.) is reported. Finally, this review focuses on recent and innovative efforts to

combine the understanding on the effect of particle processing on particle properties, and the

effect of particle properties on powder flowability and compressibility to tailor particles with

desired powder bulk behaviour.

Measurement techniques and approaches have been covered previously in the literature,

which includes reviews and books focusing on surface and bulk characterisation of particle

- 4 -

properties (Buckton and Gill, 2007; Crowder et al., 2003; Gamble et al., 2012; Schulze, 2008;

Svarovsky, 1987). Considering the availability of the literature on particle, surface and bulk

characterisation techniques, this review does not intend to discuss material characterisation in

detail. Interested readers can refer the individual reference for such information.

It is generally agreed that the powder properties affect interparticle interactions and

ultimately powder flow, however a fair amount of confusion exists in the classification of

powder properties in the existing literature. For clarification, classification of the powder

properties presented in the Scheme 1 is used for the purpose of this review. Furthermore, the

key emphasis of this manuscript is to review the breadth and depth of the literature,

specifically focusing on establishing the relationship between particle processing routes and

parameters, on particle properties, and ultimately powder bulk behaviour. Considering the

wide range of the literature covered, the discussion of individual examples is restricted to the

qualitative analysis of the data and conclusions reported to highlight the key findings of a

particular study. Interested readers can refer to the individual reference for detailed

information.

2. Insight into interparticle interaction mechanism and modelling approaches

There are two basic interaction mechanisms occurring at the particulate level that determine

the overall powder behaviour. These interactions include frictional force interaction and the

adhesion force interaction between particles or between particles and contacting surface.

The attractive interparticle interaction occurs between the particles at different operations

during the manufacturing process. Such phenomenon is desired during unit operations like

granulation, roll compaction, coating of drug particle over the carrier like lactose

monohydrate in case of dry powder inhalers (DPI’s). However, it could also prove to be

- 5 -

undesirable during handling or processing of highly cohesive powders, causing unwanted

processing problems and losses. For example, powder flow problems arising from the

cohesiveness of the particles during tablet compression and capsule filling operations could

lead to poor product quality and performance. Also, these attractive interactions during the

grinding process could be problematic as it would diminish the grinding effect, lengthen the

grinding time, and increase the energy requirement, due to the undesired agglomeration

tendencies of the particles (Pietsch, 1997). These interparticle interactions are especially

undesirable during transport, storage and in feed systems.

2.1 Interparticle force between particulate solids

The powder properties and cohesion or adhesion behaviour of fine powders is significantly

affected by the magnitude of attractive interparticle forces. The interparticle interaction forces

like van der Waals forces, electrostatic force, capillary force and solid bridge force affect the

powder behaviour and properties like powder flow, compaction etc. Scheme 2 depicts these

different interparticle interaction mechanisms.

For a dry system, the capillary force is negligible and the total adhesion force is mostly due to

van der Waals forces and electrostatic forces. Compared to van der Waals and capillary

forces, the strength of the electrostatic force is less at smaller distances but do not decrease

much with the increasing distance. Thus, in dry uncharged powder system of small size

range, the flow of the powder is dominated by van der Waals forces (Castellanos, 2005). The

magnitude of the interparticle force can be determined in terms of the force required for

detachment of one particle from the other (also called as pull-off force) which is usually

measured using Atomic force microscopy (AFM). The different types of interparticle forces

are briefly discussed in sections 2.2 to 2.5.

- 6 -

2.2 van der Waals forces

For dry powder systems, often these forces are more dominant than other interparticle forces.

The origin of these forces is quantum mechanical in nature. In a molecule, a finite electric

dipole is created due to the instantaneous positions attained by the electrons, which in turn

polarises a nearby molecule inducing a dipole. The two opposite dipoles created give rise to

an attractive force between both molecules. These fluctuating dipole interactions of the first

two molecules will be modified by a third molecule. Thus, these molecular forces are not

pairwise additive (Castellanos, 2005). This constitutes the attractive and repulsive

components, also known as Keesom, Debye and London components of van der Waals forces

between the molecules. The van der Waals force (F vw) between two spherical bodies of

radius (R) and separated by a distance (a) can be expressed as equation 1,

Fvw=A ∙ R

12∙ a2 (1)

where, A is the Hamaker’s constant.

According to the above equation van der Waals force is directly proportional to the particle

size. Several other theories like JKR (Johnson, 1999) and DMT (Derjaguin et al., 1994)

considered the surface energy of the interfaces as the interaction energy between the bodies.

However, it is observed that the calculated forces are often larger than expected in real

systems. This can be explained by the fact that in reality the particle surfaces are not smooth

but have rough, uneven structures. Thus, one of the theories proposed by Rumpf (Rumpf,

1990) which was further modified by Rabinovich et al. takes into account the contribution

from the nanoscale surface roughness, expressed as root mean square (RMS) of roughness,

- 7 -

between the contacting particles to calculate the interparticle force (Rabinovich et al., 2000a,

2000b).

Fvw=A∗R

12∗a2∗( 1

(1+ R1.48∗RMS )

+1

(1+ 1.48∗RMSa )

2 ) (2)

Thus, from equation 2, it is apparent that interparticle force is dependent more on the

particles surface properties like surface energy and surface roughness than on the bulk. This

was also confirmed by Katainen et al. from their adhesion force determination studies carried

out using AFM (Katainen et al., 2006). This surface property dependence on interparticle

force could also explain the flow promoting effect of different glidants or fines or the coating

of nanoparticles onto the surface of cohesive powders, all of which increases the separation

distance between particles as well as alters the surface roughness and surface energy of the

interacting bodies.

2.3 Electrostatic force

Electrostatic charging can occur by contact or friction. In contact charging, the two bodies

come in contact and subsequently separated without rubbing. In frictional charging or

‘tribocharging’, relative movement between two bodies in contact with each other causes

friction between them. The electrostatic force (Fe) between two charged dielectric spheres of

diameter (D) having charges (Q1) and (Q2) in a medium with permittivity (∈) is given by

equation 3:

Fe=Q2

2

4 π∈D2 [α ( Q12

Q22 +1)−β

Q1

Q2 ] (3)

where, α and β are the constants (Valverde, 2013).

- 8 -

Electrostatic force can generate either attractive interaction or repulsive interaction between

the powder particles. Attractive interaction between the powder particles can cause particle

agglomeration and can cause hindrance in powder flow through discharge hoppers. It can

lead to particle adhesion to the surfaces of the equipment thus causing processing problems

and undue losses (Kwok and Chan, 2007). Repulsive interaction on the other hand may cause

instability in the powder system and could lead to problems such as segregation.

Pharmaceutical materials are mostly organic in nature and therefore have high resistance to

charge flow and have very slow decay time for charge dissipation (Matsusaka et al., 2010).

Pharmaceutical processing involves contacts between the pharmaceutical materials and the

equipment surfaces and hence there is always chance of electrostatic charging of the

materials. Various unit operations such as sizing, fluidisation, flow through hoppers, silo

transfer, mixing can generate charges in the materials. Mostly, there is direct proportionality

between the energy involved in a process and the electrostatic charge generation.

Triboelectrification is affected by the particle size, relative humidity (Grosvenor and

Staniforth, 1996; Rowley and Mackin, 2003), temperature, surface impurities (Eilbeck et al.,

2000), surface roughness, nature of contact (Eilbeck et al., 1999; Naik et al., 2016) and

various other factors.

2.4 Capillary force

Attractive capillary forces develop due to the formation of liquid bridges between contacting

particles in the presence of vapours. Due to the close contact between particles in a powder,

capillary condensation can occur at contact points even though the vapour partial pressure is

less than the vapour pressure of the liquid (Megias-Alguacil and Gauckler, 2010). For two

- 9 -

spherical particles in the pendular state, the maximum static liquid bridge or capillary force (

F cf ¿ is given by

Fcf =2∙ π ∙ R ∙ γ (4)

where, is the surface tension of liquid, and R is the radius of the spherical particles

However, like other interaction forces, capillary forces are also sensitive to particle properties

like shape, size or surface roughness. Recently, Butt et al. provided an analytical

approximation of the capillary force between the two spherical bodies taking into account the

surface roughness of the interacting particles (Butt and Kappl, 2009). According to this

model, the capillary force is given by equation 5:

Fcf =A0G (2cr−a ) γr (5)

where, G = asperity height

A0=π R2 (6)

where, R is particle radius, a is interparticle distance and 2cr is the distance that a circular arc

can span, where c is cosθ1+cosθ2

2 , θ1, θ2 are contact angles, is the surface tension of

liquid and r is the radius of curvature of the liquid-vapour interface of the meniscus normal

to the surface, which is given by the Kelvin equation (eq.7) based on the assumption r <<< l,

r=−λk

ln pp0

(7)

where, λk is Kelvin length, p is the actual vapour pressure, p0is the saturated vapour pressure.

High relative humidity conditions could increase interparticle forces due to increased

capillary interactions resulting in the formation of larger agglomerates and can cause decrease

in powder flow property (Amidon and Houghton, 1995; Karde and Ghoroi, 2015; Mollan and

Celik, 1995; Sun, 2016). Researches have also reported decreased aerosolisation or

- 10 -

dispersibility of fine powders exposed to high humidity conditions owing to increased

capillary forces (Das et al., 2009a; Young et al., 2003).

2.5 Solid bridge force

Solid bridge force is often the extension of liquid bridge formation between the particles.

Solid bridges are formed due to part solubilisation of the material surface in the adsorbed

layer of liquid followed by recrystallisation after evaporation of the fluid. Podczeck et al.

reported strong adhesion interaction between lactose and Salmeterol xinafoate particles

exposed to high humidity conditions due to formation of irreversible solid bridges (Podczeck

et al., 1997). Caking phenomenon of powder bed can occur due to the formation of large

number of solid bridges. Caking is the state in which the powder cannot be moved by

vigorously shaking or tapping of the container and usually occurs in water soluble powders

(Dawoodbhai and Rhodes, 1989). Teunou and Fitzpatrick reported the formation of strong

lactose crystal bridges in whey powder at high humidity conditions (Teunou and Fitzpatrick,

1999).

All the above mentioned interparticle interactions pose a hindrance to powder handling and

processing by adversely affecting their flow and packing properties.

2.6 Modelling approaches employed to predict interparticle interactions

Researchers have also used theoretical modelling and simulation approaches to study and

obtain information about the different parameters affecting interparticle interactions and

powder bulk behaviour. In the pharmaceutical industry, computational modelling methods

like the finite element method (FEM), discrete element method (DEM) and computational

fluid dynamics (CFD) have been successfully utilised to predict and explain powder

- 11 -

behaviour during different processes and also to gain better understanding of these different

pharmaceutical operations and processes. However, DEM simulation tools are of particular

interest here, as DEM employs different interparticle interaction models to calculate the

various cohesion and adhesion forces. Thus, these tools could simulate the powder bulk

behaviour, i.e. powder flow, through simultaneous integration of all the incorporated

interparticle interaction forces. Various theoretical models have been developed for DEM, to

account for the different interparticle contact (friction, mechanical interlocking, solid bridges)

and non-contact (van der Waals, electrostatic, liquid bridge force, hydrogen bonding, etc.)

interaction forces (Luding, 2005; Pei et al., 2015; Tykhoniuk et al., 2007; Zhu et al., 2007).

However, there are also several limitations associated with DEM modelling such as the

uncertainty in particle polydispersity (size and shape) effects on simulated processes (Mazzei,

2011) , difficulty in simulating full-scale pharmaceutical operations owing to the restriction

of modelling in the order of 106 particles (Bharadwaj, 2012; Kremer and Hancock, 2006) and

requiring computation with higher computational processing costs. Furthermore, as far as

interparticle adhesion is concerned, soft particle DEM methods underestimate the realistic

contact deformation modelling of particles. Assumptions such as the force-overlap of

particles are considered which might be insufficient to account for the multi-contact effects

and inhomogeneous stress distribution in particles (Luding, 2008).

A recent advancement in the field of DEM simulation is provided by software like ROCKY-

DEM developed by Granular Dynamics International. It is a powerful tool capable of

modelling non-spherical geometries of particles. Williams et al. successfully generated

irregular shaped particles using ROCKY 3D DEM software tool from the particle shape

- 12 -

descriptor data of iron ore particles obtained from image segmentation techniques (Williams

et al., 2014). The advantage of such advanced tools is that the near accurate generation of

irregular particles could yield better simulation results.

