Nguyen - Tien - Thanh - d6-203 - Particle - Particle Interaction in Dry Powder Blending

PARTICLE PARTICLE INTERACTION IN DRY POWDER BLENDING
PARTICLE PARTICLE INTERACTION

IN DRY POWDER BLENDING
Applying theoretical concepts to practical systems
Nguyen Tien Thanh
Nguyen Tien Thanh

Nguyn Tin Thnh
Paranymphs: Tofan Willemsz

Ricardo Hooijmaijers
Referent:
Dr. Thanh N. Tran
The research presented in this thesis was financed and performed within the framework of
the project D6-203 of the Dutch Top Institute Pharma.
Printing of this thesis was supported by the generous contribution of University of Groningen
University Library
Graduate School of Science
Department of Pharmaceutical Technology and Biopharmacy
Copyright 2014, Nguyen Tien Thanh
All rights are reserved. No part of this thesis may be reproduced without written permission
of the author.
Cover, layout and printed by: Off Page Amsterdam
ISBN: 978-90-367-7074-3 (printed version)
978-90-367-7073-6 (electronic version)

PhD thesis
to obtain the degree of PhD at the

University of Groningen
on the authority of the
Rector Magnificus Prof. E. Sterken
and in accordance with
the decision by the College of Deans.
This thesis will be defended in public on
Tuesday 1 July 2014 at 09.00 hours
by
Nguyen Tien Thanh

born on 28 August 1980
in Hanoi, Vietnam
Supervisors
Prof. dr. ir. K. van der Voort Maarschalk
Prof. dr. H.W. Frijlink
Assessment committee
Prof. dr. E.M.J. Verpoorte
Prof. dr. J. Ketolainen
Prof. dr. R. Kohlus
TABLE OF CONTENTS
Chapter 1
Chapter 2
Introduction
1.1 Introduction
11
1.2 Lumps formation in dry blending of cohesive powder
11
1.3 Particle particle interaction forces in a powder system
13
1.4 Agglomerate strength and breakage
17
1.5 Overview of this thesis
18
Reference
20
Adhesion force measurement
23
2.1 Abstract
24
2.2 Introduction
25
2.3 Materials and methods
27
2.3.1 Preparation and characterization of particle size

fraction
27
2.3.2 Preparation and characterization of substrate surface
27
2.3.3 Cohesion force measurement by atomic force

microscope (AFM)
28
2.3.4 Cohesion force measurement by the centrifuge method
29
2.3.5 Experimental design and statistics
30
2.4 Results and discussion
Chapter 3
30
2.4.1 Cohesion force measurement by atomic force

microscope
30
31
2.5 Conclusion
38
Acknowledgement
39
References
39
Segmentation method for 3D image
41
3.1 Abstract
42
Highlights
43
Graphical abstract
43
3.2 Introduction
44
3.3 DBSCAN algorithm
46
3.4 DBSCAN for 3D binary images
47
3.5 Data
3.5.1 XMT-DBSCAN segmentation and clustering
of simulated 3D image
50
3.5.2 XMT-DBSCAN segmentation and clustering

of XMT images of powders
51
3.6 Results and discussions
Chapter 4
51
3.6.1 Segmentation of and clustering of simulated

3D image1
3.6.2 Segmentation and clustering of XMT images

of powders
53
3.7 Conclusion
55
References
55
Appendix
57
Determination of coordination number
61
4.1 Abstract
62
Highlights
62
4.2 Introduction
63
4.3 Materials and methods
63
4.3.1 Sample preparation and image capturing

4.3.2 DBSCAN analysis of coordination number
4.4 Results and discussions
4.4.1 Image processing and segmentation:
identification of individual particles
Chapter 5
50
63
65
69
69
4.4.2 Check of validity
70
4.4.3 Coordination number of Cellets
73
4.5 Conclusion
75
Acknowledgement
75
References
75
Simulation of agglomerate abrasion
79
5.1 Abstract
80
Highlights
80
Graphical abstract
81
5.2 Introduction
82
5.3 Methods
82
5.3.1 Agglomerate fracture strength determination
83
5.3.2 Agglomerate size determination
84
5.3.3 Blending test condition
85
5.4 Results and Discussion
Chapter 6
Chapter 7
Appendix
86
5.4.1 Mechanical properties of agglomerates
86
5.4.2 Abrasion of agglomerates
86
5.4.3 Effect of process conditions
91
5.4.4 Simulation vs experiment
94
5.5 Conclusion
96
Acknowledgement
96
Reference
96
Summary and perspectives
99
6.1 Summary
101
6.2 Concluding remarks and perspectives
104
Samenvatting en perspectieven
107
7.1 Samenvatting
109
7.2 Conclusies en perspectieven
112
Acknowledgement
Curriculum Vitae
List of publications
115
121
125
Publications
127
Communications
128
Chapter 1
Introduction
INTRODUCTION
1.1 INTRODUCTION
In todays pharmaceutical drug discovery pipelines, about 90% of all compounds are
reported to be poorly water soluble1. These compounds are classified in the Biopharmaceutical
Classification System (BCS) as class II or class IV compounds2. In order for these compounds
to become sufficiently bioavailable, an acceptable solubility and dissolution rate of the active
pharmaceutical ingredients (APIs) is required. Different methods have been used to improve
the bioavailability of BSC class II and IV compounds. For oral solid dosage forms, particle size
reduction and solid dispersions are among the most common approaches3.
Powder particle size reduction potentially improves the bioavailability of drug by
increasing the dissolution and dissolution rate via augmenting the contact surface area of drug
particles. Although obtaining a desired particle size by bottom-up approaches, e.g. controlled
crystallization have been documented, for practical reason, the top-down approach is often
the process of choice. The desired particle size is obtained by micronization (milling process).
Another motivation for powder micronization is to deliver the drug to the desired site
of action in human body. Pulmonary delivery of drug via dry powder for inhalation is a
typical example. In this situation, the drug particles need to be delivered to appropriate
locations of the deep lung to maximize the absorption. For this application, the particle size,
typically the aerodynamic diameter, is of crucial importance.
Micronized powders, however, cannot be solely delivered as finished products. Generally
a formulated blend of powder is required. The blend is then subjected to a number of
processing steps such as tablet compression/ capsule filling to make finished products. In
case of capsule/tablet, micronized particles are mixed with other excipients such as filler,
disintegrant and lubricant. In case of dry powder for inhalation, lactose particles are often
used as carrier excipient.
While broadly used for bioavailability improvement and delivery purposes, micronized
particles are intrinsically cohesive. This property causes significant challenges for
manufacturing regarding final product quality and sometimes safety issue. One of the
documented facts is the formation of lumps (or dry agglomerate) of micronized APIs
during powder blending46.
1.2 L UMPS FORMATION IN DRY BLENDING OF COHESIVE

POWDER
Agglomerates (lumps) formation in dry blending of cohesive materials has been
documented in both practical observations and academic researches 4,613. Complete lumps
removal during blending is one of the key challenges for the final product quality.
Micronized APIs with particle size smaller than 10 micrometer generally show strong
cohesive properties. Particles of these micronized powders tend to cluster together and
form agglomerates or lumps810. Fig. 1 shows an example of lumps found in practice at the
end of a dry blending process. Analysis of the API content was performed in some of the
lumps. Example of API content in these lumps is shown in Fig. 2.
11
CHAPTER 1
1 cm
Lumps
Figure 1. Example of lumps found at the end of a dry blending process.
100
Content [% w/w in lump]
90
80
70
60
API 1
API 2
50
40
30
20
10
0
Figure 2. Example of API contents in agglomerates found in dry mixing process.
As blend uniformity is one of the basic and crucial criteria to obtain a final product of
good quality, the presence of such lumps in the final blend poses significant risks. A deviation
in the active content of a dosage form may lead to either a safety concern (in case of overdose)
12
INTRODUCTION
or possibly an efficacy concern (under dose). Consequences of the existence of these lumps
on the product attributes have been documented46. For these reasons, understanding of
the formation and the breakage of lumps is needed in pharmaceutical manufacturing. The
ultimate goal is to obtain a powder mixture in which API is uniformly distributed.
In dry powder inhalation (DPI) formulation, micronized API particles are agglomerated
either alone, or together with micronized lactose, or with both micronized and coarse
lactose. When powder delivery is required, these agglomerates need to be broken and
dispersed into particles in an air stream. Therefore, being able to control the formation and
rupture of agglomerates is highly important for the product development 14.
Challenges with agglomeration and de-agglomeration generally arise when powder
particle size gets smaller than 10 m15. The changes in powder behaviors associated with
particle size reduction is mainly due to the increase in particle-particle interaction forces
relative to the force of gravity. When (drug) particle size is reduced by micronization, the
interaction forces become much larger than force of gravity, creating a challenging situation
for manufacturing. Therefore, understanding particulate interaction force is important in
order to manage the powder behavior to produce product of good quality.
1.3 P
ARTICLE PARTICLE INTERACTION FORCES
IN A POWDER SYSTEM
Particle-particle interaction in dry powder blending is a fundamentally important topic
in many industries and has received significant attention in academia. Significant researches
have been carried out to investigate these interactions1621. However, in pharmaceutical
industry for example, the particle interactions during blending of cohesive powders still
poses challenges for formulators as well as for process engineers to manufacture products of
good quality6,7. Therefore, it is required to gain more understanding of particle interactions
and powder behaviors in the relevant situations.
Particle-particle attraction forces are of interest in powder processing because
these forces significantly affect the powder behavior during manufacturing, the process
settings, both ultimately affect the final product property. Particle-particle attraction can
be broadly classified as adhesion and cohesion. According to Zimon 22, adhesion usually
refers to the attraction of two particles of two different chemical natures. Cohesion refers
to the attraction of two particles of the same chemical nature and of similar particle size.
However, the term adhesion is often encountered in literature to denote both adhesion and
cohesion. Adhesive and/or cohesive is defined as the force needed to separate two particles
adhering to one another.
The particle-particle interaction in a dry powder system can be caused by different
mechanisms. These can be solid bridge, liquid bridge, electrostatic interaction, molecular
(atomic) interactions and mechanical interlocking. These attraction forces are schematically
illustrated in Fig. 323,24. There may be one or more interaction forces involved in particulate
interaction, depending on the handling process and the processing environment.
13
CHAPTER 1
Figure 3. Particle-particle interaction forces in a dry powder system.
The solid bridge interaction is common in situation of wet granulation. This is a size
enlargement process which tends to overcome the cohesiveness of starting materials and
improve the powder flow. The solid bridge can be formed by a dried liquid polymer binder
or can be formed by fusion of material of two contacting particles. Due to the large particle
size formation, the solid bridge is rarely the cause of a cohesive powder.
Liquid bridge arises from the water condensation on surfaces of particles. It is largely
agreed that liquid bridge interaction is likely to occur at relatively high humidity (>60%)2427.
However, the work of Price et al. using Atomic Force Microscopy (AFM)25 showed that the onset
of capillary interaction happened at much lower relative humidity (RH). More importantly,
the onset RH depends on the nature of the particle material. Therefore, it is important to
consider the effect of liquid bridge interaction based on the humidity of environment and the
nature of particles material. The surface sorption of water may also influence other interaction
forces due to the change of particle surface energy, surface conductivity and capillary force 24.
Most powders used in pharmaceutical or food industry behave as insulators; therefore
the electrostatic interaction occurs mostly during the powder handling process. Sliding
14
INTRODUCTION
and friction between particles generates electrical charge on particles surface. The term
triboelectrification is often used to describe the process24,2832. The electrostatic interaction
force can be described by Coulombs law:
(1)
In which Fel is the electrostatic interaction force, q1 and q2 are electrical charges of particles,
d is the separation distance between particles, is the permittivity of the material in which
charges are immersed. Although many calculations have been developed, the understanding
and quantification of the triboelectrification in blending of powder is still under investigation.
However, some general prediction of the powder behavior with triboelectrification can be
derived. Powder adhesion due to triboelectric charging has been used to facilitate mixing
of ingredients, especially in case of adhering a micronized powder onto the surface of larger
carrier to create an ordered mixture33. Humidity of the mixing environment was also shown
to affect the triboelectrical interaction24. Bernet et al. showed that the addition of fine particles
to an ordered mixture system also changes the interaction between micronized particles and
carrier34. A recent work of upuk et al. showed that API charged to a higher extent and with
greater variation as compared to excipient35. It was believed that the relatively large particle
size and hydrophilicity excipients are the main reason to contribute to the low variation and
charging of the particles. In order to control the electrification, it was advised to control the
properties of API particles (e.g. particle size, morphology and surface roughness).
At molecular level, atoms and molecules can attract each other at moderate distance and
repel at closer range. The attractive forces are collectively called Van der Waals forces. These
are effective electromagnetic forces between neutral, polarizable bodies. Four different
types of molecular interactions are mainly described: permanent dipole - permanent dipole
or Keesom - Van der Waals force, permanent dipole - induced dipole or Debye - Van der
Waals force, instantaneous induced dipole - induced dipole interaction or London - Van der
Waals force, and Hydrogen bonding3638.
Van der Waals force includes all intermolecular forces that act between electrically neutral
molecules. But, these interaction forces are electromagnetic in origin. The London - Van der
Waals dispersion force is the most fundamental and universal type of Van der Waals force, often
the most important contributor to the total Van der Waals force. All molecules (no matter whether
or not they are charged, have dipole moment, or form hydrogen bonds) are attracted to nearby
molecules by the Van der Waals attraction force, at least by the London dispersion part of it39.
London calculated the interaction energy between two atoms which gave rise to the
London - Van der Waals microscopic dispersion force40.
(2)
is London - Van der Waals constant, x is the distance between two atoms.
15
CHAPTER 1
In macroscopic view, the adhesion of small particles (dust particles, micronized powder,
) is frequently observed. The Van der Waals attraction force is generally believed to be
responsible for the adhesion. The calculation presented by London, however, can only
be applied to atom or molecule in which the separation distance x is smaller than the
wavelength of the corresponding transition between the ground state and the excited state
of an atom38. To calculate the interaction force between two macroscopic bodies (particles),
by assuming the additivity property of the London - Van der Waals force, Hamaker has
integrated pair-wise interactions of all atoms / molecules in a macroscopic, solid body. The
interaction force between two spherical particles was found to be inversely proportional to
the square of separation distance38,41.
(3)
In which A is the Hamaker constant, d1 and d2 are the diameters of the spherical
particles, x is the separation distance between two spherical particles. The macroscopic
adhesion forces exert influences over a separation distance in the order of 10 nm 24.
To overcome the assumption of additivity made by Hamaker, Lifshitz and coworkers
proposed an alternative, macroscopic approach which only involves the material
properties, namely the optical properties of the material over the complete electromagnetic
spectrum42,43. This theory leads to the calculation of Van der Waals force as
(4)
In which h is the Lifshitz constant. The Hamaker constant and Lifshitz constant differ
by a factor of about 4.
(5)
From theories and calculations which have been developed over time, it seems that the
Van der Waals interaction between powder particles has been well understood. Practical
application is not easy, however. The main reason is that the calculation models are all
based on perfectly smooth and usually spherical particles. Most particles in real powder
systems have shapes far different than a sphere. The real particles show variations in surface
morphology (roughness) and mechanical properties (elastic and plastic deformation).
Due to the asperities on particle surface, the contact surface between two interacting
bodies is smaller than that theoretically predicted. This is schematically illustrated in Fig. 4.
Consequently, the interaction force calculation using Hamaker constant normally overpredicts the adhesion force as compared to experimental measurement 39,44.
On the other hand, plastic deformation of the contact point between two particles will
increase the adhesion force by increasing the contact area. Experiments done with the centrifuge
16
INTRODUCTION
1
Figure 4. Effect of surface roughness on adhesion force.
technique have shown that the adhesion force of micronized particles to a surface increased as a
result of increased press-on force or increased duration of applying press-on force45,46. Without
external force, the plastic deformation of contact point is expected to increase the adhesion force
with not more than a factor of two39. During powder processing and handling, particle-particle
collisions, particle-container wall collisions and inter-particles shear forces can be expected.
These forces can possibly lead to particle surface deformation which ultimately will influence
the particle-particle adhesion interaction47. This is illustrated in Fig. 5.
Figure 5. Influence of particle surface deformation on adhesion force.
Most particles have surfaces with asperities and imperfections. During the powder
handling and processing, there are relative movements between particles. Particles with
surface asperities which can match in the lock and key configuration, as illustrated in Fig.
3, have possibility to interlock with each other and hence increase the inter-particulate
interaction force.
1.4 AGGLOMERATE STRENGTH AND BREAKAGE

Dry blending of powder is a dynamic process regarding the lump formation and
breakage9. Earlier studies suggested that the blending of powder can be considered as a
lump abrasion process; lumps do not form again when broken5,11,12,48. Depending on the
properties of lumps, the powder blend formulation and the process settings, the powder
blending can be considered as a size reduction process of lumps.
Rumpf described the agglomerate breakage by a planar fracture model in which the
tensile strength () of an agglomerate is a function of the particle size (), the particleparticle bonding force (Fad), the agglomerate porosity (), and the coordination number (k)
which is the number of contacting neighbors of one particle 49.
17
CHAPTER 1
(6)
The validity of this model is limited due to the inhomogeneous distribution of
stress, contact area, porosity, and particle size. Furthermore, it is practically not easy to
determine the coordination number in an agglomerate. The common relationship between
coordination number and porosity is generally used based on the work of Smith on the
packing of homogeneous spheres50.
(7)
The validity of this general application to any particulate system is questionable
regarding the diversity and polydispersity of powders.
Weiler presented a total dispersion model of agglomerates in which the dispersion
strength of an agglomerate is the ratio of the total force required to disperse the agglomerate
over the surface area of the agglomerate51.
(8)
(9)
disp is the dispersion strength of the agglomerate, Fdisp is the total force required to disperse
all particles of the agglomerate, SAgg is the surface area of the agglomerate. Fad is the average
particle-particle adhesion force, XAgg is the size of the agglomerate, xp is the particle size.
Weilers model assumes that the disintegration of the agglomerate into its primary
particles occurs entirely and instantly. Besides, the calculation of the total dispersion strength
needs input of the average adhesion force, porosity and coordination number. The theoretical
calculation of these inputs is far from applicable to a real powder system. Experimental
measurement of these parameters is often required, and is one of the objectives of this thesis.
1.5 OVERVIEW OF THIS THESIS

This thesis aims at investigating factors that are related to the formation and dispersion
and breakage of lumps in a dry powder blending system. Specifically, in this thesis, we
investigated the powder cohesion and adhesion, powder structure and relate results for
lumps size reduction tests to numerical simulation results.
In Chapter 2, a method to characterize the particle-particle adhesion force was
described. This method allows to measure the adhesion or cohesion forces of a polydisperse
powder. In this method, the adhesion of powder with variations in particle characteristics
18
INTRODUCTION
(particle size distribution, surface properties, morphologies) to a substrate can be measured

by a modified centrifugation method. The experimental data were interpreted with the
force distribution concept (FDC). As result, an adhesion force distribution curve which is
representative for the powder sample was obtained. The new method has advantages over
other method, e.g. Atomic Force Microscopy (AFM) in the possibility to take into account
the polydispersity nature of a powder sample. Furthermore, variations in contact surface
roughness, press-on force can be experimentally simulated.
In chapter 3, a clustering algorithm for 3D images is presented together with an
application for 3D X-ray micro-tomography (XMT) data. The density-based spatial
clustering of applications with noises (DBSCAN) algorithm was made suitable for large
3D image datasets. By using the coordinate system of the image data, the revised algorithm
manages to overcome the computational issue in calculation of the distance table.
Additionally, the revised algorithm solved the instability in border detection which has
been documented in earlier work. With these advantages, the revised algorithm is a good
complementary method to deal with large 3D images which have objects of different sizes
and shapes together with the presence of noises.
With the method described in chapter 3, a study to characterize the coordination
number of a powder system is described in chapter 4. The coordination number is an
important parameter for understanding particulate systems, especially when agglomerated
particles are present. In this chapter, structural information of model particles of different
sizes was acquired by X-ray micro-tomography. The 3D images were analyzed with the
revised DBSCAN algorithm. The clustering results were checked for validity by comparing
the particle size distribution obtained by XMT-DBSCAN with the particle size distribution
by microscopy. The distribution of coordination number obtained with this method was in
good agreement with published work in literature.
Experimental data performed earlier suggested that the size reduction of agglomerates
in dry blending process is a plausible mechanism that dominates the blending time and
process settings48. Furthermore, a dimensionless number approach was developed to predict
the abrasion behavior of agglomerates52,53. In order to have more insights into the abrasion
and breakage mechanism of agglomerates, a numerical simulation experiment using Discrete
Element Method (DEM) was performed in chapter 5. The simulation results showed that the
particle velocity on the surface of the powder bed is a good indicator of the abrasion rate. The
study also supports the idea that the dimensionless Stoke abrasion number would lead to a
valid prediction of the abrasion behavior of agglomerates in a dry mixing process.
19
CHAPTER 1
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the adhesion and friction properties between
particles and surfaces. J. Pharm. Sci. 84, 1067
1071 (1995).
46 Lam, K. K. & Newton, J. M. Influence of particle
size on the adhesion behaviour of powders, after
application of an initial press-on force. Powder
Technol. 73, 117125 (1992).
47 Rimai, D. . & L.P, D. Physical interactions
affecting the adhesion of dry particles. Annu.
Rev. Mater. Sci. 26, 2141 (1996).
48 Willemsz, T. A. et al. Blending of agglomerates
into powders 1: Quantification of abrasion rate.
Int. J. Pharm. 387, 8792 (2010).
37 Boer, A. H. de. Optimisation of dry powder

inhalation: the application of air classifier and
laser diffraction technology for the generation
and characterisation of aerosols from adhesive
mixtures. 3034 (2005). At <http://dissertations.
ub.rug.nl/faculties/science/2005/a.h.de.boer/?p
Language=en&pFullItemRecord=ON>
49 Leuenberger, H., Bonny, J. D., Lerk, C. F. &

Vromans, H. Relation between crushing strength
and internal specific surface area of lactose
compacts. Int. J. Pharm. 52, 91100 (1989).
38 Dzyaloshinskii, I. E., Lifshitz, E. M. & Pitaevskii,

L. P. The general theory of van der Waals forces.
Adv. Phys. 10, 165209 (1961).
51 Weiler, C., Wolkenhauer, M., Trunk, M. &

Langguth, P. New model describing the total
dispersion of dry powder agglomerates. Powder
Technol. 203, 248253 (2010).
39 Walton, O. R. Review of Adhesion Fundamentals

for Micron-Scale Particles. 26, 129141 (2008).
40 London, F. The general theory of molecular
forces. Trans. Faraday Soc. 33, 8b26 (1937).
41 Hamaker, H. C. The London--van der Waals
attraction between spherical particles. Physica
4, 10581072 (1937).
42 Visser, J. On Hamaker constants: A comparision
between Hamaker constant and Lifshit-Van der
50 Smith, W. O., Foote, P. D. & Busang, P. F. Packing

of Homogeneous Spheres. Phys. Rev. 34, 1271
(1929).
52 Willemsz, T. A. et al. Kinetic energy density and

agglomerate abrasion rate during blending of
agglomerates into powders. Eur. J. Pharm. Sci.
45, 211215 (2012).
53 Willemsz, T. A. et al. The stokes number approach
to support scale-up and technology transfer of a
mixing process. AAPS PharmSciTech 13, 928
933 (2012).
21
Chapter 2
Adhesion force measurement
CHAPTER 2
2.1 ABSTRACT
Adhesion, agglomeration and de-agglomeration of micronized particles and larger
carrier particles are of special importance during manufacturing of pharmaceutical products
when the inherent cohesion property of fine particles challenges the content uniformity of
dry mixtures. To characterize particle-particle adhesion, measurements with atomic force
microscopy (AFM) and a centrifuge method were performed using microcrystalline cellulose
as model material. The variations in AFM measurements were too large to draw a conclusion.
A force distribution concept (FDC) was used in the interpretation of the results from the
centrifuge method. This solved the problem of variation caused by the polydispersity of the
sample and enabled quantitative characterization of the particle adhesion. An experimental
design was used to investigate the effect of the press-on force, press-on time and surface
roughness. All these factors were shown to have an effect although the effect of press-on
force and press-on time was merely distinguishable as a quadratic effect.
Key words: Cohesion force; Adhesion force; Dry powder mixtures; Centrifuge method;
Force distribution concept, Atomic force microscope.
A centrifuge method to measure particle cohesion forces to substrate surfaces:

The use of a force distribution concept for data interpretation
Thanh T. Nguyen 1,*, Clinton Rambanapasi 1, Anne H. de Boer1, Henderik W. Frijlink 1,
Peter M.v.d. Ven2, Joop de Vries 3, Henk J. Busscher 3, Kees v.d. Voort Maarschalk1,4
Department of Pharmaceutical Technology and Biopharmacy, University of Groningen,
Groningen, The Netherlands.
2
TNO Quality of Life, Zeist, The Netherlands.
3
Department of Biomedical Engineering, University Medical Centre Groningen, Groningen, The Netherlands.
4
Oral and Polymeric Products Development Department, Schering-Plough, Oss, The Netherlands.
1
*corresponding author: Thanh T. Nguyen

thanh.nguyen@merck.com; nguyen.t.thanh80@gmail.com
Published in:
International Journal of Pharmaceutics, Volume 393, Issues 12, 30 June 2010, Pages 8996
24
ADHESION FORCE MEASUREMENT
2.2 INTRODUCTION
Oral solid dosage forms are by far the most popular dosage forms in todays pharmaceutical
industry. The hydrophobic nature of many active pharmaceutical ingredients (APIs) requires
their formulation as microsized or even nanosized particles. However, the fine particle size
causes serious challenges for manufacturers related to poor powder flow, product dispersion
and end product homogeneity1. Fine APIs are highly susceptible to agglomeration due to
the important increase in the balance of API-API cohesion relative to the gravities of APIs.
In this paper, the term cohesion is used to denote the adhesion between particles of the
same material; the term adhesion is used more generally to denote interaction between
particles of either the same material or different materials. In practice, agglomerates of fine
particles are often found on the top of the powder beds after blending, leading to a nonuniform blend which causes high variation in drug concentration in final unit dosage. A
pragmatic solution to the problem is the application of shear-intensifying equipment such as
choppers during blending. However, the fine components in a formulation have an inherent
propensity to form agglomerates, so shear intensification alone is not enough to prevent the
re-formation of agglomerates after blending. The concept of ordered mixing 2 and cohesiveadhesive balance introduced recently in the field of dry powder inhaler formulation 3 are of
special interest in fine particles blending. Only a fundamental understanding of adhesion
properties of agglomerated particles enables the design and development of an adequate
formulation and choice of appropriate process condition.
A number of theories have been developed to describe and to estimate the adhesion
forces between particles, both qualitatively and quantitatively47. However, these
theories fail to explain or predict the behavior of real powders because of inappropriate
assumptions regarding for example, the particle shape in calculating the area of contact
between interacting bodies. These contact areas are the areas where the materials of
the interacting bodies are close to each other, usually in the ngstrom range (10-10 m).
An error in contact area estimation may lead to significant error in the adhesion force
calculated. A spherical particle is usually taken to estimate the contact area. However, APIs
exist in various shapes which makes it difficult to calculate the contact area and hence,
the force of adhesion. Additionally, surfaces of API particles are normally not smooth; the
asperities on the surfaces may become even more important than the particles in adhesion
interaction8. Especially when load or press-on conditions exist, the pressure concentrated
on tiny surface area of asperities may influence significantly the adhesion force between
two bodies. The natural variation in particles surface roughness makes the theoretical
prediction of adhesion force practically impossible. Furthermore, existing theories only
deal with monodisperse particles; the whole particle size distribution is never taken into
account which is not appropriate concerning real powders.
Beside theoretical calculations, experimental methods have been developed to measure
adhesion interaction between particles9. The introduction of the atomic force microscope
(AFM) has made it possible to measure adhesion forces as small as 10-18 N from a distance as
25
CHAPTER 2
close as 1 ngstrom10. By using a colloidal probe mounted on an AFM cantilever, adhesion

interaction between two particles or a particle and a surface can be directly measured
without any assumption concerning particle size, shape and surface roughness. However,
it is only possible to perform AFM measurements with one single particle at a time and
considerable efforts are needed to characterize a polydisperse powder with a certain size
and surface variation within the sample.
Among other methods, the centrifuge method has been introduced in the sixties 11 and
has been extensively used by researchers for measurement of adhesion strengths between
particles and surfaces1214. The advantage of the centrifuge method is the possibility to
measure the interaction of a relatively large number of particles with a surface in a single
experiment, and hence may yield a statistically more representative value for the entire
powder under consideration.
In principle, the method uses a centrifugal force to separate adhering particles from a
substrate surface. The centrifugal force is oriented perpendicularly to the contact surface
of two interacting bodies, in opposite direction of the adhesion force between particle and
surface. The particles are detached from the surface when the magnitude of centrifugal
force exceeds the magnitude of adhesion force. The centrifugal force applied to a particle
during centrifugation is proportional to the first power of particle mass (m) and centrifugal
radius (RC) and to the second power of angular velocity () as shown in equation (1)
(1)
The adhesion force can be calculated based on the retention curve which plots the
percentage of particles left on the surface as function of the centrifugal force. The force
necessary to detach 50% of particles from the substrate surface is often used to represent
the adhesion force of the particles to the surface13,14. With a polydisperse sample, the use
of centrifuge method to study a large number of particles includes a challenge with regard
to data interpretation. Since the particles studied have different sizes, the use of only one
representative particle size (usually median particle size) to calculate the centrifugal force
is not rational. For a particle with known shape, the volume and mass of the particle are
proportional to the third power of the characteristic size of the particle such as particle
diameter (dv: diameter of a sphere having the same volume) and the first power of particles
true density () as shown in equation (2)
(2)
As a result, the centrifugal force is proportional to the third power of the particle size
and is sensitive to alterations in particle size. While studying particle adhesion using the
centrifuge method, a small variation in particle size will lead to high variations in the
calculated centrifugal force, and consequently lead to the adhesion force derived thereof.
26
A force distribution concept (FDC) had been introduced by De Boer to characterize the
performance of dry powder inhalation formulations with air classifier technology 15. In this
paper, the force distribution concept is applied in the interpretation of cohesion interaction
of fine particles which are susceptible to agglomerate formation during dry blending.
Microcrystalline cellulose (MCC) was used as a model material to study the cohesion of
MCC particle and MCC surface.
2.3 MATERIALS AND METHODS

2.3.1 Preparation and characterization of particle size fraction
Microcrystalline cellulose (Avicel PH-101 and Avicel PH-105) was kindly supplied by
FMC Biopolymer (Wallingstown, Ireland).
A particle fraction with a size range from 38 to 53 m was prepared by double sieving
Avicel PH-101 (sample size 100 g) using subsequently a vibratory sieve (Retsch AS200,
Retsch, Haan, Germany) and an air jet sieve (Alpine Augsburg, Germany). Particles of this
size fraction were used as adhering particles in the centrifuge method.
A particle fraction with a size range from 100 to 160 m was prepared from Avicel
PH-105 in a similar way. This size fraction was used to make tablets with rough surfaces.
The size fraction less than 38 m from Avicel PH-101 was used to make tablets with
smooth surfaces.
The particle size distribution of 38 to 53 m fraction was characterized by laser
diffraction using a HELOS MODEL KA (Sympatec GmbH, Clausthal-Zellerfeld, Germany).
A RODOS dry powder dispenser (Sympatec) was used to disperse the powder into primary
particles at 4 bars air pressure.
The number distribution of volume equivalent diameter was calculated based on
the laser diffraction results. The first 0.65% of the distribution (0.9 to 9 m) in the laser
diffraction result was omitted from the number distribution calculations because it is of a
size that cannot be observed visually using optical microscopy. The particle size distribution
in volume and in number is shown in Figure 1.
2.3.2 Preparation and characterization of substrate surface

Substrate surfaces of different surface porosities were prepared by compacting particles
of different size fractions under the same compaction pressure. The size fraction from 100
to 160 m was used to compress tablets with rough surfaces and the size fraction less
than 38 m was used to compress tablets with smooth surfaces. A quantity of 300 mg of
powder was filled into a 15 mm non-lubricated die and compressed into round, flat tablets
using a ESH hydraulic press (Hydro Mooi, Appingedam, The Netherlands). The maximum
compaction pressure of 170 MPa was reached in 6 seconds.
The substrate with deposited particles on the surface was observed visually with an
optical microscope ELV: 78952 (ELV, Leer, Gemany) and scanning electron microscope
(SEM) (JEOL JSM-6301F microscope, Jeol, Japan). Surfaces without deposited particles
27
CHAPTER 2
Figure 1. Particle size distribution of the 38-53 m fraction. Open symbol: volume distribution. Solid symbol:
number distribution.
were also scanned to analyze for surface area of troughs found on that substrate surface.
Image analysis was done using ImageJ software (http://rsbweb.nih.gov/ij/). A Gaussian
filter (sigma =2 pixels) was applied before making the image binary. 8 bits SEM images were
made binary using Isodata threshold algorithm16. The surface porosity (i.e. the relative
area of troughs) was then calculated as the percentage of surface area of troughs in the total
scanned area as shown in equation (3)
(3)
2.3.3 Cohesion force measurement by atomic force microscope (AFM)

Cohesion forces between MCC particles (38 53 m) and MCC surfaces were measured
using a Nanoscope V AFM (Veeco Instrument, Santa Barbara, CA) operating in Contact
mode. The colloidal probes were prepared by gluing MCC particles on tipless AFM
cantilevers according to the procedure described by Busscher17. Briefly, the MCC particles
of 38-53 m size fraction were deposited on a glass slice, a tipless AFM cantilever (masch
CSC12, MikroMasch, Estonia) which was brought in contact with a freshly prepared two
components epoxy resin (Kombi Turbo, Bison International, Goes, The Netherlands) was
gently introduced to the glass slice with help of a micromanipulator (Narishige, Narishige
International USA, Inc., East Meadow, NY) to pick up one particle. The colloidal probe
was kept overnight allowing the glue mixture to solidify. Before mounting the particles, the
spring constant of tipless cantilevers were determined using the thermal method described
by Hutter18. Two colloidal probes were prepared, the cohesive interaction forces were
measured between two MCC particles and two tablets of rough surface, two tablets of
28
smooth surface. For each particle surface interaction, measurements were done at five
different positions and repeated ten times at each point.

Modified centrifuge tubes were designed and constructed at the University of Groningen.
This tube has three parts as illustrated in Figure 2: a holding tube (A), a substrate holding
plate (B), and a recipient chamber to collect the detached particles (C).
Figure 2. Modified centrifuge tube

used in this study. A: Holding tube. B:
Substrate holding plate. C: Recipient
chamber to collect the detached particles.
These tubes were designed to be used in a Hettich Rotanta D-7200 centrifuge (Hettich
AG, Switzerland) with adjustable centrifugal speed up to 4000 rotations per minute (rpm).
With this design, it is possible to turn the substrate holding plate in two opposite directions,
placing the particle on the substrate surface under two different centrifugal forces of opposite
directions. When facing the particles inward the centrifugal axis, the centrifugal force is
applied in the same direction with adhesion force which presses the particles on the surface,
strengthening the interaction. In this direction, the centrifugal force is called the press-on
force. When facing the particles outward the centrifugal axis, the centrifugal force is applied
in the opposite direction of adhesion force. The adhering particles detach when the centrifugal
force exceeds the adhesion force in magnitude. This force is called the spin-off force.
As the centrifugal force is calculated based on the particle size and particles true density,
deposition of primary particles onto the substrate surface is critical. A small amount of
MCC (hundreds of particles) of 38 to 53 m in size, was deposited onto the substrate surface
by gently sprinkling from a spatula over the MCC compacted surface.
29
CHAPTER 2
Before deposition, the powders and tablets were kept in closed glass vials at laboratory
condition. During the experiments, the temperature was stable at 201 oC, the relative
humidity varied between 35% and 45%.
After deposition, the particles were subjected to different press-on forces to the surface.
The effect of press-on force and press-on time was investigated at three different levels:
1000, 2000 and 3000 rpm of press-on speed and 5, 10 and 15 minutes of press-on duration.
To eliminate the possible effect of electrostatic forces, the MCC particles deposited on
the substrate surface were kept overnight in a humidity controlled chamber of about 30%
RH at 20oC (saturated solution of calcium chloride).
Detachment of particles from the substrate surface was studied by turning the substrate
outward the centrifugal axis and centrifuge at five incremental speeds: 1000, 1500, 2000, 3000
and 4000 rpm during 15 minutes. After each rotation experiment, the substrates with adhering
particles were investigated under an optical microscope. Because of the limited contrast between
particles and the substrate surface of the same material, a light source was placed parallel to the
substrate surface. In this way, adhering particles on the substrate surface became visible under
the microscope. Pictures of particles left on the surface were taken after each test. These pictures
were used to count the number of particles left on the substrate surface using Bacterial Counting
software developed by the Groningen University Hospital. In each experiment, the percentage
of particles left on the surface was determined at five different spin-off speeds.
2.3.5 Experimental design and statistics

Twelve experiments were designed to evaluate factors that influence the number of
particles left on the surface, which are press-on force (rpm), press-on time, the substrate
surface roughness and the interaction between these factors. Details of experimental design
and conditions are shown in Table 1. The 12 experiments were run in randomized order and
each experiment was carried out with four samples under the same conditions.
The detachment data were analyzed by fitting separate regression model for each of the
spin-off speed to evaluate the impact of each variable on particle-surface adhesion. Before
fitting the models, the surface roughness was coded -1 for the smooth surface and 1 for the
rough surface. The lower, intermediate and highest values of press-on force and press-on
time were recoded -1, 0 and 1 respectively. In this way, the regression parameters that
correspond to the main effects and two-factor interactions can be estimated independently.
The t-test for regression coefficients was used to evaluate the main effects and interactions
in the regression model.
2.4 RESULTS AND DISCUSSION

2.4.1 Cohesion force measurement by atomic force microscope
Of the two MCC particles used to prepare AFM colloidal probe, there is one particle
(called particle 1) smaller than the other (called particle 2). The average cohesive interaction
forces (mean standard deviation) of particle 1, particle 2 with the rough surfaces are 41.4
30
Table 1. Experimental design used in the cohesion experiments

Experiment
number
Surface roughness
Press-on force
(speed in rpm)
Press on time (minute)
Rough
1000
Rough
1000
15
Rough
3000
Rough
3000
15
Rough
2000
10
Rough
2000
10
Smooth
1000
Smooth
1000
15
Smooth
3000
10
Smooth
3000
15
11
Smooth
2000
10
12
Smooth
2000
10
18.4 nN and 81.8 41.7 nN respectively. The interaction forces of particle 1, particle 2
with the smooth surfaces are 38.3 23.2 nN and 90.1 40.7 nN respectively.
The interaction forces range from 11 (minimum) to 147nN (maximum) with the rough
surfaces and from 8 to 168 nN with the smooth surfaces. The difference between rough and
smooth surface is not statistically significant (z = -0.16, p=0.87, Mann-Whitney U test).
Within one position on the substrate surface the force measurement is reproducible: the
relative standard variation (RSD) of 10 repeated measurements is less than 5%. However the
variation between different measurement positions on the same surface is much higher, RSD
ranges from 44% (particle 1 with rough surface) to 60% (particle 1 with smooth surface).
This high between-point measurement variation is understandable considering the fact that
the surfaces are far from uniform. While moving the MCC probe over a substrates surface
to random positions for adhesion force measurement, there are various possibilities for a
particle to come into contact with the surface which is formed by different contact points
of different contact areas, leading to large variations in the adhesion force measured. The
variations also reflect the natural properties of most of pharmaceutical materials, especially
those materials that undergo mechanical size reduction. For this reason, the use of AFM to
characterize adhesion properties of a powder sample is fundamentally difficult concerning
the large number of particles needed to statistically represent the sample and the delicate
manipulation with the micromanipulator to mount particles on AFM cantilevers.

The detachment results of MCC particles from MCC surfaces are summarized in
Table 2, showing the retention (percentage of particles left on the entire surface) after
31
CHAPTER 2
Table 2. Centrifuge detachment of MCC particles from MCC surfaces.