3. Towards developing mechanistic understanding of the role of particle properties

on overall bulk powder behaviour

3.1 Solid state properties

Chattoraj et al. and Ghosh and Reddy have examined the relationship between crystal

structure, crystal plasticity, and its tabletability (Chattoraj et al., 2010; Ghosh and Reddy,

2012a). Co-crystals of theophylline anhydrate and methyl gallate were prepared to improve

the tabletability of methyl gallate. To explain the plasticity differences between theophylline

anhydrate, methyl gallate, and co-crystal, Chattoraj et al. investigated slip systems and

dislocations for each system. Using molecular dynamics simulations, the principal slip

planes, and potential secondary slip planes were identified and linked to the crystal plasticity

(Chattoraj et al., 2010; Sun and Kiang, 2008).

Theophylline crystal structure showed molecules arranged in hydrogen bonded V-shaped

rigid columns, which can undergo facile motion under stress increasing probability of plastic

deformation at relatively lower critical yield stress. Compared to this methyl gallate crystal

structure was hydrogen bonded through complex three-dimensional networks resulting in the

absence of potential slip planes making it difficult to deform. On the other hand, co-crystals

with hydrogen bonds in 2D-layers resulting in easy slip between the layers making plastic

deformation easy (Chattoraj et al., 2010).

- 13 -

More recently, in order to investigate the effect of crystal packing on mechanical properties,

different co-crystals of caffeine elucidated a clear correlation between intermolecular

interactions within the crystal packing with the mechanical properties of a particular

crystalline system (Ghosh and Reddy, 2012a, 2012b). It was demonstrated that the 2D layers

of crystal packing possess hydrogen bonding with the adjacent layer resulting in multiple

weak specific interactions. Such 2D layers with interlayer weak interactions results in smooth

shearing upon application of mechanical stress. On the other hand, if the crystal packing

possessed 3D interlocked packing, the crystal demonstrates brittle behaviour upon applying

mechanical stress (Chattoraj et al., 2010; Ghosh and Reddy, 2012b).

Shariare et al. evaluated potential relationship between inter-planar d-spacing within the

crystal lattice of the particle and mechanical properties. Inter-planar d-spacing was also

related to the inter-planar interaction energy using more than 10 pharmaceutically relevant

compounds, including active pharmaceutical compounds and excipients. It was evident from

the results that as inter-planar d-spacing increases, brittleness index and brittle ductile

transition size increases. The results highlighted that inter-planar d-spacing can be used as a

first order indicator whether material behaves predominantly in brittle manner resulting in

brittle fracture. A very weak correlation between inter-planar interaction energy and

mechanical energy was revealed (Shariare et al., 2012).

Moreover, defects contained within the lattice of crystalline solids are reported to affect

mechanical properties of solid, and ultimately processing. The most common defects reported

are screw dislocations and lattice vacancies, which if present in high frequency is known to

result in breaking of particles and deformation during milling. McBride et al. correlated the

crystal structure and intermolecular forces with the elasticity of crystalline particles. They

- 14 -

concluded that if compression exceeds the intermolecular forces, permanent deformation

takes place during the compression (McBride et al., 1986). Plasticity has been linked to

several different crystal packing features like twinning, dislocation motion, kinking and

perturbation of lattice stability. Dislocation motions along specific slip planes are reported to

govern plasticity (Chattoraj et al., 2010). Effects of molecular arrangement in crystal lattices

for different polymorphs of an API on compaction and powder bulk density is also well

documented in the current literature (Di Martino et al., 1996), clearly highlighting the effect

of solid state properties on bulk powder properties for solids of pharmaceutical importance

(Hou and Sun, 2008). Di Martino et al. reported the effect of different polymorphic forms of

paracetamol on direct compression, highlighting the ease of direct compression of the

orthorhombic form of paracetamol (Di Martino et al., 1996).

3.2. Particle shape, size, and surface area

Among the listed particle properties, the literature extensively reports on the effect of surface

area, particle size, and particle shape on bulk cohesion (Fichtner et al., 2008; Kaerger et al.,

2004; Lam and Newton, 1992; Podczeck and Mia, 1996; Rasenack and Müller, 2002; Wong

and Pilpel, 1990). Farley and Valentin reported an empirical correlation between bulk

cohesion and the volume surface mean particle diameter for inorganic materials. It was

reported that the shear index (n) in the yield locus equation

( τC )

n

= σT

+1 (8)

where = shear stress, T = tensile stress, = normal stress, and C = cohesion, can be

correlated with the volume mean particle diameter via equation

- 15 -

n=1+ B(d )2/3 (9)

where, B is a constant and d is volume mean diameter (Definition of volume mean diameter

and method to calculate the same can be referred in appropriate ASTM standards (2015)).

Cohesion was found to increase with decreasing particle size and increasing surface area

(Farley and Valentin, 1968). Ridgway and Moreland first reported the effect of particle shape

on bulk density (Ridgway and Morland, 1977). Podczeck and Mia reported the effect of

particle size and shape on Haunser ratio and angle of internal friction (Podczeck and Mia,

1996). They also found that particles with higher aspect ratio (e.g. needle shaped crystal)

showed a higher angle of internal friction.

Kaerger et al. investigated the effect of particle shape and size on flow and compaction

behaviour of blends, revealing that blends containing spherical paracetamol particles

(prepared by sono-crystallisation) with microcrystalline cellulose had showed an

improvement in flow properties compared to micronised particles (Kaerger et al., 2004).

Rasenack and Müller studied the effect of different crystal shapes of ibuprofen on

compression and flow properties, highlighting an improvement in the densification of smooth

disc type crystal habit compared to other crystals habits. This was attributed to the increase in

powder bed porosity (Rasenack and Müller, 2002). Gamble et al. investigated the effect of

different sub-populations, e.g. agglomerates and primary particles elucidating the effect of the

presence of a few agglomerates in enhancing the flow properties of bulk primary particles

(Gamble et al., 2011). Hou and Sun investigated the effect of particle shape using MCC as a

test material. The findings revealed that smaller but more spherical particles flow better than

larger elongated particles (Hou and Sun, 2008).

- 16 -

The influence of particle size and size distributions on the flow behaviour of powder or

granular materials have been widely studied using DEM simulations (Guo et al., 2011; Zhou

et al., 2002). The DEM simulations, further validated with experimental findings, revealed

that a fine particle size fraction could significantly affect segregation during powder flow

through a hopper (Ketterhagen et al., 2007). Apart from this, using coupled DEM /CFD

simulations, Guo et al. (2011) studied the size induced segregation in binary mixtures,

involving coarser and finer particles during the die filling process of compression. The

authors reported that the varying particle size fractions in the mixture could lead to reduced

powder flow into the die cavity as well as segregation during the process (Guo et al., 2011).

Similarly, particle shape was also found to have a profound effect on the behaviour of

particulate material as observed from DEM simulation studies (Cleary and Sawley, 2002;

Fraige et al., 2008). Cleary and Sawley included the effect of different particle shape into the

DEM modelling to study its influence on the hopper discharge of particulate material. From

the simulation studies, they concluded that the irregularity in the particle shape (elongated or

angular particles) led to a decrease in the hopper flow rate (Cleary and Sawley, 2002).

It is well known that all interparticle interactions, are mainly governed by the surface (refer

section 2) and hence surface properties can have a substantial role on particle-particle

interactions. Many different studies investigating the effect of particle size or shape on

powder flow properties have been reported (Kaerger et al., 2004; Podczeck and Mia, 1996).

None of these studies investigated the effect of particle size on cohesion by normalising other

contributing attributes, i.e. surface energy, surface area, particle shape. It would be essential

to understand effect of individual surface attributes, i.e. particle shape, surface area, surface

roughness and surface energy, on interparticle interactions to determine controlling factors

and device control strategies.

- 17 -

3.3 Surface roughness

Surface roughness is one such particle surface property which could have a substantial effect

on interparticle interaction. The roughness increases the distance between contacting particles

and also decreases the contact area, and can lead to a reduction of the attractive interparticle

interactions. The role of surface roughness has been widely explored in literature, particularly

for dry powder inhaler (DPI) formulation performance which depends on carrier-drug

interaction (Adi et al., 2013; Donovan and Smyth, 2010; Flament et al., 2004; Podczeck,

1999; Tan et al., 2016). These studies suggest that surface roughness of the carrier is critical

for the efficient drug delivery in DPI formulations. Karner et al. studied the influence of

carrier particle roughness on its charging behaviour during blending process and also the

mixing homogeneity of binary blends. They reported an increase in charge saturation and

lower mixing homogeneity with rough mannitol carrier particles as compared to the smoother

particles (Karner et al., 2014). Meyer and Zimmerman suggested that the use of glidants like

silicon dioxide aided the flow behaviour of cohesive corn starch powder by creating surface

roughness and reducing interparticle interaction (Meyer and Zimmermann, 2004). Overall,

increase in particle surface roughness has been associated with decreasing cohesion and

increasing powder flow. However, some studies have also reported an improvement in

powder flow with smoothing of the roughened particle surfaces, which was attributed to the

decreased mechanical interlocking and reduced friction between interacting particles (Ferrari

et al., 2004; Genina et al., 2010; Shi et al., 2011). Raula et al. reported a decrease in the

emission and dispersion of L-Leucine coated salbutamol powders due to mechanical

interlocking with increase in asperity size (Raula et al., 2009). It is obvious from all these

studies that the scale of surface roughness is also an important determinant while considering

its effect on interparticle interaction.

- 18 -

3.4 Surface energetics

Surface energy of crystalline pharmaceutical materials has been demonstrated to be

anisotropic (Heng and Williams, 2006). Considering facet specific surface energy of a

crystalline material, it is postulated that surface energetics of the bulk crystalline material

depends on the relative surface energy contributions of different crystal facets. For

paracetamol, Heng et al. reported that for milled paracetamol the dispersive component of

surface energy increases with decreasing particle size and it was attributed to the surface

energy of the weakest attachment energy plane for paracetamol crystals (Heng et al., 2006). It

was argued that upon milling crystals fracture along weakest attachment energy plane (Heng

et al., 2006). For paracetamol, the weakest attachment energy plane was identified to be

(010), which was found to be hydrophobic (Heng and Williams, 2006).

Comparison of surface energetics for crystalline and amorphous powders of pharmaceuticals

has been reported in the literature (Buckton and Darcy, 1999). Amorphous powders are

reported to have substantially higher surface energy compared to crystalline powder, which

can be attributed to relative thermodynamic instability of the amorphous phase (Newell et al.,

2001). Wide variations in the measured surface energy for amorphous samples were reported.

Such larger variations have been attributed to the range of the different orientations of lactose

molecules that may exist on the surface of amorphous particles resulting in variation in

surface energy (Newell and Buckton, 2004). However it was rationally established by Newell

and Buckton that the amorphous phase may have relatively higher surface energy compared

to the corresponding crystalline phase, the findings from other studies vary greatly. There are

varying literature reports suggesting that amorphous material can have higher surface energy

compared to the corresponding crystalline phase (Chamarthy and Pinal, 2008; Otte and

- 19 -

Carvajal, 2011). The surface energy values for the amorphous and corresponding crystalline

phase is reported to vary with material type and method of processing (Luner et al., 2012).

York and co-workers investigated the effect of powder surface energy on adhesion properties

of API and carrier particles. Investigating adhesion of salbutamol sulphate on lactose

particles, Grimsey et al. concluded that higher API particle dispersive surface energy results

in greater adhesion on the carrier particles (Grimsey et al., 2002). They also investigated the

effect of specific surface energy on blend homogeneity of the particles, reporting a

correlation between the strength of interaction calculated from surface energy measurements

and homogeneity of a binary blend between theophylline and different excipient particles.

After initial studies by York and co-workers (Grimsey et al., 2002), many different studies

reported effect of surface energetics on interparticle interactions.

Literature reviewed in section 3 clearly highlights the fact that experimental studies reporting

the effects of particle properties like particle size, shape, surface area, surface roughness and

surface energy on interparticle interactions has been extensively studied. Each study

discussed, investigated and reported different attributes which can influence powder bulk

behaviour. All the studies reported in section 3 investigate the effect of one particle attribute,

i.e. surface area, on cohesion. While studying the effect of one particle attribute on cohesion,

it is essential to isolate other contributing attributes, i.e. surface energy, or shape of the

particle. It may be conceptually easy but practically difficult, considering experimental

difficulties in isolating effect of each contributing attributes.

Instead of isolating individual components, experimental approaches to decouple

contributions from different particle properties on cohesion, providing a method to identify

- 20 -

the critical particle property which can be controlled to get a handle on cohesion has been

recently proposed (Shah et al., 2014b, 2014c).

3.5 Decoupling contributions from different particle properties on cohesion

Shah et al. focused on investigating the effect of crystal habit on surface energy and cohesion

of bulk crystalline pharmaceutical materials. The surface energy of different crystal facets

was then correlated to the surface energy heterogeneity measurements of bulk crystalline

mefenamic acid. Furthermore, the cohesion of mefenamic crystals with different habits was

measured using a uniaxial compression test and correlated with the surface energy and crystal

shape to elucidate their effect on cohesion. Silanisation was employed to normalise the

surface energy of particulate materials, and decouple its contribution on cohesion from the

surface area. Needle shaped crystals were found to be 2.5 times more cohesive compared to

elongated plates or hexagonal cuboids, which is not surprising. Adopting similar

experimental approach, the contribution of acid-base and dispersive surface energy on

cohesion was determined. It was revealed for the particular compound under investigation

that the contribution from acid-base surface energy on cohesion was 11.7 times higher

compared to the contributions from dispersive surface energy. However, these and other

recent studies report the relative contribution of different surface attributes on cohesion for a

particular pharmaceutical system. The approach presented by Shah et al. (Shah et al., 2014a,

2014b, 2014c) to decouple and quantify the effect of different surface attributes allows

quantification of surface attributes for any pharmaceutical system of relevance.

It is evident that particle properties, particularly particle bulk properties and particle surface

properties (as referred in Scheme 1), have a direct influence on interparticle interactions.

Intrinsic difficulties exists in systematically correlating the effect of the individual particle

- 21 -

property to components of powder bulk behaviour, e.g. flowability, compaction. Furthermore,

future challenges also lie in characterising the contribution of different particle properties on

an individual component of powder bulk behaviour, as well as overall powder bulk

behaviour. The key to bridging the current knowledge gap, in developing correlations

between particle properties and powder bulk behaviour, is experimentally isolating the

contribution of one particular particle property and investigating its effect on an individual

component of powder bulk behaviour. In this direction, Shah et al. recently demonstrated an

approach to investigate the individual contribution of surface energy, surface area and

particle shape on cohesion. However some further work needs to be undertaken in order to

provide an accurate correlation of the particle properties with specific powder bulk

behaviour. Such advances can permit the prediction of powder bulk behaviour by measuring

certain particle properties.

4. Investigating the role of particle processing on particle properties, and ultimately

on interparticle interactions

4.1 Particle processing conditions, moisture and temperature

Two main processing conditions, temperature and moisture are known to affect interparticle

interaction. These extrinsic factors can influence the particle generation process or the

characteristics of the generated particles. Role of processing temperatures, particularly during

mechanical processing, on solid state properties or processed powders has been an area of

research interest for the last three decades, with many different studies relating temperature

changes during the milling related to amorphisation of pharmaceutical compounds (Burnett et

al., 2012; Feeley et al., 1998a; Otte and Carvajal, 2011). Furthermore, processing temperature

is reported to result in temperature induce solid-solid polymorphic transformation of

- 22 -

pharmaceutical compounds (Brittain, 2002). Low temperature processing, particularly

cryogenic temperatures, has resulted in chemical decomposition of pharmaceutical

compounds (Adrjanowicz et al., 2011). Processing temperatures are also known to affect

mechanical properties and particularly hardness of the material (Olusanmi et al., 2010).

Although, it has been reported that processing temperature can influence molecular and bulk

solid-state properties as well as the breakage behaviour of particles, there are presently

limited reports that investigate the role of processing temperatures, on surface properties and

its relation to powder flow behaviour. Teunou and Fitzpatrick while studying the effect of

humidity and temperature on the flowability of food powders indicated the importance of

parameters like time and area of exposure to these conditions while determining the actual

effects (Teunou and Fitzpatrick, 1999).York and Pilpel reported an increase in the cohesion

of stearic acid particles with an increase in temperature owing to the melting of the surface

asperities and the resultant changes in interparticle contacts (York and Pilpel, 1973).

In the presence of moisture, several different mechanisms can contribute to powder

cohesion, including but not limited to interparticle forces, i.e. van der Waals, electrostatic

forces and capillary bridge formation, etc. Hygroscopic materials are particularly more

susceptible to the liquid bridges resulting in strong interparticle interactions. Increasing

moisture content results in increased thickness of adsorbed layer of water on the particulate

surface forming high strength liquid bridges between particles. However, from the examples

discussed here, an increase in moisture content may not consistently result in a decrease in

flowability. As moisture layer thickness around a particle increases van der Waals forces are

strengthened due to reduced interparticle distance. Due to conductive properties of water,

electrostatic interactions decrease with increasing moisture content. As adsorbed moisture

- 23 -

forms a layer on particle surface, friction and mechanical interlocking between particles may

reduce resulting in improved flowability (Coelho and Harnby, 1978). On the other hand,

surface amorphous content can convert to crystalline material in the presence of moisture

resulting in different functional groups on the surface affecting cohesion (Newell et al.,

2001).

Moisture induced cohesion and its effect on powder flow behaviour have been also studied

using theoretical modelling and simulation approaches (Alexander et al., 2006; McCarthy,

2003). McCarthy, while investigating mixing in wet cohesive particulate system examined

from both computational and experimental methods, indicated that at intermediate cohesion

the mixing is improved only slightly as compared to that observed in dry particulate systems

(McCarthy, 2003).

Whilst the effect of atmospheric moisture on particle properties has been widely documented,

very few studies in the literature report the effect of atmospheric moisture on surface energy

and have linked particle properties to interparticle interaction. Consistent decrease in

dispersive surface energy with increasing moisture component has been reported for

amorphous lactose. Such behaviour can be attributed to the re-crystallisation of amorphous

particulates under humid conditions, particularly at the surface which is the area of interest.

Similar observations were also reported for different APIs.

Das et al. recently reported an increase in the specific surface energy when carrier (lactose)

and API particles were stored and conditioned during IGC analysis under humid

environment, which was attributed to the increase in concentration of water present on the

surface (Das et al., 2009b). On the other hand, they also reported a decrease in the specific

- 24 -

surface energy of samples stored at humid conditions but conditioned at 0% RH prior to

analysis. Agglomeration of particles accompanied by lower accessible surface sites were

implicated for the reduction in the specific surface energy (Das et al., 2009b). At higher

relative humidity, increased adhesion between API and carrier particles was also observed

resulting in low dispersability. Such behaviour was attributed to the increase in specific

surface energy.

Karde and Ghoroi recently investigated the role of humid environments on particulate surface

energy and powder flow properties. It was observed that the dispersive component of surface

energy for both hydrophilic and hydrophobic particulate materials were found to be relatively

unchanged, whereas the specific surface energy of the hydrophilic excipient was found to

increase with increasing relative humidity. Powder cohesion for the hydrophilic excipient was

found to increase with increasing relative humidity, which was attributed to the increase in

capillary bridge formation. They reported that the specific component of surface energy and

the powder flow behavioural changes followed similar trend (Karde and Ghoroi, 2015).

4.2 Particle generation approaches to modulate particle properties and interparticle

interaction

This section discusses the effect of different particle processing methods and processing

parameters on powder properties and interparticle interactions. Particle processing methods

are classified as bottom-up and top-down approaches. Discussion focusing on processing

parameters is detailed within each subsection describing the particular processing methods.

4.2.1 Bottom-up approaches

- 25 -

4.2.1.1 Crystallisation

Effects of solvent polarity, growth inhibitors, and crystallisation conditions, have been

employed to control crystal habits (Croker et al., 2015; Hammond et al., 2007a). In addition

to control of crystal shape, the focus of recent investigations has been to control particle size

and particle size distribution (Croker et al., 2015). More often such studies focus on

controlling nucleation and growth by precisely controlling the cooling profile in close vicinity

of a super-solubility curve of a crystallisation phase diagram (Acevedo and Nagy, 2014). The

super-solubility curve refers to the line in the crystallisation phase diagram separating

conditions where spontaneous nucleation occurs from conditions where the crystallisation

solution otherwise remained clear if undisturbed. Deviating from the conventional

crystallisation approaches, recent efforts also involve innovative seeding and templating

approaches to control crystal size and size distribution. Woo et al. used impinging jet

crystallisation to control seed size with a batch crystalliser operating at a controlled constant

growth rate to control particle size and crystal size distributions (Woo et al., 2011). Thakur et

al. employed mesoporous templates to control particle size and particle size distribution of

griseofulvin (Thakur et al., 2009). Entrapment of fast precipitating drug compound within the

geometric restrictions of mesoporous silica particles to restrict particle growth to produced

submicron particle of API embedded in silica. Silica assisted in increasing bulk density and

significantly improved API particle flow.

Manipulating crystal solid state properties is also frequently employed to investigate their

influence on interparticle interactions. Sun, employed effect of crystal hydration states on

surface energy and ultimately powder flow properties. Particle surface properties, like

surface energy, depends on the surface functional end groups exposed on the surface which

- 26 -

can be directly related to the crystal structure. Because the surfaces on a crystal are affected

by the structure, modification of surface properties can be achieved by altering the crystal

structure. Citric acid anhydrate, which is known to have poor flow properties, was exposed to

humidity resulting in citric acid monohydrate. Hydrate and solvates are known to have

different crystal structures. Citric acid monohydrate particles of similar size and morphology

to citric acid anhydrate resulted in improved flow properties, which was attributed to the

change in crystal surface properties due to change in hydration state (Sun, 2009).

4.2.1.2 Spray drying

Spray drying has been employed for particle generation, particularly for the generation of

amorphous API particles (Vehring, 2008). Careful optimisation of spray drying process

parameters allows controlling particle size, particle size distribution and particle shape

(Nandiyanto and Okuyama, 2011). Furthermore, milling or quench cooling has been

employed as an alternative to spray drying to produce amorphous particles. Compared to

other amorphous particle generation methods, spray drying results in controlled particle size,

shape resulting in better powder flow properties.

Process temperature for spray drying is also used to control particle surface roughness.

Crystalline mannitol particles with varying degree of surface roughness were prepared and

surface roughness was attributed to the different spray drying temperatures. Such surface

roughness control allowed increased adhesion with API particles, proposing mannitol as an

alternative carrier material for pulmonary drug delivery (Maas et al., 2011). Furthermore,

spray drying has also been employed as a processing route to prepare co-crystals of

theophylline-urea/ saccharine/ nicotinamide, substantially influencing it shape, powder flow

behaviour, and surface energy compared to the co-crystals prepared using co-milling

- 27 -

approach. Co-crystals prepared using co-milling had substantially higher surface energy,

wider particle size distribution, and irregular particle shapes, compared to spray dried

particles, resulting in relatively poor powder flow properties (Alhalaweh et al., 2013).

4.2.2 Top down approaches

4.2.2.1 Milling

Milling of pharmaceutical materials is one of the most common top-down approaches to

achieve a target particle size for formulation. Although milling is aimed at reducing particle

size, recent publications have also suggested that milling results in changes in particles shape

and surface properties (Luner et al., 2012), which can subsequently affect powder flowability

(Feeley et al., 1998b), wetting (Heng et al., 2006), mixing (Mackin et al., 2002), compaction

(Rasenack and Müller, 2002), and dissolution behaviour (Danesh et al., 2001).

Feeley et al. compared surface energy of micronised salbutamol sulphate at infinite dilution,

reporting increase in polar and dispersive component of surface energy as a result of

micronisation (Feeley et al., 1998a, 1998b). Furthermore, flow properties of micronised

powders were also qualitatively compared with the pre-micronised powders suggesting that

post micronisation powder flow behaviour was found to be poor. Such poor flow behaviour

was attributed to the increase in surface energy. Providing more insight, how milling may

affect surface properties, Heng et al. investigated the milling of paracetamol crystals, and

observed an increase in the dispersive component of surface energy upon milling. This was

attributed to the breakage of particles along the weakest attachment energy planes, which are

known to be the most hydrophobic and have high a dispersive component of surface energy

(Heng et al., 2006).

- 28 -

Similarly the effect of milling on the dispersive component surface energy of Ibuprofen was

reported by Han et al. (Han et al., 2013). On the other hand, it has been reported that upon

milling, the dispersive component of surface energy of milled particles was found to decrease

with increasing BR (Bounding Rectangle) aspect ratio, defined as the smallest encasing

rectangle fitted to the particle on the basis of Feret diameter. The decreasing trend in the

dispersive component of surface energy was explained by needle shaped crystals fracturing

along their shortest axis, exposing (011) plane with increased hydrophobicity (Ho et al.,

2012). These studies suggest that milling can result in processed material with heterogeneous

surface energetics, which can be due to the generation of new surfaces exposing different

crystal facets varying in facet specific surface energy.