Percentage of particles left on the surface after centrifugation (%)
Experiment
number
1000 rpm
1500 rpm
2000 rpm
3000 rpm
4000 rpm
1 (R/1000/5)
82.2 6
67.2 6
53.2 3.6
25.5 4.7
10 2.9
2 (R/1000/15)
74.4 1.9
57.7 4.6
44.3 2
28.4 5.9
9.9 3.2
3 (R/3000/5)
79.7 3.9
63.6 0.7
52 2.1
38.7 6.3
20.1 5.4
4 (R/3000/15)
81 6.4
68.7 9.1
52.5 6.2
39 4.9
19.4 4.4
5 (R/2000/10)
82.3 4.9
65.2 6.5
45 5.9
22.2 8.2
7.9 4.9
6 (R/2000/10)
94.7 0.6
80.5 2.9
67 3.4
27.5 2.9
6 1.3
7 (S/1000/5)
88.8 1.9
59.2 9.4
41.4 4.2
22.7 3.2
10.2 1
8 (S/1000/15)
75.5 5.8
59.4 12.4
49.1 13.2
26.9 5.4
9.3 4.4
9 (S/3000/5)
71.4 6.1
49.8 6
40.2 6.4
19.7 2.9
9.8 2.6
10 (S/3000/15)
67.8 11.7
51.9 11.3
37.9 19.4
22.2 9.5
62
11 (S/2000/10)
88.8 2
76.3 3.6
61.9 5.2
32.9 5.1
7.1 2.6
12 (S/2000/10)
75.8 5.2
53.2 11.5
38.8 8.7
20.1 9.6
9.9 5.5
(S: Smooth surface, R: rough surface / 1000, 2000, 3000: rpm / 5, 10, 15: minutes)
each centrifugal detachment speed. The data represent the average values and standard
deviations (SD) of four independent tests carried out at the same conditions.
The cohesion of MCC particles to MCC surfaces depends on several factors 13,19,20, in this
study three frequently documented factors were taken into account in the experimental
design: press-on force, press-on time and surface roughness. To identify factors which
have a significant effect, a statistical analysis was performed by fitting multivariable linear
regression models for each centrifugal detachment speed. The parameters that estimate for
the regression model are shown in Table 3.
The adjusted R2 in Table 3 measures how well the model explains the data. R2 takes the value
from 0 to 1, with 1 corresponding to a perfect fit. The R2 values in Table 3 are low, indicating
that the models do not fit the data very well. Therefore, it is important to note that these models
should not be used for interpolation. However, the significance of each parameter in the models
does explain to which extend the variation of each factor influences the cohesion between
particle and surface. It is found that the substrates surface roughness has significant effect on
the percentage of particles left on the surfaces, with a rough surface leading to higher retention
at all detachment speeds. The press-on force shows a relatively weak but generally statistically
significant effect. The effect of press-on time is only significant at 1000 rpm spin-off speed.
According to Zimon20, the distance between asperities of a rough surface affects the particle
detachment from the surface. Particles that lay between the asperities, or in troughs, are more
difficult to detach than particles lying on top of the asperities.
In this study, the compacted surfaces were prepared from powders of different size
fraction. The roughness of surfaces was evaluated by image analysis. Figures 3a and 3b
32
Table 3. Parameters estimate for regression models

Speed (rpm)
Intercept
1000
1500
2000
3000
4000
85.41
68.81
53.18
24.37
7.72***
***
***
***
Surface roughness
2.18*
5.34**
4.53*
3.91***
1.77**
Press-on force
-2.63*
0.18
0.51
2.66*
1.98**
Press-on time
-2.92
-1.64
-1.51
0.59
-0.67
Surface roughness x Press-on time
1.30
0.57
-0.60
0.21
0.50
Surface roughness x Press-on force
3.64**
1.65
1.21
3.30*
2.90***
Press-on-time x Press-on force

Quadratic effect of press-on time and
press-on force (indistinguishable)
Adjusted R2 (measure of goodness of fit)
2.35
3.44
1.06
0.92
-0.43
-7.82***
-10.50**
-8.06*
2.87
4.11**
0.45
0.26
0.12
0.29
0.45
p-value < 0.05 (two-sided alternative)

***
*
**
show the SEM images of rough and smooth surfaces with deposited particles at 100x
magnification, Figures 3c and 3d show the SEM images of rough and smooth surfaces
without deposited particles at 1000x magnification, Figures 3e and 3f show binary images
of Figures 3c and 3d which were used to calculate the surface porosity.
The distance between asperities was expressed in two dimensions as surface area of
troughs on the tablets surface. The surface porosity of rough surface is 9%, surface porosity
of smooth surface is 7.2%. The distribution of pore sizes on the surface is shown in Figure 4.
For both the rough and the smooth surface, about 80% of the troughs have a surface
area less than 20 m2 (Figure 4), which is generally smaller than the apparent size of
adhering particles (78 m2 for a 10 m spherical particle). Hence, there is a low possibility
that particles can be found in the troughs. But, the troughs and the cohering particles all
differ from circular shape which opens the possibility that a part of a particle is positioned
inside the troughs in an optimal configuration for cohesion, especially after the press-on
procedure. The rough surface with some larger troughs may offer more possibilities for
this arrangement. We also found a significant interaction between surface roughness and
press-on force at 3 spin-off speeds (1000, 3000 and 4000 rpm) which shows the importance
of these parameters: the harder the particles are pressed on the rough surface, the more
difficult it is to dislodge them. The quadratic effect of press-on time and press-on force is
found to be significant at all spin-off speeds except at 3000 rpm. Because of the complete
confounding of quadratic effect of press-on time and press-on force, it is not possible to
distinguish which effect is significant with the current experimental design. It is possible
that both factors have a quadratic effect.
To obtain quantitative data on the cohesion force, it is necessary to map the centrifugal
force with the corresponding particle detachment after each centrifugation. To enable the
33
CHAPTER 2
Figure 3a. SEM image of a rough surface with

deposited particles at 100x magnification.
Figure 3b. SEM image of a smooth surface with

Figure 3c. SEM image of a rough surface without

Figure 3d. SEM image of a smooth surface without

Figure 3f. Binary image of a smooth surface used to

analyze for surface porosity.
Figure 3e. Binary image of a rough surface used to

analyze for surface porosity.
Figure 3. SEM and binary images of substrates surface.
34
Figure 4. Distribution of troughs surface area on substrates surface.
use of the force distribution concept, we calculated the adhesion force for each group of
experiments on rough surfaces and for each group of experiments on smooth surfaces.
The introduction mentioned that the centrifugal force applied to different particles in a
polydisperse sample is not uniform but depends on the particle size. As the centrifugal force
is proportional to the third power of particle size, it is unrealistic to calculate centrifugal force
based on an average particle size (i.e. arithmetic mean or median size) only. Therefore, we
calculated the centrifugal force for each small particle size range obtained from laser diffraction
analysis which is sufficient narrow that they may be considered as a monodisperse sample.
The volume based particle size distribution of the 38 to 53 m fraction obtained by laser
diffraction is shown in Figure 1, open symbol. The median diameter (X50) is 55 m; X10 and
X90 are 33 and 83 m respectively. The particle size distribution is larger than the sieve size
used to obtain that fraction. The fact that the particles are larger than the largest sieve aperture
used is explained by the particle shape. Avicel PH-101 particles are rather fiber-shaped
than spherical whereas the laser diffraction technique measures all particle dimensions and
calculates volume distribution based on the assumption that the particles are spherical.
As the volume of particles is of critical importance in centrifugal force calculation, the
volume equivalent diameter is used for data interpretation in this study. As the centrifuge
forces will be analyzed in the form of number distribution, the number distribution of
volume equivalent particle size was calculated based on laser diffraction distribution, result
is shown in Figure 1, solid symbol. The X10, X50 and X90 are 12, 26 and 58 m, respectively.
Centrifugal forces exerted on each particle size range at different centrifugation rate
were calculated using equation (4) and results are shown in Table 4.
(4)
35
CHAPTER 2
In which
Fc: Centrifugal force (N)
: True density of particle. In this case, = 1600 kg/m3 for the MCC used21.
dM: Arithmetic mean of upper and lower value of the size class
n: Centrifugal speed (rpm)
RC Centrifugal radius, which is the distance between rotation axis and the substrate surface.
In this case, this distance is 0.1 m.
Figure 5 shows the centrifugal force distribution curves for the polydispersed sample. The
dotted line horizontally depicts the centrifugal force applied to each particle size fraction. The
vertical axis shows the cumulative number distribution of the centrifugal force, which is derived
from the particle size distribution. We obtained 5 curves (the dotted curves) to represent the
centrifugal force distribution at the five centrifugal speeds: 1000, 1500, 2000, 3000 and 4000 rpm.
Based on the force distribution curves and the retention after each centrifugation (Table
2), the cohesion force is calculated by mapping the retention to the corresponding force curve.
In principle, a particle is detached from the surface only if the centrifugal force applied to that
particle exceeds the cohesion force of the particle and the surface. For example, in experiment
number 1 (Table 2), at 1000 rpm centrifugal detachment, 17.8% of the particles were removed
by the centrifugal force. This means that for this 17.8% of particles the centrifugal force is
higher than the cohesion force and for the remaining 82.2% of particles the centrifugal force
Table 4. Calculation of centrifugal forces (FC) for different particle size range.
Cumulative
distribution in
number (%)
FC (nN)
at 1000 rpm
FC (nN)
at 1500 rpm
FC (nN)
at 2000 rpm
9.75
6.45
0.85
1.91
11.50
14.76
1.40
3.14
13.75
23.19
2.38
16.50
30.44
4.12
d (m)
36
FC (nN)
at 3000 rpm
FC (nN)
at 4000 rpm
3.40
7.65
13.60
5.58
12.56
22.32
5.37
9.54
21.46
38.15
9.27
16.48
37.09
65.93
19.50
35.10
6.80
15.30
27.21
61.22
108.83
23.00
40.68
11.16
25.11
44.64
100.45
178.57
27.50
49.56
19.08
42.92
76.31
171.69
305.23
33.00
62.01
32.97
74.17
131.86
296.69
527.44
39.50
75.27
56.53
127.20
226.13
508.80
904.54
47.00
86.11
95.24
214.28
380.95
857.14
1523.80
56.00
93.74
161.09
362.46
644.38
1449.85
2577.50
67.00
97.83
275.89
620.76
1103.57
2483.03
4414.28
80.00
99.51
469.66
1056.74
1878.65
4226.96
7514.59
95.00
99.99
786.48
1769.57
3145.91
7078.29
12583.63
113.00
100.00
1323.58
2978.06
5294.32
11912.23
21177.29
Figure 5. Distribution of centrifugal forces and cohesion forces between MCC particles and MCC surfaces.
Dotted line: centrifugal forces at 1000, 1500, 2000, 3000, 4000 rpm
Solid lines: Cohesion forces between MCC particles and MCC surface
is lower than cohesion force. The centrifugal force distribution curve intersects the cohesion
force curve at 82.2 % on the y coordinate. The centrifugal force that corresponds to 82.2%
on the 1000 rpm centrifugal force distribution curve is 100.6 nN (this value was calculated
by fitting a linear correlation between the log of centrifugal force and cumulative force
distribution). The procedure is the same for other detachment points. Results are shown in
Table 5 and the detachment of MCC particles from rough and smooth surface is illustrated
by the two solid lines in Figure 5. The mean cohesion force of MCC particles with rough and
smooth MCC surfaces are 63 33 and 40 23 nN respectively.
Table 5 and Figure 5 show that a high centrifugal speed is required to apply sufficient
centrifugal detachment force to overcome low cohesion force of small particles. This is
because the centrifugal force is proportional to the third power of the particle size and to the
second power of the centrifugal speed. A higher increase in centrifugal speed is necessary
to compensate the decrease in particle size. The cohesion force distribution is narrower
than the centrifugal force distribution, the lower end of cohesion force curve intercept the
lower end of centrifugal force curve at high centrifugal speed which correspond to the small
particle size. The cohesion force decreases with decreasing particle size.
It should be noticed that the cohesion forces determined by the centrifuge method
are of the same order of magnitude as the cohesion forces measured with AFM, although
statistical comparison is non-appropriate due to the limited number of measurements
by AFM. In the centrifugal detachment experiment, about 300 particles are deposited
37
CHAPTER 2
Table 5. Calculation of cohesion force based on force distribution concept.

Centrifuge speed (rpm)
Rough surface
Smooth surface
1000
1500
2000
3000
4000
Retention (%)
82.38
67.15
52.34
30.21
12.23
Cohesion force (nN)
100.59
89.80
64.96
38.16
22.79
Retention (%)
78.02
56.47
43.27
22.37
8.69
Cohesion force (nN)
77.19
46.96
37.47
23.72
18.39
randomly on the substrate surface, and the experiment was carried out with four samples
under the same conditions. Results generated from more than one thousand interactions
may characterize the particle-surface adhesion in a powder mixture better.
Besides the advantages of the centrifuge method in characterizing particle-surface
adhesion, there are still challenges regarding the effect of press-on force and press-on time
and concerning the deformation of interacting material. In another image analysis of adhering
particles using Morphologie G2 (Malvern Instrument, UK) (data not shown), the smallest
apparent surface area of the particle is about 800 m2. Even if the highest press-on force in
this experiment (11912 nN at 3000 rpm) is applied to this particle, the apparent pressure
of 0.014 MPa is still much lower than the yield strength of microcrystalline cellulose (21
MPa)22. Based on this observation, one may think that particles surface or substrates surface
deformation are not likely to happen. However, the yield strength of a particle may differ
from that of a surface and the possibility of plastic deformation, or flattening of asperities is
still susceptible concerning the true contact area. Due to the uneven nature of the particles
surface and of the substrates surface, the interacting bodies only come in contact with the
other at certain contact points resulting in a very small contact area. Even if a very small
press-on force is applied on these tiny contact areas, the pressure may be high enough to
exceed the yield strength of the material; this may cause plastic deformation of asperities
and subsequently increase adhesion by increasing the contact area. Another possibility is the
existence of areas with impurities or amorphous material on the particle or substrates surface.
These areas are normally soft and more susceptible to deformation, creating large contact
surface areas with high adhesion. The influences of these surface properties have not yet been
fully understood and are still challenging factors to interpret adhesion under press-on forces.
2.5 CONCLUSION
This paper shows that the force distribution concept can be applied in the calculation
of adhesion force as studied by the centrifuge method. This concept is able to deal with
the problem of polydispersity of the powder sample. The substrates surface roughness,
press-on force and press-on time affect the adhesion of the particle to a surface although the
multiple linear regression model was not able to fully describe these factors. There are still
38
challenges in clarifying the mechanism how the load condition (press-on force) influences
the adhesion of particles to a surface.
ACKNOWLEDGEMENT
The authors would like to thank Anko Eissens for the SEM images, TI Pharma for
financial support for this research as part of D6-203-1: DeQuaPro project.
REFERENCES
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classifier technology (ACT) in dry powder
inhalation: Part 1. Introduction of a novel
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the performance of a basic air classifier. Int. J.
Pharm. 260, 187200 (2003).
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39
Chapter 3
Segmentation method for 3D image
CHAPTER 3
3.1 ABSTRACT
Density-based spatial clustering of applications with noise (DBSCAN) is an unsupervised
classification algorithm which has been widely used in many areas with its simplicity
and its ability to deal with hidden clusters of different sizes and shapes and with noise.
However, the computational issue of the distance table and the non-stability in detecting
the boundaries of adjacent clusters limit the application of the original algorithm to large
datasets such as images. In this paper, the DBSCAN algorithm was revised and improved
for image clustering and segmentation. The proposed clustering algorithm presents two
major advantages over the original one. Firstly, the revised DBSCAN algorithm made it
applicable for large 3D image dataset (often with millions of pixels) by using the coordinate
system of the image data. Secondly, the revised algorithm solved the non-stability issue of
boundary detection in the original DBSCAN. For broader applications, the image dataset
can be ordinary 3D images or in general, it can also be a classification result of other type of
image data e.g. a multivariate image.
A density-based segmentation for 3D images, an application for X-ray microtomography

Thanh N. Trana, #, *, Thanh T. Nguyenb, c, #, Tofan A. Willemszb, c, Gijs van Kessela,
Henderik W. Frijlinkb, Kees van der Voort Maarschalkb, d
Center for Mathematical Sciences Merck, MSD Molenstraat 110, 5342 CC Oss, PO Box 20, 5340 BH Oss,
The Netherlands
b
Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The
Netherlands
c
Pharmaceutical Sciences and Clinical Supplies, Merck MSD, PO Box 20, 5340 BH Oss, The Netherlands
d
Competence Center Process Technology, Purac Biochem, Gorinchem, The Netherlands
a
# Authors contributed equally to this work

* Corresponding author: Thanh N. Tran
Center for Mathematical Sciences, Merck, MSD
Molenstraat 110, 5342 CC Oss, The Netherlands
Email: thanh.tran@merck.com
Published in:
Analytica Chimica Acta, Volume 725, 6 May 2012, Pages 1421
42
SEGMENTATION METHOD FOR 3D IMAGE
Highlights
We revised the DBSCAN algorithm for segmentation and clustering of large 3D image
dataset and classified multivariate image.
The algorithm takes into account the coordinate system of the image data to improve
the computational performance.
The algorithm solved the instability problem in boundaries detection of the original
DBSCAN.
The segmentation results were successfully validated with synthetic 3D image and 3D
XMT image of a pharmaceutical powder.
Key words: Clustering; Image segmentation; Image classification; X-ray imaging;

Particle identification; DBSCAN
Graphical abstract
A density-based segmentation for 3D images

Binary 3D image
Revised DBSCAN
Fast with density Kernel
Robust to borders
Applicable for multivariate

images
Segmented 3D image
43
CHAPTER 3
3.2 INTRODUCTION
Segmentation of 3D images is an important step in quantitative and qualitative imaging,
a process that has the potential to reveal substantial information in a complicated image
structure which one cannot easily see by visual observation. The information is used to
correlate to the behavior of the process in which the image object belongs to. Recently,
the need for understanding of microstructure of granular objects has become increasingly
important in many industries. In pharmaceutical industry for example, the material structure
such as powder packing or particle arrangement in an agglomerate, or in a tablet, is a critical
parameter that directly relates to the products performance. A better understanding of this
parameter gives guidance for the process development, the development of the process
analytical technology (PAT), and the process manufacturing during the process lifecycle.
Among the available 3D imaging methods, X-ray micro-tomography (XMT) has been
used in numerous powder samples to obtain structural information. With these samples,
the structures are often complex and dense with classes of different sizes and shapes. In this
context, the segmentation is an important step in the quantitative analysis of 3D XMT images
to distinguish individual particle and quantify important parameters such as apparent density,
particle sizes and particle distribution for further process development activities.
A number of 3D segmentation methods has been developed for 3D images such as
region growing, deformable surface and level set method, fuzzy connectedness, watershed,
Bayesian method, Mumford and Shahs cost function1. The common idea of these methods is
based on the region growing methodology using different gradient (or merging) functions.
Among these methods, the watershed is the most widely used for the segmentation of 3D
images of granular materials2. The detection of contours of material objects is the central
idea of the segmentation method. However, with dense and non-homogenous data, the
watershed algorithm often results in over-segmentation. While the image in-homogeneity
is a common issue in XMT imaging due to the variation in the materials attenuation
properties, the over-segmentation problem is often encountered with this data type. The
reason for this over-segmentation is that the gradient function is very sensitive to the
degree of local intensity changes in the neighborhood and among the image regions. For
in-homogenous images, these (local) changes are different for different in-homogenous
regions. In this case, it is hard to create a global merging function for coping with the
between homogenous regions issue. It will result in an excessive number of local minima
(cores) from which the region growing process will start and the process will end up with
an overestimate of the number of clusters.
Some solutions were proposed to improve the watershed algorithm. One way of
improvement states that the watershed convolution should be controlled by proper markers
from which the region growing will start. The strategies to find these markers vary in
different cases. In a semi-supervised procedure, these markers can be introduced manually
or by a selected criterion to get the only meaningful minima in the images 3. However,
despite the efforts to extract proper markers for the watershed segmentation, the task is not
always trivial with highly noisy images4.
44
Another way to improve the watershed segmentation is to merge the over-segmented

results using a hierarchical concept as a post-processing step5,6. This approach is based on the
assumption that the over-segmentation was created by the internal in-homogeneity (within
object variation), and that these segments belong to a homogenous region i.e. one object. It
was also assumed that the within object variation is smaller than the between object variation
so that one can attempt to merge the intra-region segments by the hierarchical procedure 6,7.
In addition to the over-segmentation issue, the watershed segmentation algorithm may
also generate under-segmentation results in case of dense material with irregular shapes of
objects4. This has been shown in an extensive review of watershed segmentation 8.
Density-based spatial clustering of applications with noise (DBSCAN clustering
or segmentation) was developed based on the density concept9. Fifteen years from the
introduction, the algorithm has become popular because of its simple concept and the
relative ease of implementation. An important advantage of the algorithm is the possibility
to deal with clusters of different shapes, different sizes, and noisy images. DBSCAN was
developed originally for spatial data such as geospatial data which are usually stored as
coordinates and topology maps.
The algorithm has quickly become popular in many other fields including social
science10,11, civil engineering12, chemistry13, spectroscopy14, and medical and biomedical
image analysis1517.
Similar to other segmentation algorithms, DBSCAN expands a cluster by connecting,
or growing a core point to adjacent core points by a clustering criterion. In DBSCAN, this
clustering criterion is the local density and the density-merging constraint. Core points
are defined as points having high local density. Border points have a lower local density.
Clusters are separated by border points. Unlike the gradient merging constraint in other
algorithms1, the density-merging constraint in DBSCAN is directionless. Moreover, the
density-merging constraint in DBSCAN is also flexible. It is defined by the combination of
two parameters: the radius from the point of interest and the number of neighboring points
within this radius (this number defines the local density). Therefore, DBSCAN has the
unique feature to detect structures of objects that have different shapes and different sizes.
There are still non-ignorable drawbacks of the algorithm which have been the subject of
many recent works, i.e. i) identifying suitable density settings of the two input parameters,
ii) dealing with data of non-uniform density clusters18, iii) high computational cost of
distance matrix and density map19, and finally iv) dealing with dense structures with many
clusters in contact9. The first three issues are the main topics of many discussions about
DBSCAN which can be found in more than 2800 papers in the literature20.
Although the latter issue has been mentioned in the original work 9, it has hardly been
discussed. In this case, due to the relatively high number of border points in contact areas
between clusters, the result of DBSCAN clustering depends on the visiting order during
the expansion step of the algorithm9. The DBSCAN algorithm has a weak point in this
situation. The problem has been recognized in the original work9, however the situation was
considered to be rare for the traditional spatial data.
45
CHAPTER 3
The DBSCAN segmentation algorithm has the advantage of the flexibility to deal with
cluster of different sizes and shapes, and noisy images. Therefore, in this paper, we introduce
DBSCAN as an algorithm for segmentation of binary 3D images of irregular objects. Firstly,
we make a brief review of the DBSCAN algorithm and then we describe a revised version
of DBSCAN to work with binary 3D images and to deal with the situation of dense, highly
contacted clusters. The effectiveness of the new concept will be demonstrated in 3D simulated
data of non-spherical objects as well as 3D XMT images of pellets of microcrystalline cellulose.
3.3 DBSCAN ALGORITHM

Given a binary image X with a total number of pixels N. Pixel i in the image X is denoted
by xi. As a density-based method, DBSCAN estimates the local density for each pixel xi
and labels the pixel xi as either a core point, or a border point, or a noise depending on the
density value and the connectivity with the neighboring pixels. A cluster is then determined
by creating a connection between high density pixels (density reachable chain). Readers
are referred to original paper9 for the detailed information about the DBSCAN algorithm.
Eps and MinPts are the two main input parameters of DBSCAN. The main concepts of
the algorithm can be summarized as follows:
The local density at a pixel xiX is defined by counting the pixels in the direct
neighborhood defined by the Eps parameter with the following equation:
(1)
where
Eps : the radius around a pixel for the density calculation.
NEps(xi) : the number of neighboring pixels of xi defined by Eps,
(2)
Note that, in order to determine the neighboring pixels, a distance table containing the
Euclidian distances between all pixel pairs is needed.
In terms of computational time, this is the most time-consuming part of the algorithm.
Without special implementations such as an accelerating index structure or a searching
system, the computation time of the algorithm is basically very high, of the order of O(N2)
which is a function of the total number of points N. Many works have been focusing on
optimizing the computation procedure for the distance table 21,22 where the runtime of
the algorithm was reduced to the order of O(N log N) in which the distance queries were
efficiently supported by the spatial index structures. However, for a large image data set
with millions of pixels (samples), this computation time is still high.
Points are classified into three types; a core point, a border point or a noise. A core point
(xcore) is defined as a point that has a local density that is higher than the density threshold
46
defined by MinPts; density(xcore)MinPts. A border point (xborder) is defined as a point in the

neighborhood of a core point xcore but its local density is lower than the threshold MinPts. In
particular, density(xborder)<MinPts and xborderNEps (xcore). A point xi is defined as a noise (xnoise)
if it is neither a core point nor a border point. Hence, density(xnoise)< MinPts and xjNEps
(xnoise) where xj is a core point. Density-reachable is an important concept in DBSCAN.
Two points x1 and xn are density-reachable if there exists a chain C={x1,, xi,xi+1,...,xn| with
1in, n2} so that xi s a core point and xi+1 is a neighbor of xi. Hence, density(xi) MinPts
and xi+1NEps (xi). Note that by definition all the points except the last point in the chain
{x1,, xn-1} are core points and the last point xn can be either a core point or a border point.
A cluster is defined as a set of density-reachable points from an arbitrary core point9 (Fig. 1).
A cluster
A core point
A border point
Density-reachable
Eps
Eps
Figure 1. Illustration of the principle concepts of DBSCAN
The implementation of the DBSCAN algorithm consists of two-steps. The algorithm

identifies an arbitrary core point xc for a new cluster c in the first step. In the second step,
the algorithm retrieves all density-reachable points from the core point xc to recursively
identify all chains starting from xc which defines pixels belonging to the cluster c. Note that
the chains contain both core and border points. Noise is identified during the segmentation
procedure and confirmed at the end when all clusters are identified. Readers are referred to
the work of Ester9 for the original implementation of the DBSCAN algorithm.
In summary, the algorithm has two parameters for the local density calculation which
have to be set by the user. Without prior information, there are several tools developed such
as the k-distance graph13 which can assist the task. The algorithm is robust with images in
which there present noises.
3.4 DBSCAN FOR 3D BINARY IMAGES

An X-ray Micro-Tomography imaging of an object generates a 3D image as a stack
of cross-sectional, 2D gray scale images. To distinguish between material and void, a
binarization step is needed. Usually, the material pixels have values of 1 and void of 0 in
binary images.
For convenience, a class pixel is referred to as a material pixel in this section and is
denoted by xi,j,k X in which, (i, j, k) is the coordinate of the pixel in the 3D binary image.
47
CHAPTER 3
The extension from the original DBSCAN towards a DBSCAN for binary 3D images
(denoted by XMT-DBSCAN) in this work is firstly about the local density calculation of pixel
xi,j,k (a point in DBSCAN). Here, the w parameter is referred to as a half-window parameter (used
instead of the radius parameter Eps in the original DBSCAN) to define a sub-window around a
pixel. The sub-window with size of (2w+1) x (2w+1) x (2w+1) includes the neighboring pixels
that position within the radius of w from the centered pixel xi,j,k. The sub-window is denoted by
the data matrix XW<ixjxk>. Each element of XW<j><k> has a binary value of either 1 for the material
pixel or 0 for the background pixel. The local density is then defined by the following equation:
(3)
where
(*) is the Hadamard or element-wise product of two equally sized matrices (or data
cubes)
Kw is a kernel cube having the same size as XW<j><k> to specify the local density
calculation model. Kw can be defined as a sphere-like density kernel or a cubic kernel
around a pixel. The construction and implementation of Kw is flexible. In many cases, Kw
with all values of 1s except for 0s at all corner-points is used.
ak is the number of non-zero values in Kw
The second parameter is denoted as MinDen in XMT-DBSCAN. Similar to the original
DBSCAN, the core point and the border point are points that satisfy the conditions:
density(x<core>)MinDen, (density(x<border>)<MinDen and a core point x<core> exists such that
x<border>XW<core>), respectively. With a noise, the conditions are: density(x<noise>)<MinDen and
no core point x<core> exists that x<noise>XW<core>.
For the situation of border points, it was stated that the identified cluster is uniquely
defined and contains exactly the points which are density-reachable from any core point
of the cluster9. The statement is, however, only true for the core points. For a border point
it may be reached by different routes (density-reachable) from different core points in its
neighborhood. It may come to the situation that several density-reachable chains share the
same border point. Especially in the area between two adjacent clusters (e.g. particles in
XMT image of powder) where a border point can be reached by different density-reachable
chains belonging to different clusters. In the original DBSCAN implementation, the border
point is assigned to the cluster that discover this border point first - first reached by a
density-reachable chain of that cluster. Since the visiting (or discovered) order of clusters
is arbitrary, the assignment of border point in the joint border of adjacent clusters is also
arbitrary which leads to non-stable clustering results for border points.
The situation becomes more critical when the value of density parameter Eps (or w in
XMT-DBSCAN) increases, leading to higher number of the border points. The issue has
been recognized in the original work, but the case was considered as a rare situation for
48
spatial data9. For the case of images e.g. in XMT images of dense material in our work, this
situation is encountered more often.
To overcome the instable situation for the border pixels, in XMT-DBSCAN the definition
of density-reachable chain is modified to contain only core pixels C={x<1>,, x,x<i+1>,...,x<n>}
where with 1 i n, x is a core pixel and x<i+1>XW. Hence, during the clustering
expansion in step 2, only core points are identified and assigned to a cluster accordingly. The
border points are still recognized by the algorithm during the cluster expansion step but they
are not labeled to any cluster yet. Labeling of the border pixels is done by a post-processing
step at the end of the algorithm when all the core pixels are identified.
The implementation of the post-processing step 3 is simply done by identifying the
closest core pixel x<core>d in XW<border>d. The border pixel is then labeled to the cluster d.
The pseudocode of the XMT-DBSCAN algorithm is given in the appendix. Briefly, the
three steps algorithm begin with an arbitrary point xi. If xi is a core point, the reachable
neighbors of the point xi are stored in a list named SEEDS. During a for-loop, whenever a
point xj in the list is discovered as a core point, the list is updated with the reachable neighbors
of xj. All the core points that are discovered in a for-loop constitute a density reachable chain.
In many applications, a further transformation from the binary image to a so-called
distance image can further improve the performance of the segmentation model. In this
case, the binary value of the pixel (i, j, k) is replaced by its normalized distance to the
closest background pixel. Because of this calculation, the pixels that situate at the center of
a material area will have higher distance values than the pixels at the border of that area.
Consequently, high distance values of the center pixels will lead to higher local density
value at these points. Hence, for the density calculation, the binary sub-window XW<j><k>
in Eq.3 is replaced by the sub-window DW<j><k> in the distance image. In this case, it gives
more space to choose the threshold MinDen due to the gradual increase in distance values
from borders to centers of particles. However, in an image with noise where the noise may
be assigned as the same class with a background, the application of the distance image may
not work since the distance to noises is calculated instead of the background.
(4)
The similar concept can bring the application of XMT-DBSCAN to 3D gray-scale images.
In this case, the sub-window from the gray image GW<j><k> is used for the density calculation.
(5)
Compared to the original DBSCAN, the calculation of distance table for all pixel pairs
is not needed in XMT-DBSCAN. The neighboring information for the density calculation
is often computation cost-free by using an existing imaging system to access image co-
49
CHAPTER 3
ordinations from the database. The algorithm is fast with the linear complexity O(N). Only
one main scan is needed for the core pixels and another scan for the border pixels at the
post-processing. This feature allows application of XMT-DBSCAN for large 3D images.
The selection of the parameters, w and MinDen can be done using a small image e.g. size
100 x 100 x 100 pixels. Values of 1, 2, or 3 are often chosen for w parameter depending on
the size of the object and the image resolution. MinDen can be visually optimized and the
final parameters are kept constant for larger images.
The value of MinDen is often higher than 0.9 for binary X matrix and between 0.3 - 0.5
for the distance matrix D.
For the situation with the present of noise, the advantage of the original DBSCAN
algorithm in dealing with noises is retained. A noise outside particles should have very
low density and therefore it is labeled as noise. For the case when noise may present inside
a particle, random noise may just reduce the general density threshold defined for a corepixel so that a lower thresholdEpscan be defined for this situation. In conclusion, noise
(random noise) does not affect the results.
3.5 DATA
In this section, we describe the application of the XMT-DBSCAN algorithm for the
segmentation of 3D images. Firstly, the algorithm was applied for segmentation of a binary
3D image generated by numerical simulation by using the Discrete Element Method
(DEM)23 which results in 3D images of structures of a powder. The advantage of using
the simulated image is that the segmentation result can be directly validated by comparing
the segmented image with the original 3D image which has the information of all clusters
known beforehand. Secondly, the algorithm was applied for segmentation of real XMT
images of a powder. The assessment of the segmentation performance was done indirectly
by using the particle size distribution information.
3.5.1 XMT-DBSCAN segmentation and clustering of simulated 3D image

A synthetic 3D image was generated by a simulation. The objective of the simulation is
to mimic the random packing of particles while falling into a tube. One hundred and forty
four rod-like particles were generated. Each rod has a size of 10x20 m and was constructed
by binding 3 overlapping spheres (10 m in diameter) with high attraction force. These
particles were built using the ESyS-particles, an open source DEM package23,24.
After having all the rod-like particles in a stable state, randomly arranged in the
container, the coordinates of all the spherical particles were exported to a labeled 3D image.
In this image, each pixel obtained either the value of the particle-tag or the background
value of 0 if it does not belong to any particle. We used this image as the standard image to
check the validity of segmentation.
To generate the binary 3D image, we turned all the values of pixels with particle-tag in
the standard 3D standard image into 1 and the background pixels values into 0.
50
We applied the XMT-DBSCAN algorithm to the binary 3D image for segmentation and
clustering. The segmented 3D labeled image was compared with the standard 3D labeled
image to check the validity of the segmentation.
3.5.2 XMT-DBSCAN segmentation and clustering of XMT images of powders

Pellets of microcrystalline cellulose, a popular powder generally used as an excipient in
the pharmaceutical industry, were used as model particles for the segmentation algorithm.
Three different grades of pellets with different particle sizes were selected for XMT analysis.
Cellets 100, Cellets 200 and Cellets 350 are pellets with particle sizes range from 100 to
200 m, 300 to 355 m and 350 to 500 m, respectively.
Details of the powder characterization and the 3D XMT image acquisition and
binarization were described in our earlier publication25.
3.6 RESULTS AND DISCUSSIONS

3.6.1 Segmentation of and clustering of simulated 3D image
Fig. 2a shows the simulated particle arrangement in a tube. The coordinates and labels
of each particle were extracted and shown in Fig. 2b. In these images, each particle has a
unique label and is displayed by a unique color to be visually discriminated from the other
particles. This is the standard image to compare with the segmentation result.
a
Figure 2. Synthetic 3D image: random packing of particles in a tube (a) and labeled 3D image of particles in Fig. 2a (b).
51
CHAPTER 3
The binary 3D image of Fig. 2b is shown in Fig. 3a. This image is the input data for
DBSCAN segmentation. A sample of a 2D cross-section of the Fig. 3a is shown in Fig. 3b.
a
Figure 3. Binary 3D image of the labeled 3D image in Fig. 2b (a) and a sample of a 2D cross-section image of
the Fig. 3a (b).
The result of the segmentation of the binary 3D image in the Fig. 3a using the revised
DBSCAN algorithm is shown in Fig. 4.
Figure 4. Result of DBSCAN

segmentation of 3D binary image.
52
The rod-like particles in simulation have dimensions of 10 20 m which are similar to

the particle sizes normally used in many industries i.e. pharmaceutical and food industry.
However, the XMT-DBSCAN algorithm runs on the final image, therefore the number of
pixels per cluster is important. In this case, the particle dimensions are 10 20 pixels and
the total number of pixels per particle is 1250.
We tested the XMT-DBSCAN segmentation on rod-like particles and all the particles
were successfully separated from the others which clearly indicated that the performance
of the XMT-DBSCAN is shape-independence. As compared to the standard 3D image,
after the segmentation of the 3D binary image, we obtained the same number of particles
with the same particle size in pixel. This means that neither under-segmentation nor oversegmentation happened in this segmentation. We are confident to apply the segmentation
algorithm to the XMT data of real powder in the next step.
3.6.2 Segmentation and clustering of XMT images of powders

A sample of a 3D segmented image of Cellet 100 is shown in Fig. 5. Results of the check of
validity of the segmentation data are shown in Fig. 6. As shown in this figure, we have successfully
separated particles in the XMT image. The minimum and maximum particle sizes in XMTDBSCAN are similar to that obtained by optical microscopy. That means that the algorithm
neither merges particles together nor splits particles into small pieces. In other words, we saw no
under-segmentation or over-segmentation. There are little differences between the particle size
distribution curves obtained by the two methods; this was due to the limited number of particles
analyzed by XMT as compared to the number of particles analyzed by optical microscopy.
Figure 5. Example of segmented 3D image of

Cellet 100.
The XMT-DBSCAN segmentations of the synthetic image and the XMT 3D images of
Cellet were performed using Eq. (3) (XMT-DBSCAN segmentation of binary image). We
53
CHAPTER 3
Figure 6. Check of validity by comparing particle length and particle width distributions.
have also performed the segmentation of the synthetic image using the Eq. (4), the result
was similar to that obtained using Eq. (3).
By using the Eq. (4), an extra step of distance image calculation would require
additional computation time. Logically, when it is possible, a direct application of the Eq.
(3) is preferred. However, the XMT-DBSCAN segmentation using the Eq. (4) gives more
space to choose the threshold MinDen due to the gradual increase in distance values from
borders to centers of particles.
The Eq. (5) presents a possibility to extend the application of XMT-DBSCAN algorithm.
However, results of this modification are not presented in this study.
Concerning the computation speed, the segmentation of the synthetic image using
XMT-DBSCAN algorithm took 145 s in our desktop while the segmentation of the same
image using the original algorithm (calculation of distance tables) took 1.9 104 s (5 h). It
illustrates that the revised algorithm using the existing coordinate system of image data (x,
y, z coordinates to access the pixel value) decreases the computation time significantly. This
modification is critical to apply the segmentation method to large datasets.
Concerning the border detection of adjacent clusters, the modification of the densityreachable chain and the implementation of a post-processing step has solved the instability
in border detection of the original DBSCAN. Fig. 7 illustrates the segmentation result using
the original DBSCAN algorithm (Fig. 7a) and the revised XMT-DBSCAN (Fig. 7b). In the
Fig. 7a, the infiltration of one particle to an adjacent particle can be visually observed.
With the revised algorithm, the borders were properly detected as illustrated in Fig. 7b.
54
Figure 7. Border detection by original DBSCAN algorithm (a) and by the revised XMT-DBSCAN algorithm (b).
3.7 CONCLUSION
This paper demonstrated a revised version of the DBSCAN (density-based spatial
clustering of applications with noise) algorithm to use for the segmentation of 3D binary
image, as the classification (binarization) result of XMT 3D image, and the possible extension
to grayscale 3D image. With its advantages, the algorithm is a good complementary method
for dealing with large 3D images which have object clusters in different shapes, sizes together
with the presence of noises.
The revised version of DBSCAN has solved the instability issue of the original DBSCAN
in classifying border points of adjacent objects. By using an existing coordinate system of
the image data, the revised version run much faster than the original one and can be applied
for the segmentation of large images.
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APPENDIX
Implementation of XMT-DBSCAN for binary 3D image
Algorithm XMT_DBSCAN(data, w, MinDensity, Kw)
// data: binary 3D image

// w: kernel scale
// MinDensity: threshold to determine a core-point
// Kw: kernel matrix
Label material pixels as UNCLASSIFIED

Cluster_Id = 1;
For x in image
If
x is UNCLASSIFIED

ExpandCluster( x ,ClusterId, w, MinDensity, Kw)
If Expand successfully
Cluster_Id = Cluster_Id +1;
End
End
End
End // XMT-DBSCAN
57
CHAPTER 3
Algorithm ExpandCluster ( x , ClusterId, w, MinDensity, Kw)

//
x : a material pixel in the 3D image
SEEDS = Retrieve_Neighbors ( x , w)

Density( x )= DensityFunction ( x , w, Kw) // Apply equation (3),(4), or (5)
If Density( x ) < MinDensity
// Temporary label low density pixel as noise
Label
x as a NOISE
Return without expansion success

Else
// STEP 1:
Label
x is a identified as a starting core-point for ClusterId
x as a CORE-POINT with ClusterId // x is a core-point
// STEP 2: Identify chains

For all
x< j > in SEEDS
Nw( x < j > )= Retrieve_Neighbors ( x < j > , w)

Density( x < j > )= DensityFunction ( x < j > , w, Kw) // Apply equation (3),(4), or (5)
If Density( x < j > ) >= MinDensity
Label
//
x< j > is a core-point
x< j > as a CORE-POINT with ClusterId
// Note: chain expansion is only applied for a core-point

Add all UNCLASSIFIED in Nw ( x < j > ) to SEEDS
Label UNCLASSIFIED and NOISE points in Nw( x < j > ) as BORDER points
//Note: the noise within the neighborhood of a core-point
// is labeled as a border-point
End
End
Return with expansion success
End
End // ExpandCluster
58
// STEP 3:
// Note: All the core-points and noises are identified at this step
For all
x<border > as the BORDER points
// Border-point currently has no class ID

// Get all neighbor points
Nw( x <border > ) = Retrieve_Neighbors ( x <border > , w)
Label
x<border > with ClusterId of the closest core-points in Nw( x<border > )
End
59
Chapter 4
Determination of coordination number
CHAPTER 4
4.1 ABSTRACT
The coordination number is an important parameter for understanding the particulate
systems, especially when agglomerated particles are present. However, experimental
determination of the coordination number is not trivial. In this study, we describe a 3D
classification method, which is based on the revised DBSCAN (Density-Based Spatial
Clustering of Applications with Noise) and its application to X-ray micro-tomographic (XMT)
images to determine the coordination number distribution. Pellets of micro-crystalline
cellulose were used as model particles. The validity of the segmentation was checked by
comparing the particle size distribution (PSD) obtained by XMT-DBSCAN with PSD obtained
by optical microscopy. The results were found to be in good agreement, demonstrating the
suitability of the DBSCAN method. The means and standard deviations of coordination
numbers were (8.21.7, n=994 particles), (8.11.5, n=904) and (6.21.2, n=159) for pellets
with length based mean sizes of 157, 307 and 437 m, respectively. The coordination number
distribution was in line with previous finding in mono-sized acrylic beads.
Highlights

We developed a segmentation method based on the revised DBSCAN.