The effect of milling intensity and milling temperatures on surface energy and ultimately on

mechanical properties of the particle, and cohesion has been widely reported in the literature

(Adrjanowicz et al., 2011; Brittain, 2002; Descamps et al., 2007; Dujardin et al., 2013, 2008;

Feeley et al., 1998a, 1998b). Study investigating two different and most commonly used

milling temperatures (room temperature, and cryogenic milling temperatures) on surface

energy and cohesion reported that surface energy and cohesion of powders milled at both

temperatures increases with increasing milling time, however milling temperature may affect

the particle mechanical properties (elasticity/ brittleness) resulting in significantly higher

surface area for cryogenic temperatures compared to room temperature milling conditions.

Such behaviour can be specific to the bulk properties of the compound. Application of

decoupling approaches by Shah et al. reported that the overall contribution from the surface

energy on cohesion of powders milled at room temperatures was significantly higher as

compared to that of cryogenic temperatures (Shah et al., 2015).

- 29 -

Luner et. al evaluated effect of high shear wet milling (HSWM) on particle surface

properties, compared to dry milling. For succinic acid and sucrose, findings revealed that the

milling method has no quantifiable impact on the particle bulk properties. For both the model

compounds under investigation, dispersive surface energy of the HSWM particles was found

to be higher compared to dry milled particles. The difference is more prominent in the case of

sucrose, where the dispersive surface energy for HSWM with ethanol as the solvent was

found to be approximately 2 fold higher compared to the dry milled sucrose. A direct

correlation between HSWM solvent polarity and end particle dispersive surface energy was

established. Increase in solvent polarity was found to result in higher dispersive surface

energy. Such behaviour was attributed to the combination of particle attrition in the presence

of the solvent and solvent adsorption on the surface during milling (Luner et al., 2012) .

Milling or micronisation is the most widely used particle size reduction method. However,

the effect of milling on particle properties remains poorly understood. The intrinsic difficulty

in correlating milling parameters with particle properties lies in uncertainty and poor

understanding of mechanism of particle breakage. It is evident that milling or micronisation is

an uncontrolled particle breakage process and can result in breakage of the weakest

attachment energy plane, geometrically weakest plane, or result in surface defects and surface

amorphisation. Such breaking behaviour can result in heterogeneous surfaces, resulting in

abrupt changes in particle textural properties, and surface energy heterogeneity (Guoxian et

al., 1995; Kwan et al., 2003; Shah et al., 2015; Shariare et al., 2012) which makes it

extremely difficult to link particle bulk behaviour with particle processing routes. The key

knowledge gap remains in investigating the role of milling type, and process parameters on

the particle breakage mechanism. Combined experimental and computational approaches can

- 30 -

reveal the effect of milling, and material intrinsic properties on the particle breakage

mechanism, which can allow the prediction of milled particle properties, and ultimately

powder bulk behaviour.

4.3 Blending

Blending involves particle-particle and particle wall collision resulting in generation and

accumulation of electrostatic charges. It has been observed that uncontrolled electrostatic

charging in the blending process results in strong cohesion among the API as well as

excipient particles. It was also observed that mixing of negatively charged API particles with

positively charged excipient particles resulted in better blend homogeneity, opening up

opportunity of improving blend homogeneity by carefully selecting excipient and API on the

basis of their triboelectric charging properties (Pu et al., 2009).

Overall, the effect of particle processing methods most relevant to the pharmaceutical powder

processing has been included, however the effect of some specific processing methods on

particle properties, i.e. contact drying, can be referred from the existing reviews which covers

a wide range of experimental and computations efforts in that particular subject area) (Sahni

and Chaudhuri, 2013, 2012).

4.4 Particle interaction with processing equipment surfaces

Apart from the interparticle interactions, attractive interaction can also lead to adhesion of

powder particles to the surfaces of the processing equipment causing processing problems

and undue losses. Among the adhesion interactions, electrostatic charge induced adhesion of

- 31 -

particles to the processing equipment surface is widely observed during pharmaceutical

processing. Charge transfer occurs by contact between the powder particles and the

equipment surface, therefore the nature of the contacting surface influences the electrostatic

charge generated.

Eilbeck et al. performed a study on the effect of different materials of construction of the

equipment on electrostatic charging for lactose powders. It was observed that with PVC and

polypropylene surfaces of a cyclone, the particles were positively charged whereas stainless

steel and acetal surfaces led to negatively charged particles. Also, a smooth stainless steel

surface produced a marginally higher charge than rough stainless steel, but the difference was

smaller than that observed between different material of construction (Eilbeck et al., 1999).

Furthermore, impurities present on the surface also affected the magnitude of the electrostatic

charges generated. Eilbeck et al. reported a decrease in the charging of lactose powders with

the use of uncleaned stainless steel surfaces (Eilbeck et al., 2000). Wang et al., while

highlighting the importance of surface roughness on particle adhesion, reported an increase in

the adhesion of mefenamic acid with increased surface roughness of the interacting stainless

steel surface during milling (Wang et al., 2015). Ibrahim et al. reported that the

physicochemical properties of the interacting surface also play a vital role in particle

adhesion to a surface. They reported from the scanning probe microscopy of gelatin capsules,

that the high surface heterogeneity and contrast friction caused increased adhesion of lactose

particles to the capsule surface (Ibrahim et al., 2000).

4.5 Computational efforts

- 32 -

Modelling and simulations have been utilised to study different pharmaceutical processes and

unit operations like blending, tablet compression (Ghadiri and Zhang, 2002; Han et al., 2003;

Mehrotra et al., 2009; Sinka et al., 2004; Tsunazawa et al., 2015), fluidisation (Liu et al.,

2016), aerosolisation (Tong et al., 2015), hopper flow (Cleary and Sawley, 2002) etc., from

the perspective of interparticle interaction and its effect on overall powder behaviour.

Mehrotra et al. (2009) studied the effect of cohesion on the tablet compression process using

3D DEM simulations. They observed that the cohesiveness of the material significantly

affected the die filling time which could lead to weight variation in tablets. Also, the cohesive

powders required considerable more energy during the compression stage to achieve the

desired tablet density. Additionally, they observed that in the monodisperse powder system

the compression force required was high as compared to the poly-disperse system owing to

the better rearrangement of smaller particles around the larger ones in the later situation

(Mehrotra et al., 2009). Similarly, Baxter et al. used DEM simulations to explain the

experimental findings of discharge of cohesive fine powders through hopper. They suggested

that, although the DEM simulations were performed considering different idealisations

(particle, size, shape, number of particles), it was able to effectively predict the discharge of

fine powders through the hopper (Baxter et al., 2000).

Derdour and Chan (2015) used theoretical models and simulations to predict the crystal size

distribution and aspect ratio during the crystallisation of a drug (Derdour and Chan, 2015).

Thus the complex and dynamic nature of interparticle interaction, depending on different

parameters involved, and its effect on different pharmaceutical operations can be successfully

studied from these theoretical and computational modelling approaches. These methods could

be employed as effective investigative and predictive tools in pharmaceutical processing.

- 33 -

However, there are also several limitations associated with this DEM modelling such as the

uncertainty in particle polydispersity (size and shape) effects on simulated processes (Mazzei,

2011), difficulty in simulating full-scale pharmaceutical operations owing to the restriction of

modelling in the order of 106 particles (Bharadwaj, 2012; Kremer and Hancock, 2006) and

requiring higher computational processing time and costs. Furthermore, as far as interparticle

adhesion is concerned, soft particle DEM methods underestimate the realistic contact

deformation modelling of particles. Assumptions such as the one on the force-overlap of

particles are considered which might be insufficient to account for the multi-contact effects

and inhomogeneous stress distribution in particles (Luding, 2008).

Linkages between the particle properties and the powder bulk behaviour reported in the

literature have been reviewed. The intrinsic challenges in developing experimental

approaches to investigate the role of an isolated particle property on specific powder bulk

behaviour have been highlighted. Furthermore, any correlation between particle processing

route and processing parameters on the end particle properties reported in the literature has

been reviewed. Challenges in developing a systematic correlation between processing routes

and parameters, on powder bulk properties remains in the understanding of the role of

processing methods and parameters on specific particle attributes, and utilising the correlation

in developing tailored end particle properties. The combination of both computational and

experimental approaches is to provide such understandings.

The effect of processing routes on particle properties, and particle properties on powder bulk

behaviour has been discussed in isolation in various literature reviewed. However, it can be

useful to investigate inter connectivity of particle processing routes, particle properties, and

bulk behaviour which remains a key gap in current literature.

- 34 -

To seed the idea of investigating interconnectivity between particle processing routes and

parameters, particle properties, and powder bulk behaviour, Scheme 3 is developed

proposing the idea of identifying a powder processability region considering the various

interconnecting factors to achieve desired powder bulk behaviour. The key idea is that a

thorough understanding of the different process parameters on end particle material and

particle properties will allow the selection of appropriate particle processing methods to

engineer particles with specific properties, ultimately providing a handle on controlling the

interparticle interactions.

.

5. Novel approaches for tailored surfaces to control cohesion

A perspective on some of the current and potential approaches for tailoring particle surfaces

and modulating the interparticle interactions for pharmaceutical applications is shown in

Scheme 4.

5.1 Crystal habit modification

The ability to tailor crystal habits has provided a means to optimise the relative contribution

of different crystal facets and ultimately tailoring surface energy of the bulk crystalline

material, which can provide a handle on interparticle interactions. Considering crystallisation

as a bottom up approach for processing particles, crystals of the same polymorphic form but

different crystal shapes (habits) can be obtained due to the varying relative growth rates of

different crystals facets. This in turn can be dependent on crystal intrinsic properties or

affected by properties of the crystallisation solvent, crystal growth inhibitors or additives

(Berkovitch-Yellin, 1985; Bourne and Davey, 1976; Lovette et al., 2008). Shah et al.

- 35 -

employed the effect of solvent polarity on the growth of crystal facets to obtain mefenamic

acid crystals with habits ranging from needles to hexagonal cuboid (Shah et al., 2014a). Such

approach allowed quantification of crystal shape on cohesion, revealing that needle shape

crystals can have cohesion 2.5 higher compared to hexagonal cuboid shape crystals.

Approach demonstrated by Shah et al. can provide a tool to control crystal habits and

ultimately provide the ability to control cohesion.

The crystal habit modification is a widely investigated subject (Blagden et al., 2007;

Hammond et al., 2007b). Experimental and computational reports on investigating role of

solvent properties (Stoica et al., 2004; Tilbury et al., 2016) as well as additives (Klapwijk et

al., 2016) on crystal habit have been described and reviewed extensively over the past decade

and can be referred to from the appropriate reviews.

5.2 Surface modification

5.2.1. Wet coating method

Solvent based wet coating is the most commonly used approach in pharmaceutical industry in

order to obtain desirable properties like improved powder flow, as well as for functional or

non-functional polymeric coatings on the finished products. Among the wet coating methods

employed specifically for powder flow improvement through physical modification of

particles, the fluid bed coating method is most frequently used and popular in pharmaceutical

industry. In the fluid bed coating process simultaneous application of coating and

agglomeration of particles is achieved by spraying the polymeric coating solution onto the

fluidised bed of particles.

- 36 -

Benelli et al. successfully achieved the encapsulation and agglomeration of

phytopharmaceutical compositions with improved flow properties using fluidised bed coating

(Benelli et al., 2015). However, in some instances where the flow improvement is required

without considerable particle size or shape alterations in the raw material, such methods

which include agglomeration of particles are not desired. Ehlers et al. employed fluidised bed

particle thin-coating (PTC) to obtain coated ibuprofen powder with improved flowability

without affecting the particle size, shape and size distribution (Ehlers et al., 2009). In another

study, Genina et al. used ultrasound-assisted fine polymeric mist deposition technique to

obtain thin coating on drug particles which resulted in a decreased cohesion forces and

improved flowability (Genina et al., 2010). The improvement in the flow property was

attributed to the surface modification of ibuprofen particles achieved from the application of

trace amounts of HPMC on the surface (Ehlers et al., 2009). Fluidised coating methods

become difficult with Geldart group C powders owing to their fine cohesive nature (Geldart,

1973). In order to circumvent this problem, To and Davé dry coated the fine cohesive

ibuprofen powder and subsequently used them in fluid bed thin polymeric coating (To and

Davé, 2015).