We used the method for the segmentation of XMT images.
The segmentation result was successfully validated.
We used the segmented XMT images to determine the coordination number.
The coordination number distribution results were in line with previous study.
Key words: Coordination number; DBSCAN; Granular materials; Imaging; Powder

technology; Computation
A density based segmentation method to determine the coordination number

of a particulate system
Thanh T. Nguyena, #, *, Thanh N. Tranb, #, Tofan A. Willemsza, Henderik W. Frijlinka,
Tuomas Ervastic, Jarkko Ketolainenc, Kees van der Voort Maarschalka, d
Department of Pharmaceutical Technology and Biopharmacy, University of Groningen,
Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
b
Center for Mathematical SciencesEurope, MSD, Oss, The Netherlands
c
School of Pharmacy, University of Eastern Finland, Kuopio Campus, Kuopio, Finland
d
Competence Center Powders and Formulations, Purac Biochem, Gorinchem, The Netherlands
# Authors contributed equally to this work
a
* Corresponding author: Thanh T. Nguyen

thanh.nguyen@merck.com; Nguyen.t.thanh80@gmail.com
Published in:
Chemical Engineering Science, Volume 66, Issue 24, 15 December 2011, Pages 63856392
62
DETERMINATION OF COORDINATION NUMBER
4.2 INTRODUCTION
The coordination number is a basic attribute that influences many properties of
products made of particulate materials1,2. However, experimental determination of
coordination number is not trivial due to the distributions of particle sizes, shapes and
numbers of particles in a granular sample. There have been several attempts to determine
the coordination numbers of particles in a particulate system. One of the earliest works
was carried out by Smith et al3,4 in which the contact points between the lead shots were
identified by the capillary retention of the liquid between the lead spheres and the chemical
reaction between liquid and lead. The contacts between particles were counted manually for
every single particle. The method was further used to determine the coordination number
of a particulate system containing particles of different sizes 5,6. However, the method is only
practical for relatively large particles with sizes in the millimeter scale. For particles in the
nanometer scale, the coordination number can be estimated via film surface measurement 7,8.
The application of this method is limited to particle sizes between about 0.01 and 1 m.
Recent developments in X-ray micro-tomography (XMT) offer a new tool to noninvasively investigate the internal structure of a granular system 9. Current tabletop
instruments offer possibilities to visualize the three dimensional internal structure of an
object with a spatial resolution in the micrometer range913. With this technique, 2D X-ray
shadow images of an object are first captured at different angles. Then, these images are
reconstructed to give 3D information of the object. The reconstruction results in a stack of
2D images, which reveal the internal structure of the object layer by layer along one axis.
The next challenge is to convert the XMT images into physically meaningful properties.
Rigorous image analysis is necessary to obtain quantitative information.
For the determination of coordination numbers, the segmentation of a 3D image is
the most important step. Each particle in the 3D space should be identified and labeled
separately. Several segmentation algorithms have been used to recognize individual particles
in XMT 3D data1420. However, for dense agglomerates characterized by the presence of
large contact areas between particles together with local irregularities on the particles and
noises in the images, segmentation is still a challenging task. Popular techniques such as
watershed may result in over-segmentation of the image with breakage of particles in small
pieces or under-segmentation with merging of highly contacted particles 15,21,22.
In this study, we present a density-based segmentation method, DBSCAN, to identify particles
in XMT images. We check the validity of the segmentation method by comparing the particle size
distribution (PSD) obtained from method with the PSD obtained from optical microscopy. We
apply DBSCAN to determine the coordination number distribution of tap-densified powders.
4.3 MATERIALS AND METHODS

4.3.1 Sample preparation and image capturing
Three different grades of pellets of microcrystalline cellulose were used as model particles
(Cellets 100, Cellets 200 and Cellets 350, Pharmatrans Sanag AG, Basel, Switzerland). Cellets
63
CHAPTER 4
100, Cellets 200 and Cellets 350 are pellets with a size ranging from 100 to 200 m, from 200
to 355 m and from 350 to 500 m, respectively. SEM images of the materials are shown in
Fig. 1. The SEM images were acquired using a JEOL JSM-6301F microscope (Jeol, Japan).
Figure 1. SEM images of the model materials.

(a) Cellets 100. (b) Cellets 200. (c) Cellets 350.
The particle size distributions and particle shapes were characterized by optical
microscopy using an optical microscope (Morphologi G2, Malvern Instrument, Malvern,
United Kingdom). The samples were dry-dispersed and analyzed under 5x optical
magnification. The distributions of particle length and particle width were used to verify
the segmentation result as described in Section 3.2.
The samples of Cellets were introduced into different Eppendorf tubes, tap-densified
20 times manually, mounted on a vertical sample holder and then subjected for X-ray
tomographic scanning using a Skyscan 1172 scanner (Skyscan, Kontich, Belgium). The
source voltage was set at 60 kV, the sample was rotated 360 degrees in a 0.7 degree steps. The
reconstruction of shadow images was performed using NRecon software (Skyscan, Kontich,
Belgium); the Post-alignment was set at 2. With these settings, the spatial resolution of
tomographic images was 4.17 micrometers. A sample of one of the reconstructed images of
Cellets 100 is shown in Fig. 2a.
64
4
e
Figure 2. Quantitative image analysis process. (a) Sample of the reconstructed images of Cellets 100. (b) 2D
slice sample of one volume of interest. (c) Binary image of the gray scale image in (b). (d) Result of hole-filling of
the binary image in (c). (e) Segmented image of (d) before the post-processing step with core points colored and
border points white. (f) Segmented image of (d) after the post-processing step.
4.3.2 DBSCAN analysis of coordination number

The micro-tomographic analysis of a sample using XMT results in a stack of two
dimensional images. The stack contains structural information of the sample, including the
coordination number. To extract the coordination number, a quantitative image analysis was
performed on a selection of tomographic images. This was accomplished by introducing the
DBSCAN code developed in the Matlab environment. The calculations for this study were
performed using Matlab version 7.10.0, R2010a (The MathWorks Inc., Natick, The USA).
The quantitative image analysis can be summarized in three main steps: image
processing, segmentation and structure characterization as illustrated in Fig. 3.
i. Image processing
In each analysis, a section of the reconstructed tomographic images was chosen; this is
known as the volume of interest (VOI). The size of a VOI of 757575 pixels was chosen
based on the consideration of the computational capacity. A 2D slice sample of one VOI is
shown in Fig. 2b. For each sample of Cellets, we performed the analysis on 27 VOIs.
Depending on the size of the particles in the XMT images, larger VOIs may be used and
resized to the suitable VOI of 757575 pixels. In this study, we chose VOIs of 150150150
65
CHAPTER 4
Image processing
Segmentation
Particle
characterization
XMT images
DBSCAN
Core detection
Coordination number
determination
VOI selection
Post processing
Particle size
Binarization
determination
Hole filling
Segmented images
Figure 3. Schematic summary of the quantitative image analysis process.
pixels for Cellets 100 data, VOIs of 300300300 pixels for Cellets 200 and Cellets 350 data. These
VOIs were resized two and four times, to the desired VOI using the Gaussian Pyramid method23.
Next, XMT images within the VOI in gray scale were transformed into binary images
using the Fuzzy c-means algorithm (fcm). The fcm function provided by the MATLAB Fuzzy
Logic Toolbox was used for this purpose. The binary image of Fig. 2b is shown in Fig. 2c.
Due to non-homogenous intensity of XMT signals, the binarization step may result
in empty holes, particularly in the center of particles. The internal empty holes will have
direct influence on the segmentation result because it potentially leads to misrecognition of
particles. For this reason, the hole-filling step is necessary to complete the areas of particle.
For this purpose, the DBSCAN segmentation procedure (which will be discussed in Section
2.2.2) was applied to the complementary image of the binary image, using the following input
parameters: [EPs=1, MinPts=0.7]. A sample of a filled image is shown in Fig. 2d.
ii. Segmentation using DBSCAN
The concept of DBSCAN (Density-Based Spatial Clustering of Applications with Noise)

algorithm24 was used for the identification of particles in XMT binary 3D images. DBSCAN
was developed originally for non-image spatial data, e.g. geospatial data, which are usually
stored as coordinates and topology maps. DBSCAN is a density-based unsupervised
classification algorithm, which estimates the local density of each data point and forms
clusters of data by connecting adjacent core-points having high local density together.
Clusters are separated by border-points, which have low local density. The local density
66
at each data point is normally estimated by counting the number of neighboring points
defined by the radius EPs from the point of interest24. Due to the expansion flexibility to any
direction, DBSCAN has unique features to detect object structures of different shapes and
their arrangement within the data space24.
For our application of DBSCAN, the data were stacks of binary images, which distinguish
between the material pixels and pore or background pixels. The input parameter EPs
defines the size of the kernel, e.g. a cube or a sphere with diameter of EPs pixels surrounding
the pixel of interest xi. The local density of the kernel around pixel xi was calculated by
calculating the fraction material pixels in that kernel. The second parameter MinPts is used
as the density threshold for a core-pixel.
Instead of only one step in the original DBSCAN, we revised the DBSCAN algorithm
with a two-step procedure. The first is the identification of all connected core-points for
clusters by recursively learning all density-reachable chains from an arbitrary core-point.
The border-points are generally identified at this step but they are not labeled to any
particular cluster. The second one is a post-processing step in which the border-points are
finally classified into appropriate clusters (particles). The definitions, concepts and main
calculations of the DBSCAN algorithm can be summarized using the scheme in Fig. 4.
Fig. 4a presents a binary image in which each material pixel was assigned a value of
1, the background pixels were left blank to simplify the visualization. The calculation
starts by building a kernel of size Eps (e.g. a cube or a sphere with diameter of Eps pixels)
around a certain material pixel xi. Then, the local density of the kernel around pixel xi
was calculated by calculating the fraction material pixels in that kernel. Based on the local
density, DBSCAN assigns the pixel of interest xi to either a core-point or a general borderpoint (not yet labeled to any cluster). A core-point is defined as a material pixel that has the
local density higher than the threshold MinPts ( Fig. 4b). A border-point is a material pixel
that has a local density lower than the threshold MinPts ( Fig. 4c).
A cluster (a particle in this situation) is determined by the density-reachable concept
that applies a so-called chain. A chain [x1,, xi, xi+1, , xn] is density-reachable if, for
all core-points xi(i<n) in the chain, a core-point xi+1 can be found in the kernel around
the core-point xi. A cluster is defined as all the points that belong to one density-reachable
chain expanded from an arbitrary core-point24 as pictorially illustrated in Fig. 4d.
After this first step, every material pixel was assigned to be either a border-point or a
core-point of a specified cluster (particle) as illustrated in Figs. 2e and 4e. In the second
step, the border-points were classified into appropriate clusters (particles). This step was
done by iteratively identifying the nearest core-point in the vicinity of one pixel of each
border-point and assigning the border-point to the cluster of the nearest core-point. The
result of the post-processing is shown in Figs. 2f and 4f.
A major advantage of the proposed algorithm over the original DBSCAN is that during
the recursive procedures in the first step, only the core pixels are identified and assigned to
clusters. The border pixels are classified afterwards by post-processing when information
of all clusters is learnt. This solves the assignment issue of border-pixels of adjacent clusters
67
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CHAPTER 4
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Figure 4. Schematic summary of DBSCAN
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(particles)24, which is a frequently occurring situation in (XMT) images of dense particles.

The algorithm is fast and the parameters are stable for large XMT images. The selection of
two parameters, Eps and MinPts, can be optimized using a small image.
The parameters for analysis [Eps, MinPts] of Cellets 100, Cellets 200 and Cellets 350 are
[3 pixels, 0.97], [3 pixels, 0.97] and [4 pixels, 0.97], respectively. The optimum parameters
were identified by visual assessment of the segmented images as shown in Fig. 2f.
68
iii. Particle size distribution and coordination number
The segmentation of the XMT images identified individual particles in which each particle
was described by a set of pixels with specified coordinates in 3D. The common practice to
calculate the spherical equivalent diameter does not describe all the size and shape characteristics
of the particles. Alternatively, a multivariate latent variable statistical approach can provide 3D
information of the particles: length, width and thickness25,26. For the validation purpose, we
only used the particle length and the particle width obtained from XMT segmented images to
compare with the length and the width obtained by optical microscopy.
To calculate the particle length and the particle width, two orthogonal latent variables
(eigenvectors) in the latent space of each particle were determined. The first eigenvector
positioned at the direction that explained most of the variations of the particle structure in
3D. The second eigenvector (orthogonal to the first one) captured the rest of the variations
of the particle structure. The length and the width of a particle are calculated as the length
of the projection areas of all the particle pixels to the first and the second eigenvectors,
respectively. We performed this calculation for all particles to obtain the number-based
particle size distribution (width and length).
The coordination number is the number of neighbor particles that is in contact with one
particular particle. We define that two particles are in contact if they are not separated by
any background pixel. Hence, we counted the number of neighbor particles in the vicinity
of one pixel of every single particle. We saw that there are some partial particles on the
edges of every VOI. To determine the coordination number, those particles were only used
as guest particles to count the number of neighboring particles in contact with a host
particle. The particles, which stay completely inside a VOI, can be used as host particle as
well as guest particle. The VOI sampling was calculated so that we had some overlapping
space between VOIs. In this way, the guest particles in one VOI would be completely inside
the next VOI and can be counted as a host particle as well.
4.4 RESULTS AND DISCUSSIONS

4.4.1 Image processing and segmentation: identification of individual
particles
Fig. 2 depicts the quantitative image analysis process. The final identification of
individual particles is shown in Figs. 2f and 5 in which particles were separately recognized
and were presented in different colors.
In Fig. 2b, the intensity distribution of brightness is not homogenous in the whole
image. This can be explained by the non-homogenous density of the microcrystalline
cellulose pellets. The application of Fuzzy c-means algorithm in the binarization process
reduces the loss of data due to non-homogenous density distribution and subjectdependent thresholding27,28. Other image segmentation techniques may also be applied for
the binarization as summarized by Tran et al29. However, in Fig. 2c, one can see that some
hollow particles were created. These cavities in particles should not be identified as pores.
69
CHAPTER 4
Figure 5. 3D segmentation.
We used DBSCAN for our convenience to fill these cavities. Fig. 2d shows the result of the
hole-filling of Fig. 2c in which most of the holes were filled.
The second step in the particle identification process is the segmentation. In order to have
a proper segmentation, the input parameters for DBSCAN need to be optimized. This can be
done visually. The Eps value, which is the size of the kernel, should be chosen in such a way that
it is large enough to cover the contact areas between particles. A small kernel will be engulfed in
the contact area between particles and it would be impossible to separate different particles. As
a consequence, two contacting particles with a large contact area will be recognized as one big
particle (Fig. 6a). If a large kernel is used for segmentation, many pixels would be recognized as
border-points after the post-processing step (white pixels in Fig. 6b). Consequently, relatively
small particles will not be detected. The situation is similar with high or a low MinPts values.
Hence, the selection of Eps and MinPts is flexible for each tomographic data set. One important
prerequisite of the DBSCAN segmentation method is that the contact area between individual
particles is small relative to the size of the particles. If this is not the case (e.g. when the particles
are fibrous), misidentification of the particles will occur.
As a result of the segmentation process, we are able to identify every single particle
individually in 3D space. Improper segmentation leads to large particles when the kernel is
small and loss of small particles when the kernel is big. Therefore, particle size measurement
is a way to check the chosen values of Eps and MinPts in the segmentation process.
4.4.2 Check of validity

One difficulty encountered when we tried to verify the validity of the segmentation is
that we do not have a standard to compare the XMT data. Therefore, we chose to compare a
statistical parameter, which can describe the sample. The particle size distributions (lengths
and widths) were selected as criteria to check the validity of the segmentation. The particle
70
4
Figure 6. Example of inappropriate input parameters for DBSCAN. (a) Result of segmentation of Cellets 100
with small kernel [Eps=2 pixels, MinPts=0.95]. The kernel was relatively small as compared to the contact area.
In 3 cases, two particles were recognized as one. (b) Result of segmentation of Cellets 100 with large kernel
[Eps=4 pixels, MinPts=0.95]. The kernel was relatively large as compared to the size of some particles. Three
particles were not properly recognized. These particles were recognized as border pixels (white pixels).
size distributions of three samples of Cellets from XMT data were calculated and compared
with the particle size distributions obtained from optical microscopy. Figs. 7a and b show
the particle length and width distributions of Cellets 100, 200 and 350 as determined by the
two methods: calculation from XMT images and optical microscopy analysis, respectively.
The particle size distributions (PSDs) calculated from XMT are almost the same as the PSDs
obtained from optical microscopy. The differences in particle length and particle width at
10%, 50% and 90% of the distribution curves are shown in Table 1. Most of the differences
are less than 10%. We consider this result as a good indication that the method and the
parameters chosen were suitable for segmentation. The particles in XMT data were properly
segmented without either a significant loss of small particles or a merging of particles into
bigger ones. The particle size limits found either with XMT or with microscopy were in
good agreement as well. With this result, we are confident to use the segmented data from
XMT to calculate the coordination number of every single particle.
Table 1. Differences in particle length and particle width (%) between values calculated from XMT images
and values determined by optical microscopy. The differences were calculated at 10, 50 and 90% of the
distribution curves.
Cellets 100
Cellets 200
Cellets 350
L10 differences (%)
1.52
3.70
1.76
L50 differences (%)
1.03
4.67
2.31
L90 differences (%)
5.14
1.47
5.54
W10 differences (%)
2.48
8.11
1.42
W50 differences (%)
2.92
10.17
2.28
71
CHAPTER 4
Figure 7a. Check of validity by comparing particle length distributions.
Figure 7b. Check of validity by comparing particle width distributions.

Figure 7. Check of validity by comparing particle length and particle width distributions. (a) Particle length
distributions. (b) Particle width distributions.
72
4.4.3 Coordination number of Cellets

Fig. 8 shows an example of the neighbor counting process. Each particle in the vicinity
of one pixel of the particle in consideration will be counted as one contact. The process
scans for neighboring particles of every particle in the space of the volume of interest.
Figure 8. Determination of coordination number:

counting the neighboring particles.
Figs. 9a, b and c show the distributions of coordination numbers of Cellets 100, Cellets
200 and Cellets 350, respectively. The means and standard deviations (numbers of particles
in brackets) of coordination numbers of each sample are 8.21.7 (n=994), 8.11.5 (n=904),
6.21.2 (n=159), respectively. For the Cellets 350 sample, the number of particles analyzed
was relatively low as compared to other samples. That may explain why the distribution
curve was not smooth. The average coordination numbers of Cellets 100 and Cellets 200 are
similar. The coordination number of Cellets 350 is lower than that of Cellets 100 and Cellets
200. This is probably due to the high porosity of the last sample. We define the porosity as
the percentage of the volume of the void in the total volume of the sample. The porosities
were calculated as the fraction of empty pixels in the binary image of the VOI after holefilling (i.e. Fig. 2d). Fig. 10 shows a plot of coordination number against porosity of three
samples. For each sample, results of quantitative analyses of 27 data sets are shown.
Despite the fact that XMT images of Cellets samples presented heterogeneous density
distributions and the contact areas are relatively large due to tap-densification, the
quantitative image analysis with DBSCAN showed results similar to the previous study
done by Aste et al14. In that work, the coordination number distribution of monosized
acrylic beads (more homogenous signals in XMT images) ranged from 6 to 7.5 with the
porosity range from 35 to 38%. Furthermore, Cellets particles used in this study were much
smaller than the beads used in the previous study (0.1 to 0.5 mm vs. 1 and 1.6 mm), the
segmentation with DBSCAN generated results in good agreement.
73
CHAPTER 4
Figure 9. Coordination number distributions of Cellets 100, Cellets 200 and Cellets 350. (a) Coordination
number distributions of Cellets 100. Average coordination number=8.21.7; n=994. (b) Coordination
number distributions of Cellets 200. Average coordination number=8.11.5; n=904. (c) Coordination number
distributions of Cellets 350. Average coordination number=6.21.2; n=159.
In this study, the XMT images of Cellets were properly segmented even when the
images were resized to smaller ones to reduce the computation time. This fact implies that
XMT images of smaller particles can be as well segmented by the same algorithm without
resizing the images. Moreover, with current equipments, the spatial resolution of XMT
images can be increased to sub-micrometer30,31. It is possible to detect and classify particles
in micrometer scale with DBSCAN.
74
Figure 10. Porosity vs. coordination number.
4.5 CONCLUSION
This paper shows that it is possible to apply the DBSCAN for segmentation of XMT
images. The distribution of coordination numbers was in good agreement with the previous
results on mono-sized beads. The method is suitable to study particulate systems in the
micrometer scale. An additional benefit of this segmentation is that it is able to measure the
particle size distribution in a particulate product in a location dependent manner.
ACKNOWLEDGEMENT
The authors would like to thank Ari Halvari, University of Savonia, Finland, for the
micro-tomography; Monique D.M. van Veldhoven, MSD for PSD measurements; Anko
Eissens, University of Groningen for the SEM images. We would like to thank TI Pharma
for financial support for this research as part of D6-203-1: DeQuaPro project.
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Chapter 5
Simulation of agglomerate abrasion
CHAPTER 5
5.1 ABSTRACT
A numerical simulation using the Discrete Element Method (DEM) was performed
to investigate the phenomena concerning the abrasion and breakage of agglomerates in
a diffusion powder mixer. Agglomerates were created by defining a single structure of
particles with bonds of different strengths using the Bonded Particle Model (BPM). By
comparing the agglomerate size reduction calculated by intact and broken bonds with that
agglomerate size calculated by particle number, it was possible to differentiate abrasion and
breakage behavior of the agglomerate in the system. The DEM simulations gave support to
earlier investigations which concluded that definition of a Stoke abrasion number is a valid
approach to predict agglomerate abrasion in a powder blending system.
Highlights