Alternatively, researchers have also utilised spray drying method for surface modification of

particles, reducing the cohesion and improving bulk behaviour of pharmaceutical powders

(Shi and Sun, 2011; Vanhoorne et al., 2014). In an attempt to improve drug delivery to the

lungs from DPI, Pilcer et al. reported an increased flowability and high fine particle fraction

(FPF) for lipid coated tobramycin particles generated using a spray drying method (Pilcer et

al., 2006). Although all these wet coating techniques are capable of modifying the surface

properties of particles, thereby reducing interparticle interaction and improving powder bulk

behaviour, there are several drawbacks associated with these methods. Wet coating

- 37 -

techniques are expensive, have high energy consumption and are also time consuming as they

involve long processing times and require additional operations like drying (Pandey et al.,

2014). There are safety and environmental concerns linked with wet coating approach,

whenever organic solvents are involved during processing. Thus, in order to overcome these

limitations, use of solvent less techniques like dry particle coating seems to be more effective

and efficient for creating engineered particle surfaces for better handling and processing.

5.2.2 Dry coating of particles

Recent trends in pharmaceutical technologies are towards the development of particle

engineering methods which overcomes the various disadvantages associated with solvent

based techniques. One such novel surface modification technique is known as dry powder or

particle coating (Pfeffer et al., 2001). It involves mechanical treatment of the powders

resulting in coating of bigger sized host particles with smaller sized guest particles.

Interparticle interaction force like van der Waals attraction between the smaller and larger

particles assisted by impaction forces provided by different coating or mixing devices helps

in clinging of the guest particles over host particles. Dry particle coating can be discrete or

continuous in nature depending on the amount or type of coating particles, type of coating

device and surface morphology of the host particles.

Davé and co-workers have extensively employed the dry particle coating technique in order

to reduce cohesion and improve the flow behaviour of pharmaceutical powders (Huang et al.,

2015a; Jallo et al., 2012; Mullarney et al., 2011). Han et al. reported that the reduction in

cohesion through surface modification of drug particles pre-blended with nano-silica could be

achieved simultaneously during the micronisation process using fluid energy mill (Han et al.,

2011). Sun and co-workers have reported improved manufacturability of pharmaceutical

- 38 -

powders and blends during tablet compression through surface modification (Osei-Yeboah

and Sun, 2015; Zhou et al., 2013, 2012). Likewise, Morton and co-workers have described

that dry coating could help to improve the drug delivery efficiency of DPI formulations by

modifying the cohesive–adhesive balance in the carrier and drug particles (Zhou and Morton,

2012; Zhou et al., 2010a, 2010b). In addition to the flow enhancement, Ghoroi et al. have

also reported an improvement in dispersibility of dry coated pharmaceutical powders, from

the pressure titrated particle size distribution results obtained using a dry dispenser and laser

diffraction system, by the virtue of reduced cohesion tendency (Ghoroi et al., 2013b).

Also, Karde et al. reported that the dry coating of corn starch with hydrophobic nano-silica

led to improved powder flow properties even at high relative humidity conditions as

compared to the raw corn starch powders (Karde et al., 2015). The reduction in interparticle

interactions of cohesive powders after dry coating was attributed to the increased nano-

scale roughness created by the guest particles (Chen et al., 2009; Yang et al., 2005) as well as

due to the passivation of higher energy sites on the host surface leading to decrease in

dispersive surface energy (Han et al., 2013; Karde and Ghoroi, 2014). A recent study by Jallo

and Davé also suggests that dry coating could be helpful in reducing the electrostatic

charging of micronised powders (Jallo and Dave, 2015). As far as the quality of coating is

concerned, Otles et al. reported that larger ratio of host to guest particle size and the higher

energy input during mixing, the better is the strength of the coating (Otles et al., 2011).

In principle, although the dry particle coating is similar to the conventional blending process,

it provides much better results than the later method in terms of bulk property improvement

and the overall quality of coating achieved (Han et al., 2012). However like any other

process, optimisation of dry particle coating process is necessary. Although this technique has

- 39 -

shown considerable potential in modifying particle surfaces and improving the bulk

behaviour of powders, it has some constraints related to the size and shape of particles (Chen

et al., 2008; Pfeffer et al., 2001). Sometimes size reduction can occur in case of highly brittle

materials during such highly intensive mixing (Han et al., 2011; Sato et al., 2012).

Furthermore, in some cases such drastic changes in bulk properties like powder flow and

compressibility can impact subsequent operations like tablet compression, mixing or can

impact the final product performance characteristics such as dissolution and content

uniformity (Tay et al., 2012). Thus, investigations involving effects of dry coating in relation

to process variables and final product performance needs to be investigated when utilising

dry coated materials. That being said, overall the solventless dry particle coating technique

offers a number of advantages over the conventional wet or solvent based techniques for

surface modification and flow improvement of powders. Apart from improving the overall

processes of pharmaceutical manufacturing it can provide huge benefits in reducing the

health, safety and environmental related issues. Being a dry technique it is much more

economical than processes involving liquids or solvents. Thus, it is a potential and promising

method producing tailored particles, which may provide a better control over pharmaceutical

processing and manufacturing.

5.2.3 Other potential approaches

Over the years, pharmaceutical powder processing has adopted many different processing

solutions to improve powder flowability from other material science disciplines. For

example, plasma treatment of metal and polymeric material has been used commonly to

improve adhesion properties. Recent efforts to control powder flow properties of

pharmaceutical powders involve low pressure plasma surface coating. Nanoparticle heating

and surface deposition of nanoparticle models has been employed to coat pharmaceutical

- 40 -

powders with nanoparticles (Pourali and Foroutan, 2015). Roth et al. have employed a

plasma coating method to coat SiOx nanoparticles on the lactose surfaces (Roth et al., 2011).

It was argued that such coated surface results in increase interparticle distance, with

minimum van der Waals forces between the two lactose particles, ultimately resulting in

improved flow. For different lactose particle sizes under investigation, it was revealed that

bulk density and flow factor increases with increasing particle sizes. More recently, Pourali

and Foroutan simulated nanoparticle coating in a low pressure plasma reactor (Pourali and

Foroutan, 2015). Plasma coating of pharmaceutical materials may have many advantages

over other coating methods, i.e. low processing temperature, uniform deposition, wide variety

of selection of coating material and chemistries, and resistance to agglomeration due to high

degree of charging, non-contact non-intrusive coating methods providing regulatory edge.

However, at present the major challenge lies with the application and optimisation of a

plasma coating technique for full-scale pharmaceutical coating operations. Also, mitigating

the risk of degradation or impurity generation during plasma irradiation or treatment needs to

be considered in pharmaceutical manufacturing (Ito et al., 2001; Weikart and Yasuda, 2000).

Consequently, the experimental approaches employing plasma coating for improving powder

flow of pharmaceutical powders is rare in current literature.

The use of an acoustic technique for mixing and dry coating operations in powders has been

tested employing devices referred to as resonant acoustic mixers (RAM). This technique does

not require the use of impellers or blades for mixing the powders but instead uses low

frequency, high intensity acoustic vibrations for mixing. Davé and co-workers have

successfully utilised this acoustic mixing technique for dry particle coating in order to

improve the bulk behaviour of fine pharmaceutical powders (Capece et al., 2014; Huang et

al., 2015b). These studies indicated that the surface modification led to improvement in

- 41 -

packing properties (reduced porosity), flow and compactibility of powders. These RAM

mixers can be used for mixing of wide variety of materials reducing the operation costs and

time due to requirement of almost negligible clean-up procedures. Considering the numerous

advantages listed, these approaches demonstrate great potential for surface treatment of

pharmaceutical powders.

Furthermore, due to the advances in colloids, it is possible to prepare nanoparticles with

desired surface properties. However, the challenge remains in effectively integrating such

nanoparticles on the surfaces of any relevant particulate material. Almost a decade ago,

gravure printing technology was developed to position sub-100 nm particles directly on the

specific surface feature of the carrier surface with high placement accuracy (Kraus et al.,

2007). Surfaces are carefully chosen so that wetting properties and geometry of the surface

only permits specific features of the surface to be covered by the nanoparticles.

Nanofabricated plate with specific surface features was used as a surface to study controlled

adhesion. Self-assembly of nanoparticle was used as a coating method to ink specific surface

features on the nanofabricated plates allowing printing at single particle resolution (Kraus et

al., 2007).

Although, the referred system has been developed for printing dry inorganic particles on the

polymers, semiconductors, and oxides, these principles can be used for covering surface

features and inconsistencies of milled pharmaceutical materials. Such coating can aid powder

flowability. Instead of selecting the surfaces as it has been demonstrated in the literature for

the semiconductors, selection of nanoparticles with optimum adhesion properties and

geometry to complement specific surface features of the milled pharmaceutical materials can

cover such features allowing controlled powder flow properties.

- 42 -

6. Summary and Outlook

This review provides a discussion on the studies linking particle properties, either innate or

those transformed through different particle processing approaches and parameters, to

powder bulk behaviour. Overall, it is evident from the literature that developing a

mechanistic understanding of different factors affecting interparticle interaction of

pharmaceutical powders is a work in progress. Particle engineering focuses traditionally on

understanding the effect of particle processing on particle properties, and effect of particle

properties on powder bulk behaviour in isolation. What appears to be missing in the current

spectrum is utilisation of understanding of how particle processing affects particle properties

to tune desired particle properties to obtain desired interparticle interactions and favoured

powder bulk behaviour. This review hints that a combination of experimental and

computational approaches could immensely help in understanding these complex inter-

relationships between different factors affecting powder behaviour, which could ultimately

pave the way for a successful pharmaceutical operation. However, establishing particle to

powder bulk behavioural linkages with a view of predicting powder behaviour in actual

pharmaceutical settings indicate a level of complexity involved, owing to difficulty in

identifying the critical and relevant performance characteristics. Additionally, sometimes the

bulk measurement indicators during characterisation may not be able to define or resolve the

suitable aspect of performance.

Reflection on various solutions obtained by particle engineers to improve understanding of

powder processing reveals great degree of adaptations from other engineering disciplines.

Understanding adapted from other disciplines on how plasma etching, resonant acoustic

- 43 -

mixing, and nanoparticle printing affects particle properties, and potential use of such

understanding to apply these particle processing methods to control interparticle interactions

is demonstrated. Thus, the future work can focus extensively on the innovation of such

platform technologies for particle engineering in pharmaceutical applications.

In conclusion, owing to the multifactorial dependence of powder behaviour, the future

research should focus on gaining insight into the particle to powder bulk level inter-relation,

which eventually can be exploited for employing simple and cost effective approaches in

pharmaceutical manufacturing. In other words, a holistic view towards these factors

influencing the powder behaviour is recommended for efficient powder processing and

product manufacturing.

- 44 -

References

Acevedo, D., Nagy, Z.K., 2014. Systematic classification of unseeded batch crystallization systems for achievable shape and size analysis. J. Cryst. Growth 394, 97–105.

Adi, S., Adi, H., Chan, H.K., Tong, Z., Yang, R., Yu, A., 2013. Effects of mechanical impaction on aerosol performance of particles with different surface roughness. Powder Technol. 236, 164–170.

Adrjanowicz, K., Kaminski, K., Grzybowska, K., Hawelek, L., Paluch, M., Gruszka, I., Zakowiecki, D., Sawicki, W., Lepek, P., Kamysz, W., Guzik, L., 2011. Effect of cryogrinding on chemical stability of the sparingly water-soluble drug furosemide. Pharm. Res. 28, 3220–3236.

Alexander, A.W., Chaudhuri, B., Faqih, A., Muzzio, F.J., Davies, C., Tomassone, M.S., 2006. Avalanching flow of cohesive powders. Powder Technol. 164, 13–21.

Alhalaweh, A., Kaialy, W., Buckton, G., Gill, H., Nokhodchi, A., Velaga, S.P., 2013. Theophylline cocrystals prepared by spray drying: Physicochemical properties and aerosolization performance. AAPS PharmSciTech 14, 265–276.

Amidon, G.E., Houghton, M.E., 1995. The effect of moisture on the mechanical and powder flow properties of microcrystalline cellulose. Pharm. Res. 12, 923–929.

Baxter, J., Abou-Chakra, H., Tüzün, U., Mills Lamptey, B., 2000. A DEM simulation and experimental strategy for solving fine powder flow problems. Chem. Eng. Res. Des. 78, 1019–1025.

Benelli, L., Cortes-Rojas, D.F., Souza, C.R.F., Oliveira, W.P., 2015. Fluid bed drying and agglomeration of phytopharmaceutical compositions. Powder Technol. 273, 145–153.

Berkovitch-Yellin, Z., 1985. Toward an ab initio derivation of crystal morphology. J. Am. Chem. Soc. 107, 8239–8253.

Bharadwaj, R., 2012. Using DEM to solve bulk material handling problems. Chem. Eng. Prog. 108, 54–58.

Blagden, N., de Matas, M., Gavan, P.T., York, P., 2007. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Adv. Drug Deliv. Rev. 59, 617–630.

Bourne, J.R., Davey, R.J., 1976. The role of solvent-solute interactions in determining crystal growth mechanisms from solution: I. The surface entropy factor. J. Cryst. Growth 36, 278–286.

Brittain, H.G., 2002. Effects of mechanical processing on phase composition. J. Pharm. Sci. 91, 1573–1580.

- 45 -

Buckton, G., 2000. Interfacial phenomena in drug delivery and targeting. Harwood Academic, Switzerland.

Buckton, G., 1995. Surface characterization: understanding sources of variability in the production and use of pharmaceuticals. J. Pharm. Pharmacol. 47, 265–75.

Buckton, G., Darcy, P., 1999. Assessment of disorder in crystalline powders—a review of analytical techniques and their application. Int. J. Pharm. 179, 141–158.

Buckton, G., Gill, H., 2007. The importance of surface energetics of powders for drug delivery and the establishment of inverse gas chromatography. Adv. Drug Deliv. Rev. 59, 1474–1479.

Burnett, D.J., Khoo, J., Naderi, M., Heng, J.Y.Y., Wang, G.D., Thielmann, F., 2012. Effect of processing route on the surface properties of amorphous indomethacin measured by inverse gas chromatography. AAPS PharmSciTech 13, 1511–1517.

Butt, H.-J., Kappl, M., 2009. Normal capillary forces. Adv. Colloid Interface Sci. 146, 48–60.

Capece, M., Huang, Z., To, D., Aloia, M., Muchira, C., Dave, R.N., Yu, A.B., 2014. Prediction of porosity from particle scale interactions: Surface modification of fine cohesive powders. Powder Technol. 254, 103–113.

Castellanos, A., 2005. The relationship between attractive interparticle forces and bulk behaviour in dry and uncharged fine powders. Adv. Phys. 54, 263–376.

Chamarthy, S.P., Pinal, R., 2008. The nature of crystal disorder in milled pharmaceutical materials. Colloids Surf. A Phys. Eng. Asp. 331, 68–75.

Chattoraj, S., Shi, L., Sun, C.C., 2010. Understanding the relationship between crystal structure, plasticity and compaction behaviour of theophylline, methyl gallate, and their 1 : 1 co-crystal. CrystEngComm 12, 2466–2472.

Chen, Y., Yang, J., Dave, R.N., Pfeffer, R., 2009. Granulation of cohesive Geldart group C powders in a Mini-Glatt fluidized bed by pre-coating with nanoparticles. Powder Technol. 191, 206–217.

Chen, Y., Yang, J., Dave, R.N., Pfeffer, R., 2008. Fluidization of coated group C powders. AIChE J. 54, 104–121.

Cleary, P.W., Sawley, M.L., 2002. DEM modelling of industrial granular flows : 3D case studies and the effect of particle shape on hopper discharge. Appl. Math. Model. 26, 89–111.

Coelho, M.C., Harnby, N., 1978. Moisture bonding in powders. Powder Technol. 20, 201–205.

Croker, D.M., Kelly, D.M., Horgan, D.E., Hodnett, B.K., Lawrence, S.E., Moynihan, H.A., Rasmuson, Å.C., 2015. Demonstrating the influence of solvent choice and crystallization conditions on phenacetin crystal habit and particle size distribution. Org. Process Res. Dev. 19, 1826–1836.

Crowder, T.M., Hickey, A.J., Louey, M.D., Orr, N., 2003. A Guide to Pharmaceutical Particulate Science. Interpharm/CRC, Boca Raton London New York Washington, D.C.

- 46 -

Danesh, A., Connell, S., Davies, M., Roberts, C., Tendler, S.B., Williams, P., Wilkins, M.J., 2001. An in situ dissolution study of aspirin crystal planes (100) and (001) by atomic force microscopy. Pharm. Res. 18, 299–303.

Das, S., Larson, I., Young, P., Stewart, P., 2009a. Agglomerate properties and dispersibility changes of salmeterol xinafoate from powders for inhalation after storage at high relative humidity. Eur. J. Pharm. Sci. 37, 442–450.

Das, S., Larson, I., Young, P., Stewart, P., 2009b. Surface energy changes and their relationship with the dispersibility of salmeterol xinafoate powders for inhalation after storage at high RH. Eur. J. Pharm. Sci. 38, 347–54.

Dawoodbhai, S., Rhodes, C.T., 1989. The effect of moisture on powder flow and on compaction and physical stability of tablets. Drug Dev. Ind. Pharm. 15, 1577–1600.

Derdour, L., Chan, E.J., 2015. A model for supersaturation and aspect ratio for growth dominated crystallization from solution. AIChE J. 61, 4456–4469.

Derjaguin, B. V, Muller, V.M., Toporov, Y.P., 1994. Effect of contact deformations on the adhesion of particles. Prog. Surf. Sci. 45, 131–143.

Descamps, M., Willart, J.F., Dudognon, E., Caron, V., 2007. Transformation of pharmaceutical compounds upon milling and comilling: The role of Tg. J. Pharm. Sci. 96, 1398–1407.

Di Martino, P., Guyot-Hermann, A.M., Conflant, P., Drache, M., Guyot, J.C., 1996. A new pure paracetamol for direct compression: The orthorhombic form. Int. J. Pharm. 128, 1–8.

Donovan, M.J., Smyth, H.D.C., 2010. Influence of size and surface roughness of large lactose carrier particles in dry powder inhaler formulations. Int. J. Pharm. 402, 1–9.

Dujardin, N., Willart, J.F., Dudognon, E., Danède, F., Descamps, M., 2013. Mechanism of solid state amorphization of glucose upon milling. J. Phys. Chem. B 117, 1437–1443.

Dujardin, N., Willart, J.F., Dudognon, E., Hédoux, A., Guinet, Y., Paccou, L., Chazallon, B., Descamps, M., 2008. Solid state vitrification of crystalline and -D-glucose by mechanical milling. Solid State Commun. 148, 78–82.

Ehlers, H., Räikkönen, H., Antikainen, O., Heinämäki, J., Yliruusi, J., 2009. Improving flow properties of ibuprofen by fluidized bed particle thin-coating. Int. J. Pharm. 368, 165–170.

Eilbeck, J., Rowley, G., Carter, P.A., Fletcher, E.J., 2000. Effect of contamination of pharmaceutical equipment on powder triboelectrification. Int. J. Pharm. 195, 7–11.

Eilbeck, J., Rowley, G., Carter, P.A., Fletcher, E.J., 1999. Effect of materials of construction of pharmaceutical processing equipment and drug delivery devices on the triboelectrification of size-fractionated Lactose. Pharm. Pharmacol. Commun. 5, 429–433.

Farley, R., Valentin, F.H.H., 1968. Effect of particle size upon the strength of powders. Powder Technol. 1, 344–354.

- 47 -

Feeley, J.C., York, P., Sumby, B.S., Dicks, H., 1998a. Comparison of the surface properties of salbutamol sulphate prepared by micronization and a supercritical fluid technique. J. Pharm. Pharmacol. 50, 54.

Feeley, J.C., York, P., Sumby, B.S., Dicks, H., 1998b. Determination of surface properties and flow characteristics of salbutamol sulphate, before and after micronisation. Int. J. Pharm. 172, 89–96.

Feng, Y., Grant, D.J.W., Sun, C.C., 2007. Influence of crystal structure on the tableting properties of n-alkyl 4-hydroxybenzoate esters (parabens). J. Pharm. Sci. 96, 3324–3333.

Ferrari, F., Cocconi, D., Bettini, R., Giordano, F., Santi, P., Tobyn, M., Price, R., Young, P., Caramella, C., Colombo, P., 2004. The surface roughness of lactose particles can be modulated by wet-smoothing using a high-shear mixer. AAPS PharmSciTech 5, 69–74.

Fichtner, F., Mahlin, D., Welch, K., Gaisford, S., Alderborn, G., 2008. Effect of surface energy on powder compactibility. Pharm. Res. 25, 2750–2759.

Flament, M.-P., Leterme, P., Gayot, A., 2004. The influence of carrier roughness on adhesion, content uniformity and the in vitro deposition of terbutaline sulphate from dry powder inhalers. Int. J. Pharm. 275, 201–209.

Fraige, F.Y., Langston, P.A., Chen, G.Z., 2008. Distinct element modelling of cubic particle packing and flow. Powder Technol. 186, 224–240.

Gamble, J.F., Chiu, W.S., Tobyn, M.J., 2011. Investigation into the impact of sub-populations of agglomerates on the particle size distribution and flow properties of conventional microcrystalline cellulose grades. Pharm. Dev. Technol. 16, 542–548.

Gamble, J.F., Leane, M., Olusanmi, D., Tobyn, M., Šupuk, E., Khoo, J., Naderi, M., 2012. Surface energy analysis as a tool to probe the surface energy characteristics of micronized materials—A comparison with inverse gas chromatography. Int. J. Pharm. 422, 238–244.

Geldart, D., 1973. Types of gas fluidization. Powder Technol. 7, 285–292.

Genina, N., Raikkonen, H., Ehlers, H., Heinamaki, J., Veski, P., Yliruusi, J., 2010. Thin-coating as an alternative approach to improve flow properties of ibuprofen powder. Int. J. Pharm. 387, 65–70.

Ghadiri, M., Zhang, Z., 2002. Impact attrition of particulate solids. Part 1: A theoretical model of chipping. Chem. Eng. Sci. 57, 3659–3669.

Ghoroi, C., Gurumurthy, L., McDaniel, D.J., Jallo, L.J., Davé, R.N., 2013a. Multi-faceted characterization of pharmaceutical powders to discern the influence of surface modification. Powder Technol. 236, 63–74.

Ghoroi, C., Han, X., To, D., Jallo, L., Gurumurthy, L., Davé, R.N., 2013b. Dispersion of fine and ultrafine powders through surface modification and rapid expansion. Chem. Eng. Sci. 85, 11–24.

Ghosh, S., Reddy, C.M., 2012a. Elastic and bendable caffeine cocrystals: Implications for the design of flexible organic materials. Angew. Chemie Int. Ed. 51, 10319–10323.

- 48 -

Ghosh, S., Reddy, C.M., 2012b. Co-crystals of caffeine with substituted nitroanilines and nitrobenzoic acids: Structure-mechanical property and thermal studies. CrystEngComm 14, 2444–2453.

Grimsey, I.M., Feeley, J.C., York, P., 2002. Analysis of the surface energy of pharmaceutical powders by inverse gas chromatography. J. Pharm. Sci. 91, 571–583.

Grosvenor, M.P., Staniforth, J.N., 1996. The influence of water on electrostatic charge retention and dissipation in pharmaceutical compacts for powder coating. Pharm. Res. 13, 1725–1729.

Guo, Y., Wu, C.Y., Kafui, K.D., Thornton, C., 2011. 3D DEM/CFD analysis of size-induced segregation during die filling. Powder Technol. 206, 177–188.

Guoxian, L., Erde, W., Zhongren, W., 1995. Effects of ball-milling intensity on the amorphization rate of mixed Ni50Ti50 powders. J. Mater. Process. Technol. 51, 122–130.

Hammond, R.B., Pencheva, K., Ramachandran, V., Roberts, K.J., 2007a. Application of grid-based molecular methods for modeling solvent-dependent crystal growth morphology: Aspirin crystallized from aqueous ethanolic solution. Cryst. Growth Des. 7, 1571–1574.

Hammond, R.B., Pencheva, K., Roberts, K.J., Auffret, T., 2007b. Quantifying solubility enhancement due to particle size reduction and crystal habit modification: case study of acetyl salicylic acid. J. Pharm. Sci. 96, 1967–1973.

Han, T., Levy, A., Kalman, H., 2003. DEM simulation for attrition of salt during dilute-phase pneumatic conveying. Powder Technol. 129, 92–100.

Han, X., Ghoroi, C., Davé, R., 2012. Dry coating of micronized API powders for improved dissolution of directly compacted tablets with high drug loading. Int. J. Pharm. 442, 74–85.

Han, X., Ghoroi, C., To, D., Chen, Y., Davé, R., 2011. Simultaneous micronization and surface modification for improvement of flow and dissolution of drug particles. Int. J. Pharm. 415, 185–195.

Han, X., Jallo, L., To, D., Ghoroi, C., Davé, R., 2013. Passivation of high-surface-energy sites of milled ibuprofen crystals via dry coating for reduced cohesion and improved flowability. J. Pharm. Sci. 102, 2282–2296.

Heng, J.Y.Y., Thielmann, F., Williams, D.R., 2006. The effects of milling on the surface properties of form I paracetamol crystals. Pharm. Res. 23, 1918–27.