Abrasion of dry agglomerates in dry powder blends were investigated using DEM
Size reduction mode varies with agglomerates mechanical properties, bond strengths
Size reduction rate varies with blend condition: filler size, mixer size, mixing rate
Stoke abrasion number gave good prediction of agglomerate abrasion behavior
Key words: Agglomerate; Powder mixing; Discrete Element Method; DEM; Bonded
Particle Model; Stokes abrasion number
Numerical study of agglomerate abrasion in a tumbling mixer

Thanh Nguyen1,2,*, Tofan Willemsz1,2, Henderik Frijlink1, Kees van der Voort Maarschalk1,3
University of Groningen, Groningen, The Netherlands.
MSD, Oss, The Netherlands.
3
Corbion, Gorinchem, The Netherlands.
1
2
* Corresponding author: Thanh Nguyen

thanh.nguyen@merck.com, Nguyen.t.thanh80@gmail.com
Published in:
Chemical Engineering Science (2014), http://dx.doi.org/10.1016/j.ces.2014.03.015
80
Graphical abstract
4,0E-04
6,0E-04
8,0E-04
Stokes abrasion number (-)
2,0E-04
R = 0,69
0,0
0,0E+00
0,2
0,4
0,6
0,8
1,0
SIMULATION OF AGGLOMERATE ABRASION
81
Abrasion rate (1/T)
CHAPTER 5
5.2 INTRODUCTION
Production of powder blends is an important operation in many industries. A common
operation in mixing is to make a blend consisting of a small amount of a cohesive powder
and a non-cohesive bulk material. A typical example is a cohesive micronized drug that
has to be mixed with a free-flowing filler. In such blending processes, it is essential that
the cohesive material becomes well-distributed in the powder blend. Because a cohesive
powder generally forms aggregates or lumps13, fracture of the lumps is needed. Previous
reports showed that the time to achieve a sufficiently uniform blend (the mixing time) is
dominated by the rate of abrasion of the lumps1,47. In fact, the blending process is basically
dominated by a rate of abrasion or rate of breakage issue.
Experimental work done earlier810 showed that it is possible to define a Stokes number
that relates the strength of agglomerates to the mixing intensity of the moving powder.
In these studies, lumps were designed and made as brittle calibrated test particles which
showed porosity dependent abrasion behavior1. The particle velocities on the surface of
powder beds were determined by high speed camera imaging and an in-house developed
image processing algorithm11. Results of these studies gave strong indications that the
impact intensity and frequency encountered by the aggregates is a determining factor in
this process.
Discrete Element Method (DEM) is a numerical method that is gaining increasing
interest in academics as well as in industry to study powder behavior in processes.
Introduced in 1979, DEM was first used to study rock mechanics12. Later on, the use of
DEM has been extended to different type of particulate systems which find applications
in different industry e.g. chemical, food and pharmaceutical industry. In DEM, lateral and
rotational motions of every particle are calculated by integrating the Newtons equation of
motion. For further details about the method, readers are referred to other reviews 13,14.
To obtain a better understanding of the processes occurring in the bulk during blending
of aggregates in a bed of inert fillers, it has been decided to perform a number of Discrete
Element Analyses. These give the possibility to obtain information of processes occurring in
the bulk of the mixture. The experimental tests were able to obtain information of particle
speed at the surface of the powder bed. Lump properties can only be obtained off-line. The
aim of this study was to obtain more background information concerning the mechanism
of aggregate attrition or breakage.
5.3 METHODS
DEM simulations were performed using a commercially available 3D DEM package,
EDEM15. EDEM treated particles as soft spheres. Particles deform elastically and do not
suffer from permanent deformation16. Two different types of particles were used in this
study: fine cohesive Active Pharmaceutical Ingredients (APIs) particles and coarse filler
particles. Fine particles (r = 30 m) were used to form an agglomerate using the Bonded
Particle Model (BPM)17,18. Coarse particles with rod like shape, more or less similar to many
82
fillers in pharmaceutical blends, were constructed of three overlapping spheres (r = 70 m)

as described earlier in literature16,19. The length / width ratio was 2.
The overall particle-particle interaction followed the Hertz-Mindlin contact model in
which the contact mechanics can be considered as spring-dashpot configuration 17. Only
in case that a bond exists between fine particles, the fine particle fine particle interaction
follows the Bonded Particle Model which over rule the Hertz-Mindlin contact model17.
The container mixer used in this simulation has the geometry of a tumbling mixer in
which the particles are mixed by tumbling over each other on the surface of the powder
bed20. A 3D mesh of the mixer was made using Gmsh, a general public license 3D CAD
engine21. Two mixer sizes were used in this study. The small mixer was 3 mm height x 3
mm large, the large mixer was 4.5 mm height x 4.5 mm large.
Due to the limitation of calculation capacity in using DEM, the mixer sizes in simulation
are miniature as compared to the real mixers that are generally used in industries e.g. food
or pharmaceuticals. To avoid confusion in direct interpretation of simulation values to real
large scale, we use L as a length unit, F as force unit and T as time unit. Therefore, the
volume unit and the pressure unit would be L3 and F/L2, respectively. The size of the fine and
coarse particle (r = 30 m and r = 70 m) would be 30 L and 70 L respectively.
A model agglomerate was made by randomly placing 500 mono-sized fine particles
(r = 30L) in a 500 x 500 x 500 L3 cube. These particles were generated and felt down from
the top of the cube. When all the spheres have settled down by gravity, a compression plate
was used to gently compress these particles. The plate was then slowly retracted to make a
densified powder. This process made that the porosity of the agglomerate reached a steady
packing, i.e. an agglomerate with fixed structure. This structure was used in all simulations.
Fig. 1 depicts the structure used.
Right after densification, bonds between spheres were created using the BPM. For
details about BPM, readers are referred to relevant publications18. Briefly, bonds with predefined spring constant and critical stress were created between contacting particles. The
values of these parameters are hypothetical and were set similar to a recent work done on
EDEM with BPM model22 (Table 1 gives values of these parameters). Stresses applied to the
bonds either during compression tests or during mixing were updated at every simulation
step. Bonds broke when stress applied exceeded the critical stress of the bond. In BPM, a
broken bond would not be formed again. All particle-particle interactions without bond
follow the Hertz-Mindlin (no slip) interaction rule23.
5.3.1 Agglomerate fracture strength determination

Four agglomerates of the same structure but with different mechanical properties
of bonds were created. The strengths of these agglomerates were determined by axial
compression tests. The test setup is depicted in Fig. 2. Based on the stress and strain
(agglomerate deformation) curve, the Youngs moduli and the fracture strengths of the
agglomerates were calculated. To facilitate further reading, the agglomerates were denoted
by their fracture strength as shown in Table 1 (see also Section 5.4.1).
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CHAPTER 5
Figure 1. Agglomerate creation.
Table 1. Hypothetical bond parameters and agglomerate properties.

Spring constant
of bond (F/L)
Critical stress
of bond (F/L2)
Modulus
of agglomerate (F/L2)
Fracture strength
of agglomerate (F/L2)
A514
7.1 x 10-1
1x10+4
108
514
A328
7.1 x 10
5x10
+3
95
328
A102
7.1 x 10-2
1x10+4
16
102
A95
7.1 x 10
5x10
15
95
Agglomerate
-1
-2
+3
5.3.2 Agglomerate size determination

The size and degree of size reduction of the agglomerate was calculated for each
simulation step using a so-called distance extension clusterization algorithm. An
agglomerate is defined as the largest cluster of particles in contact.
Similar to the density-reachable concept described in our previous papers24, the
distance extension algorithm starts with an arbitrary particle in a set of particles and takes
it as the core of a cluster. Next, the algorithm searches for other particles in contact with the
84
Figure 2. Compression test setup.
core and includes these particles in the cluster. It was arbitrarily decided that two particles
are in contact if the separation distance is less than 1 L (the Euclidean distance between the
cores of two particle is less than 2*r+1 L), irrespective of the bond status (broken or intact).
The algorithm repeats the search and include procedure with each of the newly added
particles until no further particle is found to be in contact with any particle of a cluster.
The cluster is then defined to be an agglomerate. The process of taking a core, searching
and including contact particles repeats until all particles in consideration are assigned to
clusters. Agglomerate size is defined as the number of particles in an agglomerate.
The clusterization code was developed in-house and was executed in Matlab version
R2012b (The MathWorksInc., Natick, The USA) using the particle positions (x, y, z)
exported from EDEM.
5.3.3 Blending test condition

Blending tests were performed with variation in mechanical properties of agglomerate (bond
property, see Table 1) and variations in process conditions (rotation rate, container size, filler
particle size). These parameters variations were hypothetical and were summarized in Table 2.
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CHAPTER 5
Table 2. Hypothetical blending parameters variation.

Parameter
Values
Spring constant (F/L)
7.1x10-1, 7.1x10-2
Bonds critical stress (F/L2)
1x10-4, 5x10-3
Filler particle length (L)
140, 200
Container mixer size (L3)
1.63x1010, 5.5x1010
Rotation rate (Rev/T)
40, 120
5.4 RESULTS AND DISCUSSION

5.4.1 Mechanical properties of agglomerates
Compression test simulations have been performed to identify the mechanical properties
of the agglomerates. Fig. 3 shows the stress-strain relationships from which the moduli and
fracture strengths have been calculated, which are shown in Table 1.
Figure 3. Stress-strain relationship of agglomerates.

Agglomerates are sorted as A514, A328, A102 and
A95 according to the corresponding fracture strengths.
5.4.2 Abrasion of agglomerates

Blending test simulations using the same process settings were performed using
agglomerates of different hypothetical mechanical properties (see Table 3).
When blending simulations were finished, agglomerate size was determined at each time
point using the methodology described in Section 5.3.2. The agglomerate size reduction in
time was calculated as the ratio of the number of particles in the agglomerate at a time point
Np(t) and the number of initial particles in the agglomerate Np(t0), being 500. The abrasion
behaviors of different agglomerates are shown in Fig. 4.
86
Table 3. Blending test conditions.

Parameter
Values
A514, A328, A102, A95
Agglomerate
Filler particle size (L)
140
Container mixer size (L )
1.63x1010
Rotation rate (rev/time)
120
Figure 4. Abrasion of agglomerates during blending calculated using the distance extension clusterization algorithm.
Fig. 4 shows that agglomerates with high fracture strength have lower size reduction rates
as compared to agglomerates of low fracture strength, which is according to expectations.
Furthermore, the figure shows that agglomerate size sometimes seems to increase during
mixing. This is the typical result of the distance extension clustering algorithm. One characteristic
of the algorithm is that it cannot recognize if there is a bond or there is no bond between two
contacting particles. In situations where two separate API particles come into contact as a matter
of mixing probability, no bond will be formed. For the clustering algorithm, these particles formed
a common cluster. This may explain why the agglomerate size increased at certain time points.
The algorithm is of relevance when the cohesive interaction is taken into account and the bonds
can be formed during mixing. In case of the Bonded Particle Model, results of the algorithm need
to be considered together with other information e.g. number of intact bond.
An alternative method to characterize the abrasion is to use the total number of intact
bonds between API particles. This number decreases as a result of breakage of bonds between
87
CHAPTER 5
particles. Fig. 5 shows the numbers of intact bonds in the agglomerates. The number of intact
bonds decreases in time which reflects the agglomerate degradation process during mixing.
As the bonds between particles cannot be restored again after breakage, the agglomerate
size determined this way monotonously decreases during mixing, which is in accordance
with experimental observations1.
In previous work1 using a similar approach, it was demonstrated that, it is possible to fit
the number of intact bonds using a simple first order size reduction rate:
(1)
In which Nb(t) is the number of intact bonds at time t, Nb(t0) is the initial number of
intact bonds and Xi () is a constant, which has previously been referred to as the abrasion
rate constant or abrasion coefficient1. It is also possible to perform a similar exercise on
the agglomerate size calculated by methodology in Section 5.3.2. The abrasion coefficient of
different agglomerates is shown as in Fig. 5. Clearly, weaker agglomerates reduce faster in
size under the same blending conditions.
Figure 5. Abrasion characterization by the number of intact bonds.
A comparison between the agglomerate size reduction and the number of intact bonds
gives an indication of the agglomerate fracture mechanism. When the agglomerates reduce
in size purely via abrasion, only particles disappear from the surface. So, it is easy to
distinguish the mother particle from debris because the mother particle is large, certainly at
88
the early stages of abrasion. In that case, the curves shown in Fig. 4 would be monotonously
decreasing, and the curves in Figs. 4 and 5 would be very similar. Hence a comparison of
the curves for agglomerate size reduction and that of reduction of number of intact bond
gives an indication of the agglomerate fracture mechanism.
Fig. 6 compares the size reductions calculated by bond numbers and by particle numbers
for the agglomerates A328 (strong agglomerate) and A102 (weak agglomerate). With
agglomerate A102, the bond number reduction happens in an earlier stage when compared
to the particle size reduction. Apparently, internal bonds break before a particle breaks. At
a certain moment, very rapid reduction of particle size occurs: the agglomerate breaks. This
is visualized in Fig. 7a where a lot of small, loose particles are visible.
Figure 6. Agglomerate size reduction based on particle number and bond number.
In contrast with the behavior of a weak agglomerate, the curves of intact bonds
and particle sizes of A328 (Fig. 6, A328) precisely follow each other. This is a clear sign
that abrasion is the mechanism of size reduction. The snapshot in Fig. 7b confirms this
conclusion. Interestingly, there is a small gap between the bond numbers reduction and the
size reduction for the strong agglomerates (Fig. 6, A328). The reason for this gap is that a
particle adheres to the agglomerate via more than one bond. All bonds have to break before
a particle is able to separate. In the remainder of the text we will focus on the reduction of
the number of bonds.
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CHAPTER 5
Figure 7a. Snapshot of the size reduction of A102.
Figure 7b. Snapshot of the size reduction of A328.
90
In order to be able to discuss the effects of process conditions on the rates of abrasion
of the agglomerates, the next section will start with a discussion on the particle velocity
profiles in the blender.
5.4.3 Effect of process conditions

DEM simulations have been performed assuming different blending conditions.
Specifically, mixer size, mixer rotational rate and particle size of the filler have been varied.
Fig. 8 shows an example of the velocity profile in the blender.
It can be seen from Fig. 8 that particles are likely to have high velocities on the surface
of the moving powder bed. In contrast, particles in the center of the moving powder bed
hardly move at all. In order to have an overview of the particle velocity distribution in the
powder bed, a combination plot of cumulative velocity distributions in a certain time frame
(1T) was made (see Fig. 9). Each cumulative distribution curve shows the distribution in a
time step of 5 milliT, therefore Fig. 8 was the combination of 200 curves at 200 time points.
Figure 8. Particle velocity profile in the blender.
From Fig. 9, it can be seen that there is variation in velocity distribution between time
points. However, a common picture of a distinct region of high velocities is consistently
present. This is visible from the fact that only 5% of the particles have high speed (95%
of the particles have a speed lower than 0.04 L/T while 5% of the particles have speeds
91
CHAPTER 5
Figure 9. Cumulative distribution of particle velocity in 1000 time points of 1 milliT.
between 0.04 and 0.1 L/T). A comparison with Fig. 8 makes clear that the particles with
high speeds are present on the surface of the powder bed. Hence, the velocity at 95% of
the distribution curve (v95) is a good representation of the velocity of particles on the
surface of the powder bed.
A number of simulations with agglomerate A102 have been performed to evaluate the
effects of process conditions on the abrasion rate of agglomerates. The process settings
and resulting abrasion rates are summarized in Table 4. The distributions of filler particle
velocities during different tests are summarized in Fig. 10.
By comparing process number 1 and process number 2 (Table 4, Fig. 10), it can be seen
that an increase in the mixing rate would lead to an increase in the filler particle surface
velocity and an increase in the abrasion rate. The effect of mixer size can be seen by comparing
Table 4. Process settings and abrasion rates.
Granule strength
(F/L^2)
Filler particle
size (L)
Rotational rate
(Rotation/T)
102
140
102
140
102
102
Process No
92
Mixer size
L^3
Abrasion rate
constant (1/T)
120
1.63e+10
0.869
40
1.63e+10
0.163
200
40
5.50e+10
0.480
140
40
5.50e+10
0.300
Figure 10. Cumulative distributions of filler particle velocity in different process settings.
process number 2 and process number 4. A larger mixer would lead to higher filler particle
velocity and higher abrasion rate. Process number 3 and 4 showed that the filler particle size
does not have influence on the filler surface velocity but does influence the abrasion rate.
Larger filler particle size lead to higher abrasion rate. The effects of mixer size and mixing
rate on abrasion were found in agreement with experimental work done on agglomerate
of fine particle of Acetaminophen6,7. With different process settings, we observed different
effects (filler particle size, mixing rate and mixer size) on filler particle velocity and abrasion
rate. These effects may have interactions on the abrasion of agglomerate in the blending
process. Table 5 summarizes the observations on the effect of process settings. Experimental
works that have been performed also evaluated similar variations6,8.
Table 5. Effects of process setting on abrasion rate.
Factors
Process number comparison
Results
Filler particle size
3 vs. 4
Similar filler particle velocity.

Higher abrasion rate with larger filler particle.
Mixing rate
1 vs. 2
Higher mixing rate results in higher filler

particle velocity and higher abrasion rate.
Mixer size
2 vs. 4
Larger mixer size results in higher filler

particle velocity and higher abrasion rate.
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CHAPTER 5
5.4.4 Simulation vs experiment

The data presented in the previous section were used to compare with experimental
work of Willemsz et al9 discussing the Stokes abrasion number concept. The dimensionless
Stokes abrasion number has been used to predict the abrasion behavior of agglomerates
in a powder blending system. In this work, we want to compare that approach with results
from simulations.
In short, the Stokes abrasion number is the ratio of the kinetic energy density of a powder
bed over the work of fracture of an agglomerate. The calculation can be summarized in
equation 2. For further details, readers are referred to9.
(2)
95 : Powder surface velocity at the surface of the powder bed. The value at 95% of the
cumulative particle velocity distribution was taken as the powder surface velocity.
c : fracture stress of agglomerate
Y : Young modulus of agglomerate
b: bulk density of the powder
From Fig. 11, it becomes apparent that neither the particle velocity nor the granule
strength alone lead to meaningful relationships with abrasion rate.
Fig. 12 plots the Stokes abrasion number vs. the abrasion rate. In general a higher
Stokes abrasion number corresponds to a high abrasion rate, which is in line with previous
experimental data810. Although the model for this simulation data can only explain for 69%
of the variation, the similar trend observed in this study does strengthen the rationale in
using the combination of work of fracture and kinetic energy density to predict the abrasion
of agglomerate in a powder bed.
A similar calculation has been made assuming that the median value, v50, of the
particle velocity distribution is the abrasion rate determining particle velocity. These results
(Fig. 13) show that the model can explain 51% of the variation observed in simulation. This
Abrasion rate (1/T)
1,0
0,8
R = 0,03
0,6
0,4
0,2
0,0
0,0E+00
1,0E-02
2,0E-02
Particle velocity (L/T)
Figure 11a. Particle velocity vs. abrasion number (current simulation data).
94
sion rate (1/T)
1,0
R = 0,41
0,8
0,6
3,0E-02
0,0
0,0E+00
1,0E-02
2,0E-02
3,0E-02
Particle velocity (L/T)

Abrasion rate (1/T)
1,0
R = 0,41
0,8
0,6
0,4
0,2
0,0
0,0E+00 2,0E+02 4,0E+02 6,0E+02 8,0E+02 1,0E+03 1,2E+03 1,4E+03
Work of fracture (F/L2)
Figure 11b. Work of fracture of agglomerate vs. abrasion rate (current simulation data).
Abrasion rate (1/T)
1,0
0,8
R = 0,69
0,6
0,4
0,2
0,0
0,0E+00
2,0E-04
4,0E-04
6,0E-04
8,0E-04
Figure 12. Stokes abrasion number as calculated by the v95 v.s abrasion rate (current simulation data).
Abrasion rate (1/T)
1,0
0,8
R = 0,51
0,6
0,4
0,2
0,0
0,0E+00
2,0E-05
4,0E-05
6,0E-05
8,0E-05
1,0E-04
Figure 13. Stokes abrasion number as calculated by the median particle velocity (v50) vs abrasion rate (current
simulation data).
means that v95 which is the velocity of the particle on the surface of the powder bed gives
a better prediction than v50.
The fixed structure of the agglomerate made it possible to compare the influence of
different process conditions on agglomerate abrasion. However, the strength of agglomerates
95
CHAPTER 5
was governed solely by bonds properties. The influence of agglomerate structure is not
addressed in this study and could be an interesting topic for further investigation.
There is a gap between simulation data and experimental data in predicting the abrasion
of agglomerates in a dry blending system. This is probably due to the current limitation
of the simulation model to mimic different variations in real particulate systems. More
specifically, systems of real particles possess distributions of properties, such as particle
size and particle shape distributions as well as distributions in the magnitude of particleparticle interactions. The extremes in the distributions may affect the mixing behavior
more than the average values. Currently it is not (yet) possible, for EDEM and other
softwares, to include these distribution extremes in the models, especially the variation in
particle-particle interaction. Therefore the relationships are to be considered as qualitative
descriptions of the effects that variation in conditions and parameters may have, rather than
precise quantitative relationships.
5.5 CONCLUSION
The mechanical properties and abrasion behavior of agglomerates in dry powder
blending system were studied by DEM simulation. It was found that weak granules tend to
break into large pieces, while stronger agglomerates gradually abrade and reduce in size. The
particle velocity at the powder surface was shown to be a good indicator of abrasion rate.
This is because the abrasion rates are highest at the highest velocities. Moreover, aggregates
tend to have a low density and therefore have a tendency to float on the powder bed. Other
parameters affecting the abrasion of agglomerates include filler particle size, container mixer
size, mixer rotation rate and the mechanical property of agglomerates, these parameters are
summarized in the work of fracture. The DEM simulation performed in this study supports
the idea that the Stokes number approach leads to a valid prediction of the abrasion behavior
of agglomerates during mixing of powders. The Stoke number abrasion relationship in this
study is to be considered as qualitative descriptions of the effects that variation in conditions
and parameters may have, rather than precise quantitative relationships.
ACKNOWLEDGEMENT
The authors would like to thank TI Pharma for financial support for this research as part
of D6-203-1: DeQuaPro project.
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96
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19 Hare, C. & Ghadiri, M. The influence of aspect ratio

and roughness on flowability. 887, 887890 (2013).
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97
Chapter 6
Summary and perspectives
SUMMARY AND PERSPECTIVES
6.1 SUMMARY
Many powders are cohesive: which means that the powder particles attract each other.
Such powders possess the ability to spontaneously form lumps or agglomerates. In many
applications presence of such lumps is undesired or even leads to safety concerns. For example,
many active pharmaceutical ingredients have the tendency to form lumps and presence of
such lumps in the pharmaceutical end product should not be tolerated. Understanding
the mechanisms of formation and rupture of such lumps is the key to identification of the
technical solutions that solve this issue in a reliable fashion. This thesis looks at the formation
and deformation of the dry powder agglomerate from the particle interaction point of view.
The scientific challenge of lump formation and rupture is that the understanding of model
systems is well developed. Unfortunately, the assumptions and simplifications that have to be
made imply that the predictive power of the model systems is very limited when considering
a more realistic system. This is for reason that even small deviations from the assumptions,
such as presence of small surface asperities or some distribution on particle size, leads to
drastically different particle interactions. For this reason there is a need of more (analytical)
tools that detect basic properties of particles and lumps. These tools should lead to more
understanding of the mechanism of formation and rupture of agglomerate of cohesive
powders. This thesis focuses on lumps formation and rupture from the particle interaction
perspective. The thesis of TA Willemsz [Willemsz, T. (2013). Blending of Agglomerates into
Powders. University of Groningen] discusses the same topic from a technology perspective.
Chapter 2 discusses particle interactions. It describes a method to characterize the
adhesion of a real powder to a substrate, i.e. a powder with a particle size distribution and
complex particle shape.
Although a number of theories have been developed to predict the adhesion and cohesion
forces between particles, these have not been successfully applied to real powders. The critical
point lies in the theoretical calculation of contact surface area of interacting bodies. Variation or
polydispersity in particle shape, particle size and particle surface is the nature of real powders.
An inappropriate assumption in one of these parameters leads to an error in estimation of
contact surface area, which in turn, leads to significant errors in adhesion force calculation.
Atomic Force Microscopy (AFM) is a sensitive method which can be used to precisely
measure the adhesion forces between two bodies. Using this method for a powder sample,
a particle is normally glued to a cantilever. The cantilever brings the particle to a surface
until the two bodies are pulled together by the attractive forces. The pull-off force which
is necessary to separate the two bodies is measured by the deflection of the cantilever. The
challenge in using AFM to characterize adhesion of a real-life powder is that many tests
need to be performed to obtain the statistically representative indication of a sample. This
fact makes it nearly impossible to use the method for real powders.
In order to have a method which overcomes the issues related to poly-disperse powders,
a centrifuge-based method was developed. This method uses centrifugal forces to detach
particles which were previously adhered to a surface. The particles are only removed from
the surface when the centrifugal force exceeds the magnitude of the adhesion force. The
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CHAPTER 6
centrifugal forces are calculated based on the rotation rate of the centrifuge and the size
which is connected to the weight of particles. Because particle size varies in a powder sample,
the centrifugal force distribution was calculated based on the particle size distribution and
rotation speed. The force distribution curves give results for the adhesion force distributions.
The adhesions of microcrystalline cellulose (MCC) on MCC surfaces were measured
both by the centrifuge method and by the AFM, the results are in agreement. The centrifuge
method makes it practically possible to characterize the adhesion of a powder sample that has
variation in particle properties, e.g. particle size, particle shape and particle surface properties.
Chapter 3 discusses the structure of agglomerates. Key aspect is to identify the locations
of individual particles that form the building blocks of an agglomerate. This chapter
describes an algorithm for clustering of 3D images with an application to 3D X-ray microtomography. The algorithm is a revised form of the density based spatial clustering of
application with noises (DBSCAN) with a special focus on 3D images.
In the DBSCAN algorithm, the calculation of the distance table is computationally
challenging when a large 3D dataset needs to be analyzed. However, with the 3D image
dataset, by using the coordinate system of a 3D image, a kernel (volume of interest) can be
constructed around the pixel of interest to evaluate the local density.
Additionally, the border detection in using the DBSCAN for dense structure of which
many clusters are in contact is a challenge. The original work documents that in case there
is a large number of contact points between clusters, the results of DBSCAN depend on
the visiting order. This leads to instability in the border detection (i.e. separation between
particles). The situation of high density was considered rare, so the problem has hardly been
discussed. Unfortunately, this issue is very common when studying agglomerates or lumps.
In the revised algorithm, during the expansion step, the density reachable chain is redefined to contain only the core pixels (core points). The border points are detected but are
not yet labeled to any cluster. The labeling of the border points is done in a post-processing
step, when all the core points are detected. The post-processing is done by assigning the
border points to the closest core pixels.
The revised algorithm was applied for clustering a simulated 3D image dataset which was
generated by Discrete Element Method (DEM). The clustering result was directly validated
by comparing with the generated data of which information about clusters were known
beforehand. This comparison showed that the clustered results had the same number of
particles and the same particle size as the generated data. This means that neither undersegmentation nor over-segmentation happened.
After this proof of validity, datasets obtained from real life pellets with different sizes
were analyzed by DBSCAN. The results of the segmentations were used to calculate the
particle size distribution (PSD). The PSD results as obtained by XMTDBSCAN were
compared with the PSD results analyzed by optical microscopy. The distribution curves
were in good agreement. Small gaps between the distribution curves were observed. These
were probably the results of small number of particles analyzed by XMT-DBSCAN. Neither
under-segmentation nor over-segmentation was observed.
102
SUMMARY AND PERSPECTIVES
Coordination number is the number of contacting neighbors. It is an important

parameter to characterize a powder system. In literature, the coordination system can be
investigated by using the capillary retention of liquid in the contact area between particles.
However, this method can only be applied to systems of relatively large particle sizes,
typically in millimeter scale. Another method to investigate the coordination number was
also described, but it is only applicable to the other extreme e.g. from 10 nm to 1 m.
With powders that are generally used in pharmaceutical industry, these two methods are
not applicable. In chapter 4, the coordination number distributions of powder systems
containing MCC pellets of different size were investigated. The identification method
described in chapter 3 was used to detect the coordination number distribution. Chapter
4 shows that the coordination numbers are not uniformly distributed in a powder sample.
The average coordination numbers of agglomerates constructed from small building blocks
are higher than of samples made of large building blocks. However, when porosity was
plotted against the coordination number, a clear trend was observed. Particles in a dense
powder with low porosity tend to have higher coordination number. This is in line with
previous research carried out on larger spherical particles.
The study so far aimed at obtaining information about the strength of agglomerates via
understanding of the interaction forces and contact numbers. In production processes these
agglomerates are exposed to a stress field that aims at reducing the size of the agglomerates.
This was the next step in this research. In chapter 5, a numerical simulation study using
DEM was performed to gain insights in the size reduction mechanism of agglomerates in a
dry blending system. A commercially available DEM code, EDEM (DEM Solution, UK), was
used. Agglomerates of different strengths with one fixed structure were generated using the
Bonded Particle Model (BPM) with different bond properties. The dry blending in a diffusion
mixer was simulated with powder systems that contain filler particles and an agglomerate.
The blending tests were performed with variation in mechanical properties of agglomerate,
powder system (filler particle size), and in process settings (mixer size and mixing speed).
The simulation results showed that agglomerates reduced in size during blending. The
size reduction rate can be determined by using a first order fitting to the agglomerate size
versus blending time. It was shown that weak agglomerates reduce in size faster than the
strong ones in the same mixing conditions. A comparison between the agglomerate size
reduction rate and the number of intact bond reduction rate gives an indication of the
agglomerate fracture mechanism. In case of pure abrasion, the agglomerate size decreases
monotonously and similarly to the reduction of the number of intact bonds. In case of
breakage, the intact bond number decreases in an earlier stage than the agglomerate
size reduction which gives sign to internal bond breakage. At some certain moment, the
agglomerate size reduces rapidly: overall structure breakage occurs.
It was also observed that there was a spatial distribution of the particle velocities in the
moving powder bed. Particles are likely to have high velocity on the surface of a moving
powder bed. This is line with earlier observations. In contrast, particles in the center of a
moving powder bed hardly move. The particle velocity distributions in different blending
103
CHAPTER 6
systems were compared. In all situations, a common picture can be seen: a distinct region of
about 5% of particles move with high velocity, the rest move with lower velocity. Therefore,
the powder surface velocity would be the focus of interest regarding the size reduction of
agglomerates in a powder bed.
Different mixing conditions have different effect on both powder surface velocity and
abrasion rate. These conditions may have interaction on the size reduction of agglomerate.
The variation was also observed in experimental tests.
The concept of a dimensionless Stokes abrasion number was used to analyze the
simulation data with the experimental data which was published earlier. In short, the Stokes
abrasion number is the ratio of the kinetic energy density of a powder bed over the work of
fracture of an agglomerate. In general, we observed a high abrasion rate corresponds to a
high Stokes abrasion number. In simulation data, the correlation between Stokes abrasion
number and the abrasion rate explains 69% of all variations vs. 80% in experimental data.
Despite the gap between simulation data and experimental data, which is probably due to
the limitation of the current simulation model to mimic real particulate systems, the DEM
simulation performed in this study supports the idea that Stokes number approach lead to a
valid prediction of the abrasion behavior of agglomerates during mixing of powder.
6.2 CONCLUDING REMARKS AND PERSPECTIVES

Fine powder particles are normally cohesive and have the tendency to form dry powder
agglomerates. In the pharmaceutical industry, the presence of such agglomerates is usually
intolerable with regard to product quality and safety. The agglomerates need to be broken and
uniformly dispersed in a powder blend. This can be done by understanding the agglomerate
properties, by properly choosing the other components of the powder blend (excipients) and
by choosing the suitable process-settings (mixer, mixing speed, mixing time).
Models with (sufficient) quantitative predictive power are needed to understand the
practical impact of observations obtained during laboratory or pilot-scale studies. It is
the only way to step out of the step-wise, cost-intensive, scale-up of production processes.
Real-life powders obviously possess distributions in properties, e.g. size, but also shape
and mechanical properties. One of the observations from this research is that selection
of appropriate assumptions concerning the distributions of properties is crucial to make
models with some predictive power. Creation of models that are fully based on distributions
poses enormous challenges related to computational time of the model and the analytics
to generate the data on sufficient scale of scrutiny. Selections have to be made and research
questions around these topics are scientifically challenging and practically relevant. This
observation is in line with discussions within (industrial) consortia focusing on particle
technology, such as the International Fine Particle Research Institute.
This thesis has touched on the basic measurements of adhesion, agglomerate property
and a related blending process in a tumbling mixer. There are further works to be done in
integrating material and process properties into a guidance to obtain desired product qualities.
104
Chapter 7
Samenvatting en perspectieven
SAMENVATTING EN PERSPECTIEVEN
7.1 SAMENVATTING
Geneesmiddelen zijn bijna altijd mengsels van een of meer actieve stoffen en een aantal
hulpstoffen. Heel vaak zijn deze grondstoffen poedervormig. Omdat patinten zeker moeten
zijn van juiste dosering van het geneesmiddel en juiste werking van het product, zoals een
tablet of capsule, moeten zeer hoge eisen worden gesteld aan de verdeling van de componenten
in het mengsel. Het (droog) mengen van poeders is daarom een kritische processtap. Veel
grondstoffen bestaan uit cohesieve deeltjes. Dergelijke deeltjes hebben de neiging om
aan elkaar te plakken, te agglomereren. Hierdoor ontstaan grote, vaak sterkte, klonten.
Aanwezigheid van deze klonten in het eindproduct leidt tot verschillende gezondheidsrisicos
als gevolg van overdosering van het geneesmiddel. Begrip hoe klonten ontstaan en breken is
daarom essentieel om garanties ten aanzien van productkwaliteit te kunnen geven.
Een agglomeraat bestaat uit een aantal deeltjes die elkaar aantrekken. De grootte van
de aantrekkende kracht tussen een deeltje tezamen met het aantal naaste buren bepaalt de
uiteindelijke sterkte van een agglomeraat. Voor modelsystemen die bijvoorbeeld uit even
grote bolletjes bestaan is het opstellen van de relaties die agglomeraatsterkte voorspellen
betrekkelijk eenvoudig. Op het moment dat deeltjesvorm of deeltjesgrootte geen vaste
waarde hebben maar een verdeling, blijken de eenvoudige relaties niet meer te werken.
Eenvoudige relaties die uitgaan van bijvoorbeeld een vaste deeltjesgrootte of deeltjesvorm
zijn niet in staat relevante voorspellingen te geven en modellen welke rekening houden
met verdelingen zijn uiterst complex. Bovendien zijn de analytische middelen om relevante
verdelingen te meten niet of maar beperkt voorhanden.
Dit proefschrift gaat in op deeltjesinteracties tussen deeltjes die een complexe vorm hebben
en poogt relaties te leggen met de sterkte van agglomeraten. Het proefschrift sluit aan bij dat van
TA Willemsz [Willemsz, T. (2013). Blending of agglomerates into powders. Rijksuniversiteit
Groningen] welke hetzelfde onderwerp bespreekt vanuit een technologisch perspectief.
In hoofdstuk 2 wordt de verdeling van de interactiekracht, de adhesiekracht,
tussen poederdeeltjes behandeld. We beschrijven een methode om de verdeling van de
adhesiekracht tussen veel deeltjes te karakteriseren. Hier is gekozen voor een veelgebruikte
hulpstof, microkristallijne cellulose (MCC). MCC deeltjes variren erg in grootte en vorm.
Adhesiekrachten kunnen nauwkeurig met atomic force microscopy (AFM) worden gemeten.
Voor een meting wordt n deeltje op een bladveer (cantilever) geplakt. Het deeltje wordt
voorzichtig tegen een oppervlak gezet en vervolgens van het oppervlak getrokken. De kracht
die hiervoor nodig is, is de adhesie en is te meten. Omdat deeltjesvorm en deeltjesgrootte
van poederdeeltjes zo varieert, moeten voor een representatieve analyse vele honderden tot
een aantal duizenden deeltjes worden gevalueerd. Dit maakt het bijna onmogelijk om de
methode toe te passen voor echte poeders.
In dit hoofdstuk beschrijven we de ontwikkeling van een methode die gebruik maakt
van centrifugale krachten. Deze methode is in staat om veel meer deeltjes tegelijk in
behandeling te nemen. De methode maakt gebruik van centrifugale krachten om deeltjes
eerst op een oppervlak te plakken en deze vervolgens los te slingeren. De deeltjes komen
alleen van het oppervlak los wanneer de centrifugale kracht groter is dan de adhesiekracht.
109
CHAPTER 7
De adhesiekrachten worden gemeten en gecorreleerd aan de deeltjesgrootteverdeling. Het

is dan mogelijk de verdeling van adhesiekracht als functie van deeltjesgrootte te berekenen.
De adhesie van MCC deeltjes op MCC oppervlakken werd gemeten met zowel de
centrifuge-methode als de AFM. De resultaten van beide methodes zijn vergelijkbaar.
De centrifuge methode maakt het echter praktisch mogelijk om de adhesie van een
poedermonster met een verdelingen van eigenschappen (zoals deeltjesgrootte, deeltjesvorm
en deeltjesoppervlakte) te bepalen.
De sterkte van een agglomeraat is het resultaat van de grootte van interacties zoals in
hoofdstuk 2 beschreven en het aantal naaste buren van het deeltje. Daarom gaat hoofdstuk
3 in op de kwantitatieve beschrijving van de structuur van agglomeraten. Dit hoofdstuk
beschrijft een methode om individuele deeltjes in een agglomeraat te identificeren. Met
een techniek welke 3D Rntgen microtomografie (XMT) heet, zijn 3-dimensionale beelden
gemaakt van de interne structuur van het agglomeraat. Voor de bewerking van de beelden is
een algoritme toegepast dat is gebaseerd op de density based spatial clustering of application
with noises (DBSCAN) techniek. De toepassing van DBSCAN voor het analyseren van
grote hoeveelheden 3D data vergt veel computer analyse tijd. Door aanpassing van de
techniek was het mogelijk de analysetijd te verlagen, waardoor het vervolgens mogelijk was
voldoende grote structuren te analyseren.
Verder is ook de detectie van pixels op de grens van objecten (clusters) met een hoge
dichtheid een uitdaging. In dit geval bleken de resultaten afhankelijk te zijn van de start van
het analyseproces.
In het gewijzigde algoritme worden eerst alleen de kernpunten (ongeveer het midden
van het deeltje) gedefinieerd. De randen (grenspixels) worden wel gedetecteerd, maar
worden nog niet aan een specifiek deeltje toegewezen. Het toewijzen van de grenspunten
wordt gedaan nadat alle kernpunten zijn gedetecteerd. De post-processing wordt gedaan
door de grenspunten toe te kennen aan de dichtstbijzijnde kernpunten.
Het herziende algoritme werd getest met een gesimuleerde 3D-beeld dataset welke
werd gegenereerd met eindige elementen analyse (Discrete Element Method, DEM). Het
resultaat werd direct gevalideerd door het te vergelijken met de gesimuleerde gegevens
van clusters waarvan de informatie al bekend was. Het bleek dat de clustering resultaten
een vergelijkbaar aantal deeltjes en dezelfde deeltjesgrootte hadden ten opzichte van de
gesimuleerde gegevens. Dit betekent dat noch onder-segmentatie, noch over-segmentatie
plaats heeft gevonden.
Vervolgens is de aangepaste DBSCAN methode gebruikt voor het analyseren van 3D
fotos van agglomeraten van pellets van verschillende deeltjesgrootte. De resultaten werden
gebruikt om de deeltjesgrootteverdeling (PSD) van de pellets te berekenen. Deze resultaten
zijn vervolgens vergeleken met de PSD resultaten verkregen via optische microscopie. De
resultaten toonden aan dat de deeltjesgrootteverdelingen goed vergelijkbaar waren. Er was
geen onder- of over-segmentatie waargenomen.
Het uiteindelijk doel van de structuuranalyse met de aangepaste DBSCAN methode is
bepaling van het aantal naaste buren van een deeltje, het cordinatiegetal.
110
SAMENVATTING EN PERSPECTIEVEN
Dit is het thema van hoofdstuk 4, waar de verdeling van het cordinatiegetal van
pellets met verschillende deeltjesgrootte in een agglomeraat is onderzocht. De methode uit
hoofdstuk 3 is gebruikt om de verdeling van het cordinatiegetal te berekenen. Het blijkt dat
de cordinatiegetallen niet gelijkmatig zijn verdeeld in het poedermonster. Het gemiddelde
cordinatiegetal van agglomeraten opgebouwd uit kleine deeltjes is hoger dan dat van
agglomeraten opgebouwd uit grotere deeltjes. Er werd tevens een duidelijke trend waargenomen
wanneer de porositeit werd uitgezet tegen het cordinatiegetal. Het cordinatiegetal van
systemen met lage porositeit is meestal hoger dan die van systemen met een minder hoge
dichtheid. Dit is in lijn met eerder onderzoek wat is uitgevoerd met grotere deeltjes.
Het onderzoek tot zo ver richtte zich op het verkrijgen van informatie over de sterkte
van agglomeraten, het meten van verdelingen van adhesiekrachten en cordinatiegetallen.
In productieprocessen worden deze agglomeraten blootgesteld aan bepaalde
procesomstandigheden welke kunnen leiden tot slijtage of breuk van de agglomeraten.
Het doel van hoofdstuk 5 is om meer inzicht te krijgen in de mechanismen die
verantwoordelijk zijn voor deeltjesgrootteverkleining en uiteenvallen van agglomeraten
in een mengproces. Hiervoor is een numerieke simulatie studie uitgevoerd met eindige
elementen analyse. Agglomeraten van een vaste structuur werden gegenereerd met behulp
van het Bonded Particle Model (BPM). Agglomeraten met verschillende sterktes werden
verkregen door de adhesiekrachten tussen deeltjes te variren. Het droog mengen in een
tuimelmenger werd gesimuleerd met poedersystemen die vulstoffen en een agglomeraat
bevatten. Het mengen werd uitgevoerd met variatie in mechanische eigenschappen van
agglomeraat, poedersysteem (deeltjesgrootte van vulstof) en procesomstandigheden
(mixergrootte en mengsnelheid).
Uit de simulatieresultaten blijkt dat agglomeraten meestal geleidelijk in grootte afnemen
en dus afslijten. Uiteraard slijten zwakke agglomeraten sneller dan sterke. Hele zwakke
agglomeraten breken, deze slijten niet. De berekeningen tonen aan dat in een zeer zwak
agglomeraat een groot aantal binden breekt voordat het deeltje uiteenvalt. Bij slijtende
agglomeraten verloopt breuk van bindingen en verkleining van de deeltjes veel meer parallel.
Naast de afname in deeltjesgrootte lieten de resultaten ook een ruimtelijke verdeling
van de deeltjessnelheden in het bewegende poeder zien. Vooral aan het oppervlak van
het poedermengsel werden een hoge snelheden waargenomen. Dit is in lijn met eerdere
waarnemingen. De deeltjes in het midden van het bewegend poedermengsel bewegen
daarentegen nauwelijks. De verdelingen in deeltjessnelheid zijn vergeleken in verschillende
mengsystemen. In alle gevallen is een gemeenschappelijk beeld waargenomen: ongeveer
5% van de deeltjes beweegt met een hoge snelheid aan het oppervlak, terwijl de rest van
de deeltjes zich met veel lagere snelheid verplaatst. Omdat agglomeraten vooral slijten of
breken door contact met de vulstof is het snel bewegende poeder aan het oppervlak van het
bed de dominante factor bij het verkleinen van agglomeraten.
De opzet van de simulaties was zodanig dat een vergelijk met eerder gepubliceerde
resultaten mogelijk was. In deze publicaties is een dimensieloos getal, een Stokes-slijtage
getal, voorgesteld om oorzaak-gevolg relaties te kunnen beschrijven en voorspellen.
111
CHAPTER 7
Het Stokes slijtage getal is de verhouding tussen de energiedichtheid van een bewegend
poederbed en de breukenergie van een agglomeraat. Een hoge slijtagesnelheid komt voor
wanneer het Stokes slijtage getal groot is. Net als bij de experimentele resultaten was het
Stokes getal behoorlijk in staat de simulaties te beschrijven, hoewel minder goed. Hiervoor
is een aantal redenen aan te wijzen, waaronder omvang van het systeem (de simulaties
veronderstellen een extreem kleine menger) en het feit dat het niet mogelijk is om rekening
te houden met verdelingen van eigenschappen in simulaties.
7.2 CONCLUSIES EN PERSPECTIEVEN