Heng, J.Y.Y., Williams, D.R., 2006. Wettability of paracetamol polymorphic forms I and II. Langmuir 22, 6905–6909.

Ho, R., Naderi, M., Heng, J.Y.Y., Williams, D.R., Thielmann, F., Bouza, P., Keith, A., Thiele, G., Burnett, D., 2012. Effect of milling on particle shape and surface energy heterogeneity of needle-shaped crystals. Pharm. Res. 29, 2806–2816.

Hou, H., Sun, C.C., 2008. Quantifying effects of particulate properties on powder flow properties using a ring shear tester. J. Pharm. Sci. 97, 4030–4039.

- 49 -

Huang, Z., Scicolone, J. V., Gurumuthy, L., Dave, R.N., 2015a. Flow and bulk density enhancements of pharmaceutical powders using a conical screen mill: A continuous dry coating device. Chem. Eng. Sci. 125, 209–224.

Huang, Z., Scicolone, J. V., Han, X., Dave, R.N., 2015b. Improved blend and tablet properties of fine pharmaceutical powders via dry particle coating. Int. J. Pharm. 478, 447–455.

Ibrahim, T.H., Burk, T.R., Etzler, F.M., Neuman, R.D., 2000. Direct adhesion measurements of pharmaceutical particles to gelatin capsule surfaces. J. Adhes. Sci. Technol. 14, 1225–1242.

Ito, K., Kondo, S., Kuzuya, M., 2001. A new drug delivery system using plasma-irradiated pharmaceutical aids. IX. Controlled-release of theophylline from double-compressed tablet composed of cellulose derivatives as wall material. Chem. Pharm. Bull. (Tokyo). 49, 1615–20.

Jallo, L.J., Dave, R.N., 2015. Explaining electrostatic charging and flow of surface-modified acetaminophen powders as a function of relative humidity through surface energetics. J. Pharm. Sci. 107, 2252–22.

Jallo, L.J., Ghoroi, C., Gurumurthy, L., Patel, U., Davé, R.N., 2012. Improvement of flow and bulk density of pharmaceutical powders using surface modification. Int. J. Pharm. 423, 213–25.

Johnson, K.L., 1999. Mechanics of adhesion. Tribol. Int. 31, 413–418.

Kaerger, J.S., Edge, S., Price, R., 2004. Influence of particle size and shape on flowability and compactibility of binary mixtures of paracetamol and microcrystalline cellulose. Eur. J. Pharm. Sci. 22, 173–179.

Karde, V., Ghoroi, C., 2015. Fine powder flow under humid environmental conditions from the perspective of surface energy. Int. J. Pharm. 485, 192–201.

Karde, V., Ghoroi, C., 2014. Influence of surface modification on wettability and surface energy characteristics of pharmaceutical excipient powders. Int. J. Pharm. 475, 351–363.

Karde, V., Panda, S., Ghoroi, C., 2015. Surface modification to improve powder bulk behavior under humid conditions. Powder Technol. 278, 181–188.

Karner, S., Maier, M., Littringer, E., Urbanetz, N.A., 2014. Surface roughness effects on the tribo-charging and mixing homogeneity of adhesive mixtures used in dry powder inhalers. Powder Technol. 264, 544–549.

Katainen, J., Paajanen, M., Ahtola, E., Pore, V., Lahtinen, J., 2006. Adhesion as an interplay between particle size and surface roughness. J. Colloid Interface Sci. 304, 524–9.

Ketterhagen, W.R., Curtis, J.S., Wassgren, C.R., Kong, A., Narayan, P.J., Hancock, B.C., 2007. Granular segregation in discharging cylindrical hoppers : A discrete element and experimental study. Chem. Eng. Sci. 62, 6423–6439.

Klapwijk, A.R., Simone, E., Nagy, Z.K., Wilson, C.C., 2016. Tuning crystal morphology of succinic acid using a polymer additive. Cryst. Growth Des. 16, 4349–4359.

- 50 -

Kraus, T., Malaquin, L., Schmid, H., Riess, W., Spencer, N.D., Wolf, H., 2007. Nanoparticle printing with single-particle resolution. Nat Nano 2, 570–576.

Kremer, D.M., Hancock, B.C., 2006. Process simulation in the pharmaceutical industry: a review of some basic physical models. J. Pharm. Sci. 95, 517–529.

Kumar, A., Staedler, T., Jiang, X., 2013. Role of relative size of asperities and adhering particles on the adhesion force. J. Colloid Interface Sci. 409, 211–218.

Kwan, C.C., Ghadiri, M., Papadopoulos, D.G., Bentham, A.C., 2003. The effects of operating conditions on the milling of microcrystalline cellulose. Chem. Eng. Technol. 26, 185–190.

Kwok, P.C.L., Chan, L.K., 2007. Electrostatic charge in pharmaceutical systems Informa Healthcare, in: J, S. (Ed.), Encyclopedia of Pharmaceutical Technology. Marcel Dekker, New York, pp. 1535–1547.

Lam, D.C.C., Nakagawa, M., 1994. Packing of particles (Part 3) Effect of particle size distribution shape on composite packing density of bimodal mixtures. J. Ceram. Soc. Japan 102, 133–138.

Lam, K.K., Newton, J.M., 1992. Influence of particle size on the adhesion behaviour of powders, after application of an initial press-on force. Powder Technol. 73, 117–125.

Liu, P., LaMarche, C.Q., Kellogg, K.M., Hrenya, C.M., 2016. Fine-particle defluidization: Interaction between cohesion, Young׳s modulus and static bed height. Chem. Eng. Sci. 145, 266–278.

Lovette, M.A., Browning, A.R., Griffin, D.W., Sizemore, J.P., Snyder, R.C., Doherty, M.F., 2008. Crystal shape engineering. Ind. Eng. Chem. Res. 47, 9812–9833.

Luding, S., 2008. Cohesive, frictional powders: contact models for tension. Granul. Matter 10, 235.

Luding, S., 2005. Shear flow modeling of cohesive and frictional fine powder. Powder Technol. 158, 45–50.

Luner, P.E., Zhang, Y., Abramov, Y.A., Carvajal, M.T., 2012. Evaluation of milling method on the surface energetics of molecular crystals using inverse gas chromatography. Cryst. Growth Des. 12, 5271–5282.

Maas, S.G., Schaldach, G., Littringer, E.M., Mescher, A., Griesser, U.J., Braun, D.E., Walzel, P.E., Urbanetz, N.A., 2011. The impact of spray drying outlet temperature on the particle morphology of mannitol. Powder Technol. 213, 27–35.

Mackin, L., Sartnurak, S., Thomas, I., Moore, S., 2002. The impact of low levels of amorphous material (<5%) on the blending characteristics of a direct compression formulation. Int. J. Pharm. 231, 213–226.

Matsusaka, S., Maruyama, H., Matsuyama, T., Ghadiri, M., 2010. Triboelectric charging of powders: A review. Chem. Eng. Sci. 65, 5781–5807.

Mazzei, L., 2011. Limitations of quadrature-based moment methods for modeling inhomogeneous polydisperse fluidized powders. Chem. Eng. Sci. 66, 3628–3640.

- 51 -

McBride, J.M., Segmuller, B.E., Hollingsworth, M.D., Mills, D.E., Weber, B.A., 1986. Mechanical stress and reactivity in organic solids. Science . 234, 830–835.

McCarthy, J.J., 2003. Micro-modeling of cohesive mixing processes. Powder Technol. 138, 63–67.

Megias-Alguacil, D., Gauckler, L.J., 2010. Analysis of the capillary forces between two small solid spheres binded by a convex liquid bridge. Powder Technol. 198, 211–218.

Mehrotra, A., Chaudhuri, B., Faqih, A., Tomassone, M.S., Muzzio, F.J., 2009. A modeling approach for understanding effects of powder flow properties on tablet weight variability. Powder Technol. 188, 295–300.

Meyer, K., Zimmermann, I., 2004. Effect of glidants in binary powder mixtures. Powder Technol. 139, 40–54.

Mollan, M.J., Celik, M., 1995. The effects of humidity and storage time on the behavior of maltodextrins for direct compression. Int. J. Pharm. 114, 23–32.

Mullarney, M.P., Beach, L.E., Davé, R.N., Langdon, B.A., Polizzi, M., Blackwood, D.O., 2011. Applying dry powder coatings to pharmaceutical powders using a comil for improving powder flow and bulk density. Powder Technol. 212, 397–402.

Naik, S., Sarkar, S., Hancock, B., Rowland, M., Abramov, Y., Yu, W., Chaudhuri, B., 2016. An experimental and numerical modeling study of tribocharging in pharmaceutical granular mixtures. Powder Technol. 297, 211–219.

Nandiyanto, A.B.D., Okuyama, K., 2011. Progress in developing spray-drying methods for the production of controlled morphology particles: From the nanometer to submicrometer size ranges. Adv. Powder Technol. 22, 1–19.

Newell, H., Buckton, G., 2004. Inverse gas chromatography: investigating whether the technique preferentially probes high energy sites for mixtures of crystalline and amorphous lactose. Pharm. Res. 21, 1440–1444.

Newell, H.E., Buckton, G., Butler, D.A., Thielmann, F., Williams, D.R., 2001. The use of inverse phase gas chromatography to study the change of surface energy of amorphous lactose as a function of relative humidity and the processes of collapse and crystallisation. Int. J. Pharm. 217, 45–56.

Olusanmi, D., Wang, C., Ghadiri, M., Ding, Y., Roberts, K.J., 2010. Effect of temperature and humidity on the breakage behaviour of Aspirin and sucrose particles. Powder Technol. 201, 248–252.

Osei-Yeboah, F., Sun, C.C., 2015. Tabletability modulation through surface engineering. J. Pharm. Sci. 104, 2645–2648.

Otles, S., Lecoq, O., Dodds, J. a., 2011. Dry particle high coating of biopowders: An energy approach. Powder Technol. 208, 378–382.

Otte, A., Carvajal, M.T., 2011. Assessment of milling-induced disorder of two pharmaceutical compounds. J. Pharm. Sci. 100, 1793–1804.

Pandey, P., Bindra, D.S., Gour, S., Trinh, J., Buckley, D., Badawy, S., 2014. Excipient–

- 52 -

Process interactions and their impact on tablet compaction and film coating. J. Pharm. Sci. 103, 3666–3674.

Pei, C., Wu, C.Y., Adams, M., 2015. Numerical analysis of contact electrification of non-spherical particles in a rotating drum. Powder Technol. 285, 110–122.

Pfeffer, R., Dave, R.N., Wei, D., Ramlakhan, M., 2001. Synthesis of engineered particulates with tailored properties using dry particle coating. Powder Technol. 117, 40–67.

Pietsch, W., 1997. Size enlargement by agglomeration, in: Fayed, M.E., Otten, L. (Eds.), Hand Book of Powder Science and Technology. Chapman and Hall, New York, pp. 202–377.

Pilcer, G., Sebti, T., Amighi, K., 2006. Formulation and characterization of lipid-coated tobramycin particles for dry powder inhalation. Pharm. Res. 23, 931–940.

Planins̄ek, O., Zadnik, J., Kunaver, M., Src̄ic̄, S., Godec, A., 2010. Structural evolution of indomethacin particles upon milling: Time-resolved quantification and localization of disordered structure studied by IGC and DSC. J. Pharm. Sci. 99, 1968–1981.

Podczeck, F., 1999. The influence of particle size distribution and surface roughness of carrier particles on the in vitro properties of dry powder inhalations. Aerosol Sci. Technol. 31, 301–321.

Podczeck, F., Mia, Y., 1996. The influence of particle size and shape on the angle of internal friction and the flow factor of unlubricated and lubricated powders. Int. J. Pharm. 144, 187–194.

Podczeck, F., Newton, J.M., James, M.B., 1997. Influence of relative humidity of storage air on the adhesion and autoadhesion of micronized particles to particulate and compacted powder surfaces. J. Colloid Interface Sci. 187, 484–491.

Podczeck, F., Révész, P., 1993. Evaluation of the properties of microcrystalline and microfine cellulose powders. Int. J. Pharm. 91, 183–193.

Pourali, N., Foroutan, G., 2015. Simulation study of nanoparticle coating in a low pressure plasma reactor. Phys. Plasmas 22, 23503.

Pu, Y., Mazumder, M., Cooney, C., 2009. Effects of electrostatic charging on pharmaceutical powder blending homogeneity. J. Pharm. Sci. 98, 2412–2421.

Rabinovich, Y.I., Adler, J.J., Ata, A., Singh, R.K., Moudgil, B.M., 2000a. Adhesion between nanoscale rough surfaces: I. Role of asperity geometry. J. Colloid Interface Sci. 232, 10–16.

Rabinovich, Y.I., Adler, J.J., Ata, A., Singh, R.K., Moudgil, B.M., 2000b. Adhesion between nanoscale rough surfaces:II.Measurement and comparison with theory. J. Colloid Interface Sci. 232, 17–24.

Rasenack, N., Müller, B.W., 2002. Crystal habit and tableting behavior. Int. J. Pharm. 244, 45–57.

Raula, J., Lähde, A., Kauppinen, E.I., 2009. Aerosolization behavior of carrier-free l-leucine coated salbutamol sulphate powders. Int. J. Pharm. 365, 18–25.

- 53 -

Ridgway, K., Morland, I., 1977. The bulk density of mixtures of particles of different shapes. J. Pharm. Pharmacol. 29, 58P–58P.

Roth, C., Künsch, Z., Sonnenfeld, A., Rudolf von Rohr, P., 2011. Plasma surface modification of powders for pharmaceutical applications. Surf. Coatings Technol. 205, S597–S600.

Rowley, G., Mackin, L.A., 2003. The effect of moisture sorption on electrostatic charging of selected pharmaceutical excipient powders. Powder Technol. 135–136, 50–58.

Rumpf, H., 1990. Particle Technology. Chapman and Hall, London.

Sahni, E.K., Chaudhuri, B., 2013. Numerical simulations of contact drying in agitated filter-dryer. Chem. Eng. Sci. 97, 34–49.

Sahni, E.K., Chaudhuri, B., 2012. Contact drying: A review of experimental and mechanistic modeling approaches. Int. J. Pharm. 434, 334–348.

Sato, A., Serris, E., Grosseau, P., Thomas, G., Chamayou, A., Galet, L., Baron, M., 2012. Effect of operating conditions on dry particle coating in a high shear mixer. Powder Technol. 229, 97–103.

Schulze, 2008. Bulk solids and powder flow, Behavior, Characterization, Storage and Flow. Springer, New York.

Shah, U. V, Olusanmi, D., Narang, A.S., Hussain, M.A., Gamble, J.F., Tobyn, M.J., Heng, J.Y.Y., 2014a. Effect of crystal habits on the surface energy and cohesion of crystalline powders. Int. J. Pharm. 472, 140–147.

Shah, U. V, Olusanmi, D., Narang, A.S., Hussain, M.A., Tobyn, M.J., Heng, J.Y.Y., 2014b. Decoupling the contribution of dispersive and acid-base components of surface energy on the cohesion of pharmaceutical powders. Int. J. Pharm. 475, 592–596.

Shah, U. V, Olusanmi, D., Narang, A.S., Hussain, M.A., Tobyn, M.J., Hinder, S.J., Heng, J.Y.Y., 2014c. Decoupling the contribution of surface energy and surface area on the cohesion of pharmaceutical powders. Pharm. Res. 32, 1–12.

Shah, U. V, Wang, Z., Olusanmi, D., Narang, A.S., Hussain, M.A., Tobyn, M.J., Heng, J.Y.Y., 2015. Effect of milling temperatures on surface area, surface energy and cohesion of pharmaceutical powders. Int. J. Pharm. 495, 234–240.

Shariare, M.H., Leusen, F.J.J., de Matas, M., York, P., Anwar, J., 2012. Prediction of the mechanical behaviour of crystalline solids. Pharm. Res. 29, 319–31.

Shi, L., Feng, Y., Sun, C.C., 2011. Origin of profound changes in powder properties during wetting and nucleation stages of high-shear wet granulation of microcrystalline cellulose. Powder Technol. 208, 663–668.

Shi, L., Sun, C.C., 2011. Overcoming poor tabletability of pharmaceutical crystals by surface modification. Pharm. Res. 28, 3248–3255.

Sinka, I.C., Schneider, L.C.R., Cocks, A.C.F., 2004. Measurement of the flow properties of powders with special reference to die fill. Int. J. Pharm. 280, 27–38.

- 54 -

Smith, A.P., Shay, J.S., Spontak, R.J., Balik, C.M., Ade, H., Smith, S.D., Koch, C.C., 2000. High-energy mechanical milling of poly(methyl methacrylate), polyisoprene and poly(ethylene-alt-propylene). Polymer. 41, 6271–6283.

Stoica, C., Verwer, P., Meekes, H., Van Hoof, P., Kaspersen, F.M., Vlieg, E., 2004. Understanding the effect of a solvent on the crystal habit. Cryst. Growth Des. 4, 765–768.

Sun, C.C., 2016. Quantifying effects of moisture content on flow properties of microcrystalline cellulose using a ring shear tester. Powder Technol. 289, 104–108.

Sun, C.C., 2009. Improving powder flow properties of citric acid by crystal hydration. J. Pharm. Sci. 98, 1744–1749.

Sun, C.C., Kiang, Y.H., 2008. On the identification of slip planes in organic crystals based on attachment energy calculation. J. Pharm. Sci. 97, 3456–3461.

Svarovsky, 1987. Powder Testing Guide, Method of Measuring the Physical properties of Bulk Powders. Elsevier Applied Science, London.

Tan, B.M.J., Chan, L.W., Heng, P.W.S., 2016. Improving dry powder inhaler performance by surface roughening of lactose carrier particles. Pharm. Res. 33, 1923–1935.

Tay, T., Morton, D.A.V., Gengenbach, T.R., Stewart, P.J., 2012. Dissolution of a poorly water-soluble drug dry coated with magnesium and sodium stearate. Eur. J. Pharm. Biopharm. 80, 443–452.

Teunou, E., Fitzpatrick, J.J., 1999. Effect of relative humidity and temperature on food powder flowability. J. Food Eng. 42, 109–116.

Thakur, R., Hudgins, A.E., Goncalves, E., Muhrer, G., 2009. Particle size and bulk powder flow control by supercritical antisolvent precipitation. Ind. Eng. Chem. Res. 48, 5302–5309.

Tilbury, C.J., Green, D.A., Marshall, W.J., Doherty, M.F., 2016. Predicting the effect of solvent on the crystal habit of small organic molecules. Cryst. Growth Des. 16, 2590–2604.

To, D., Davé, R.N., 2015. Fluid bed film coating of fine ibuprofen particles. Powder Technol. 290, 102–113.

Tong, Z., Kamiya, H., Yu, A., Chan, H.-K., Yang, R., 2015. Multi-Scale modelling of powder dispersion in a carrier-based inhalation system. Pharm. Res. 32, 2086–2096.

Tsunazawa, Y., Shigeto, Y., Tokoro, C., Sakai, M., 2015. Numerical simulation of industrial die filling using the discrete element method. Chem. Eng. Sci. 138, 791–809.

Tykhoniuk, R., Tomas, J., Luding, S., Kappl, M., Heim, L., Butt, H.J., 2007. Ultrafine cohesive powders: From interparticle contacts to continuum behaviour. Chem. Eng. Sci. 62, 2843–2864.

Valverde, J.M., 2013. Fluidization of Fine Powders: Cohesive versus Dynamical Aggregation. Springer Science & Business Media, Dordrecht-Heidelberg-New York-London.

- 55 -

Vanhoorne, V., Peeters, E., Van Snick, B., Remon, J.P., Vervaet, C., 2014. Crystal coating via spray drying to improve powder tabletability. Eur. J. Pharm. Biopharm. 88, 939–944.

Vehring, R., 2008. Pharmaceutical particle engineering via spray drying. Pharm. Res. 25, 999–1022.

Wang, Z., Shah, U. V., Olusanmi, D., Narang, A.S., Hussain, M.A., Gamble, J.F., Tobyn, M.J., Heng, J.Y.Y., 2015. Measuring the sticking of mefenamic acid powders on stainless steel surface. Int. J. Pharm. 496, 407–413.

Weikart, C.M., Yasuda, H.K., 2000. Modification, degradation, and stability of polymeric surfaces treated with reactive plasmas. J. Polym. Sci. Part A Polym. Chem. 38, 3028–3042.

Williams, D.R., 2015. Particle Engineering in Pharmaceutical Solids Processing: Surface Energy Considerations. Curr. Pharm. Des. 21, 2677–2694.

Williams, K.C., Chen, W., Weeger, S., Donohue, T.J., 2014. Particle shape characterisation and its application to discrete element modelling. Particuology 12, 80–89.

Wong, L.W., Pilpel, N., 1990. The effect of particle shape on the mechanical properties of powders. Int. J. Pharm. 59, 145–154.

Woo, X.Y., Tan, R.B.H., Braatz, R.D., 2011. Precise tailoring of the crystal size distribution by controlled growth and continuous seeding from impinging jet crystallizers. CrystEngComm 13, 2006–2014.

Yang, J., Sliva, A., Banerjee, A., Dave, R.N., Pfeffer, R., 2005. Dry particle coating for improving the flowability of cohesive powders. Powder Technol. 158, 21–33.

York, P., Pilpel, N., 1973. The effect of temperature on the mechanical properties of powders part 2. Presence of liquid films. Mater. Sci. Eng. 12, 295–304.

Young, P.M., Price, R., Tobyn, M.J., Buttrum, M., Dey, F., 2003. Effect of humidity on aerosolization of micronized drugs. Drug Dev. Ind. Pharm. 29, 959–966.

Zhou, Q., Shi, L., Chattoraj, S., Sun, C.C., 2012. Preparation and characterization of surface-engineered coarse microcrystalline cellulose through dry coating with silica nanoparticles. J. Pharm. Sci. 101, 4258–4266.

Zhou, Q., Shi, L., Marinaro, W., Lu, Q., Sun, C.C., 2013. Improving manufacturability of an ibuprofen powder blend by surface coating with silica nanoparticles. Powder Technol. 249, 290–296.

Zhou, Q.T., Armstrong, B., Larson, I., Stewart, P.J., Morton, D.A.V., 2010a. Understanding the influence of powder flowability, fluidization and de-agglomeration characteristics on the aerosolization of pharmaceutical model powders. Eur. J. Pharm. Sci. 40, 412–21.

Zhou, Q.T., Morton, D.A.V., 2012. Drug-lactose binding aspects in adhesive mixtures: controlling performance in dry powder inhaler formulations by altering lactose carrier surfaces. Adv. Drug Deliv. Rev. 64, 275–284.

Zhou, Q.T., Qu, L., Larson, I., Stewart, P.J., Morton, D.A.V., 2010b. Improving aerosolization of drug powders by reducing powder intrinsic cohesion via a mechanical

- 56 -

dry coating approach. Int. J. Pharm. 394, 50–59.

Zhou, Y.C., Xu, B.H., Yu, A.B., Zulli, P., 2002. A numerical and experimental study of the angle of repose of granular particles. Powder Technol. 125, 45–54.

Zhu, H.P., Zhou, Z.Y., Yang, R.Y., Yu, A.B., 2007. Discrete particle simulation of particulate systems: Theoretical developments. Chem. Eng. Sci. 62, 3378–3396.

- 57 -

Scheme Captions

Scheme-1 Classification of powder properties used for the review

Scheme-2 Different interparticle interaction mechanisms

Scheme-3 Powder processability region identification

Scheme-4 Perspective of current and potential approaches to control cohesion

- 58 -

List of Schemes:

Powder Properties

Powder Bulk BehaviourParticle Properties

Particle Surface Properties• Surface Roughness• Surface Energy• Surface Area

• Flow• Compressibility• Dispersibility• Fluidisation

Particle Bulk Properties• Size and Size distribution• Shape• Hardness• Density• Solid state properties

Scheme-1 Classification of powder properties used for the review.

- 59 -

van der Waals forces

+-

Dipole on the surface of particle

Electrostatic forces Solid Bridge forces

Liquid Bridge forces

Recrystallisation Contact fusion or chemical solid reaction

Mechanical Interlocking Polymer Brush

+--------

+++++++

Scheme-2 Different interparticle interaction mechanisms

- 60 -

Pro

cess

ing

Tim

e an

d In

tens

ity

Environmental Conditions

Pow

der Bulk

Behaviour

Powder Processibility

Powder Processibility

Sheme-3 Powder processability region identification

- 61 -

Current Approaches

Potential Approaches

Crystal habit modification

Dry coating and co-blending with silica & excipients

Wet coating

Particle

Dry

Wet

Co-crystals with excipients or other actives for multi-component formulations

Printing nanoparticles on target particle areas to

improve flow

Molecular

Particle

Coating of particle using

plasma

External Stimuli

Plasma etching for surface activation

Scheme-4 Perspective of current and potential approaches to control cohesion

- 62 -