Fijne poederdeeltjes zijn over het algemeen cohesief en hebben daarom de neiging om
agglomeraten te vormen. De aanwezigheid van dergelijke agglomeraten in het eindproduct is
in de meeste gevallen onacceptabel. De agglomeraten moeten daarom gebroken en vervolgens
uniform verdeeld worden in het poedermengsel. Kennis van de belangrijkste eigenschappen
van agglomeraten, in combinatie met kennis van eigenschappen van de bewegende vulstoffen,
zorgen voor voldoende garantie op afwezigheid van klonten in het eindproduct.
Het is noodzakelijk om modellen met (voldoende) kwantitatieve voorspellende
kracht te hebben om zowel de opzet van experimenten, als de interpretatie van resultaten
verkregen op laboratorium of pilot-schaal, te doorgronden. Dit maakt het mogelijk om
de stapsgewijs, dure, opschaling van productieprocessen zo efficint mogelijk te laten
verlopen. De grondstoffen welke normaliter in de farmaceutische industrie worden gebruikt
hebben allemaal distributies van fysische eigenschappen zoals grootte en vorm. Een van de
conclusies van dit onderzoek is dat het kwantificeren van de distributies essentieel is om de
juiste modellen te kunnen maken.
Dit proefschrift heeft een bijdrage geleverd met betrekking tot het ontwikkelen van
een aantal methodes voor het bepalen van de 1) hechting (adhesie) van poederdeeltjes, 2)
agglomeraat eigenschapen en 3) het simuleren van een mengproces in een tuimelmenger.
Verder onderzoek moet nog uitgevoerd worden met betrekking tot het integreren van
materiaal eigenschappen en procesomstandigheden om meer inzicht te krijgen hoe de
gewenste producteigenschappen verkregen kunnen worden.
112
Appendix
Acknowledgement
ACKNOWLEDGEMENT
To reach this milestone, I am gratefully indebted to my family, to my friends and to

my colleagues. There are many names to mention, please pardon me if I forget someone.
Without you and your support this thesis could hardly have been completed.
Firstly, I am deeply grateful to my supervisor, Prof. dr. ir. K. van der Voort Maarschalk.
Kees, from the very first email, I felt the click that we can work together. Thank you for giving
me the opportunity to work on this project, and for guiding me along the journey. Despite
other hectic activities, you are always available for discussion. Your openness to consider my
arguments gave me a lot of confidence in doing my research. Your clear, determined action
and your efficiency are qualities that I still need to learn and train myself. Thank you, Kees!
Secondly, I am truly thankful to my second supervisor, Prof. dr. H. W. Frijlink. Although
not having you as my first supervisor, I received your close supervision every day during
my four years in Groningen. Your energy, your enthusiasm and your constructive criticism
provided a strong motivation for your students. I am really happy to have had a great time
to develop myself in your group. Besides having learned technologies, and learning about
the research culture, I was also among the luckiest foreign students who had chance to
learn things that simply do not exist in any book or dictionary. Thank you Erik, four years
working under your supervision has been a fantastic and unforgettable experience.
Thirdly, I would like to thank Dr. Thanh N. Tran. It was a tipping point of our project
when we came into contact with you. Magic vector and matrix operations helped us out
with major obstacles in our data analysis. I also would like to thank Hu, Thi and Vn for
their sympathies for the work that we did together. It claimed many extra hours that Thanh
had to work at home. I really enjoy warm receptions whenever I come to your place, which
made me feel like being in Viet Nam.
I would like to express my appreciation to the reading committee, Prof. dr. E.M.J.
Verpoorte, Prof. dr. J. Ketolainen, Prof. dr. R. Kohlus. Thank you very much for having
accepted to review my manuscript, and for making your time available for the defense of
this thesis. Your comments contributed significantly to the quality of this thesis.
Tofan Willemsz, thank you very much for being my good friend! six years knowing
each other, six years working together has always been a great time. With your intrinsic
trigger, we can burst out laughing at any time, any situation. I enjoy and appreciate all
the moments we have shared together, personally as well as professionally. Send my deep
affection to your beloved Sandra and Alicia.
Ricardo Hooijmaijers, this book would never be nicely finished without your intensive work
in reviewing all the chapters, especially the Dutch summary. I always appreciate our collaboration,
right from the beginning of DeQuaPro project until this time at MSD. Our Kibling Friday is
really great, will always try to keep this routine. Thank you very much for your friendship and
your support all the time. Also thanks for your terrifying plan for the day of my thesis defense.
I would like to thank Prof. dr. Henk J. Busscher and Joop de Vries for giving me instruction
and for allowing me to use the AFM at the Department of Biomedical Engineering, University
Medical Centre Groningen. I would like to thank Tuomas Ervasti, University of Eastern Finland,
Ari Halvari, University of Savonia, Finland for helping me with the X-ray microtomography.
&
117
APPENDIX
My four years in Groningen are a fantastic memory. This time could not have been nice
without my dear colleagues around me.
Dr. Anne de Boer, thank you very much for the intensive, in-depth discussion on particleparticle interaction, for your criticism and support along my project. Marinella, thank you for
being my office mate and for sharing with me many up and down moments in my research!
Dr. Wouter Hinrichs, thank you for your friendship and for introducing many aspects of the
Dutch culture to me. The Lytje Pole Eilander Kruidenbitter is a name that I still need to practice
before I can clearly order it in Schiermonnikoog. Sonja, thank you for being always cheerful and
welcoming whenever I ask for any administrative help! Anko, thank you very much for all the
SEM images and for helping me with different lab settings! Paul, thank you for showing me the
laser diffraction and the QicPic! Vinay, Hans, Parinda, Wouter, the Indian wedding experience
was fantastic even though no one, except Vinay, came back with a ring. I always laugh when I think
about the King Fischer mineral water. Christina, thank you for being a caring big mama! Thank
you for hanging out and around with me from the very first day I came to Groningen. Maarten
van den Noort, thank you for being a colleague and a friend of mine. I think about Zakopane and
TahBoeSch every winter holiday. I would like to thank other colleagues, Jan, Dorenda, Doetie,
Herman, Peter, Milica, Tng, Senthil, Niels, Floris, Wouter T, Anne L, Marcel, Maarten M, for
being so kind and friendly. You made my work environment so adorable.
A part of this thesis was completed during my work at MSD in Oss. Supports from
my managers and my colleagues have been very important, either directly or indirectly, in
helping me to finalize this thesis. I would like to thank Piet van den Oetelaar, Wim Oostra,
Ad Gerich and Martine van der Kruijssen for having given me the opportunity to work in
Oss while I can still finalize my thesis. Martine, jij bent een erg geduldige baas. Jij kunt erg
goed luisteren naar verhalen over mijn onderzoek in het Nederlands. Bedankt voor jouw
ondersteuning. Niels, Albert, Rut, Tofan, this Wilhelmina active group is the beautiful
place where we can freely talk science without any application border. Thank you very much
for the nice time. Mari, Cees, Michel, Tofan, Jan, Niels, Albert, Jan-Piet, Michiel, Rut,
Monika, Alex, Aloysia, Peter, Roy, Christa, Erwin, Joop, Joost, Ricardo, and many others
I cannot mention all the names, you are the important part of my every day in Oss. I would
like to thank you for all the nice moments in the office, for your collaboration and for your
kindness which made my professional life enjoyable.
I would like to thank my Vietnamese friends in Groningen. Ha, Tng, Giang, Linh, H
Lan, Diu Linh, Minh, Ln, Dip, sharing activities with you, I feel closer to home.
Diu Linh, thank you for being interested in my work, for listening to my long stories
about particle interaction and for the special celebration when my first paper was accepted
for publication.
Ngc Dip, thank you for being next to me, and for sharing with me stressful moments
as well as fantastic times. I appreciate the work you did in checking my manuscript for
publication; it must not be easy for an outsider.
Cm n Minh, Thy lun lun dnh mi tnh cm tt p cho anh. Cm n chu Tin
Long, chu lun lun l nim vui, l hnh phc ca c nh. Mong chu s c nhng c hi
118
ACKNOWLEDGEMENT
tt nht t c nhng c m ca mnh. Mong cho s nghip ca Tin Long s cn

tin xa hn nhng g bc c c ngy hm nay.
Thank you Minh, my brother, Thy, my sister in law, for saving your love for me! Thank
you Tin Long, my nephew, for being the love, and happiness of the family! May your future
career go even further, be better than what Im having now.
Cui cng, v trn ht, con xin cm n b m sinh thnh v nui dy con khn ln.
Nhng bi hc lm ngi lun i theo con trn mi chng ng. D con sng xa nh
nhng b m, gia nh vn lun lun l ch da tnh cm, tinh thn vng chc nht, an
ton nht bn con mi lc, mi ni.
Last, and foremost, mom, dad, thank you for introducing me to this world and for
raising me up! Lessons for being a good person have been and will always be with me along
all journeys of my life. Thank you for being my permanent and everlasting spiritual support.
Nguyn Tin Thnh
&
119
Appendix
Curriculum Vitae
CURRICULUM VITAE
Name:
Nguyen Tien Thanh,
Date of birth: 28th August 1980

Place of birth: Ha Noi, Viet Nam
Contact:
Nguyen.t.thanh80@gmail.com
1998 2003 Bachelor in pharmacy

Hanoi College of Pharmacy, Hanoi Vietnam
2003 - 2004 Chemical analyst
National Institute of Drug Quality Control of Vietnam, Hanoi, Vietnam.
2004 2005 Master of research
Skin barrier function and percutaneous bioavailability
University Claude Bernard Lyon1, Lyon, France
2005 2006 University research
&
2006 - 2007 Master professional: Formulation and Industrial Chemistry

2007 2008 Formulator, product development
Bayer Sant Familiale International Technical Center Gaillard, France.
2008 2012 PhD researcher
University of Groningen, Groningen, The Netherlands
2012 - current Senior scientist, preclinical development
Merck & Co., Inc. Oss, The Netherlands.
123
Appendix
List of publications
LIST OF PUBLICATIONS
PUBLICATIONS
T. T. Nguyen, T. Willemsz, H. Frijlink, and K. van der V. Maarschalk, Numerical study of
agglomerate abrasion in a tumbling mixer, Chem. Eng. Sci., vol. 114, pp. 2129, Jul. 2014.
T. Willemsz, T. T. Nguyen, R. Hooijmaijers, H. W. Frijlink, H. Vromans, and K. van
der Voort Maarschalk, Quantitative characterization of agglomerate abrasion in a
tumbling blender by using the Stokes number approach., AAPS PharmSciTech, vol. 14,
no. 1, pp. 183188, Mar. 2013.
T. N. Tran, T. T. Nguyen, T. A. Willemsz, G. van Kessel, H. W. Frijlink, and K. van der
V. Maarschalk, A density-based segmentation for 3D images, an application for X-ray
micro-tomography, Anal. Chim. Acta, vol. 725, no. 6, pp. 1421, Mar. 2012.
T. T. Nguyen, T. N. Tran, T. A. Willemsz, H. W. Frijlink, T. Ervasti, J. Ketolainen, and K. van
der Voort Maarschalk, A density based segmentation method to determine the coordination
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Vries, H. J. Busscher, and K. V. V Maarschalk, A centrifuge method to measure particle
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Sarciron, and F. Falson, Study on the hydatid cyst membrane: Permeation of model
molecules and interactions with drug-loaded nanoparticles, Int. J. Pharm., vol. 353, no.
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Trinh Hong Son, Nguyen Van Tuan, Do Duc Van, Dao Kim Chi (2006). Effect of
ASLEM as adjuvant immunotherapy in the treatment of primary liver cancer: report of
115 cases. Vietnamese journal of pharmaceutics; 343(44): 12-15.
Nguyen Tien Thanh, Nguyen Hoang Anh, Nguyen Quang Nghia, Nguyen Xuan Hung,
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cancer patients. Surgery of Vietnam; 53(6):41-47.
Nguyen Hoang Anh, Nguyen Tien Thanh, Dao Kim Chi, Do Mai Lam, Do Duc
Van, Bach Khanh Hoa, Phan Thi Phi Phi (2002). ASLEM as post-operative adjuvant
immunotherapy in patients with carcinoma in gastric cardia region: A preliminary
study. Vietnamese journal of pharmaceutics; 42(11): 20-23.
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Bach Khanh Hoa, Phan Thi Phi Phi (2001). Study of cellular immunodeficiency and
mutant p53 expression in patients with in gastric cardia carcinoma for the application
of an adjuvant immunotherapy. Surgery of Vietnam; 30(4): 22-27.
&
127
APPENDIX
COMMUNICATIONS
AAPS 2013: 10-15 November 2013, San Antonio, USA. Numerical simulation of
agglomerate abrasion in a tumbling mixer. Poster presentation.
Particulate Processes in the Pharmaceutical Industry III: 24-29 July 2011, Brisbane,
Australia. A density based segmentation method to determine the coordination number
of a particulate system. Oral presentation.
PharSciFair: 8-12 June 2009, Nice, France. Cohesion force measurement using centrifuge
technique. Oral presentation.
TI Pharma Spring Meeting 23 April 2009, Utrecht, Netherlands: Particle Particle
interaction in dry blending using centrifuge technique. Oral presentation.
PharSciFair 12-17 june 2005, Nice - France. Albendazole loaded poly (D,L-lactide)
nanosphere as potential treatment of hepatic cystic echinococcosis. Oral presentation.
12th Joint Meeting of the young researchers of Hanoi College of Pharmacy: 9 January
2004, Hanoi, Vietnam. In vitro effect of ASLEM on the balastogenensis and cytokine
production of lymphocytes from colorectal cancer patients. Oral presentation.
11th Joint Meeting of the young researchers of Hanoi College of Pharmacy. 18-19 January
2002, Hanoi, Vietnam. ASLEM as post-operative adjuvant immunotherapy in patients
with carcinoma in gastric cardia region: A preliminary study. Oral presentation.
128

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PARTICLE PARTICLE INTERACTION IN DRY POWDER BLENDING

PARTICLE PARTICLE INTERACTION

Nguyen Tien Thanh

PARTICLE PARTICLE INTERACTION

Nguyn Tin Thnh

Paranymphs: Tofan Willemsz

Dr. Thanh N. Tran

PARTICLE PARTICLE INTERACTION

to obtain the degree of PhD at the

Nguyen Tien Thanh

1.2 Lumps formation in dry blending of cohesive powder

1.3 Particle particle interaction forces in a powder system

1.4 Agglomerate strength and breakage

1.5 Overview of this thesis

Adhesion force measurement

2.3 Materials and methods

2.3.1 Preparation and characterization of particle size

2.3.2 Preparation and characterization of substrate surface 

2.3.3 Cohesion force measurement by atomic force

2.3.4 Cohesion force measurement by the centrifuge method

2.3.5 Experimental design and statistics

2.4 Results and discussion

2.4.1 Cohesion force measurement by atomic force

2.4.2 Cohesion force measurement by the centrifuge method

Segmentation method for 3D image

3.3 DBSCAN algorithm

3.4 DBSCAN for 3D binary images

3.5.2 XMT-DBSCAN segmentation and clustering

3.6 Results and discussions

3.6.1 Segmentation of and clustering of simulated

3.6.2 Segmentation and clustering of XMT images

Determination of coordination number

4.3 Materials and methods

4.3.1 Sample preparation and image capturing

4.4.2 Check of validity

4.4.3 Coordination number of Cellets

Simulation of agglomerate abrasion

5.3.1 Agglomerate fracture strength determination

5.3.2 Agglomerate size determination

5.3.3 Blending test condition

5.4 Results and Discussion

5.4.1 Mechanical properties of agglomerates

5.4.2 Abrasion of agglomerates

5.4.3 Effect of process conditions

5.4.4 Simulation vs experiment

Summary and perspectives

6.2 Concluding remarks and perspectives

7.2 Conclusies en perspectieven

1.2 L UMPS FORMATION IN DRY BLENDING OF COHESIVE

Figure 1. Example of lumps found at the end of a dry blending process.

Figure 2. Example of API contents in agglomerates found in dry mixing process.

Figure 3. Particle-particle interaction forces in a dry powder system.

Figure 5. Influence of particle surface deformation on adhesion force.

1.4 AGGLOMERATE STRENGTH AND BREAKAGE

1.5 OVERVIEW OF THIS THESIS

(particle size distribution, surface properties, morphologies) to a substrate can be measured

Siddalingappa, B., Nekkanti, V. & Betageri, G.

Kendall, K. & Stainton, C. Adhesion and

Lachiver, E. D., Abatzoglou, N., Cartilier, L. &

10 Cartilier, L. H. & Mos, A. J. Effect of drug

agglomerate strength of the cohesive powder.

29 A-G-Bailey. Electrostatic phenomena during

Waals constants. Adv. Colloid Interface Sci. 3,

Paranymphs: Tofan Willemsz

1.2 Lumps formation in dry blending of cohesive powder

1.3 Particle particle interaction forces in a powder system

1.4 Agglomerate strength and breakage

1.5 Overview of this thesis

2.3 Materials and methods

2.3.1 Preparation and characterization of particle size

2.3.2 Preparation and characterization of substrate surface

2.3.3 Cohesion force measurement by atomic force

2.3.4 Cohesion force measurement by the centrifuge method

2.3.5 Experimental design and statistics

2.4 Results and discussion

2.4.1 Cohesion force measurement by atomic force

2.4.2 Cohesion force measurement by the centrifuge method

3.3 DBSCAN algorithm

3.4 DBSCAN for 3D binary images

3.5.2 XMT-DBSCAN segmentation and clustering

3.6 Results and discussions

3.6.1 Segmentation of and clustering of simulated

3.6.2 Segmentation and clustering of XMT images

4.3 Materials and methods

4.3.1 Sample preparation and image capturing

4.4.2 Check of validity

4.4.3 Coordination number of Cellets

5.3.1 Agglomerate fracture strength determination

5.3.2 Agglomerate size determination

5.3.3 Blending test condition

5.4 Results and Discussion

5.4.1 Mechanical properties of agglomerates

5.4.2 Abrasion of agglomerates

5.4.3 Effect of process conditions

5.4.4 Simulation vs experiment

6.2 Concluding remarks and perspectives

7.2 Conclusies en perspectieven

1.2 L UMPS FORMATION IN DRY BLENDING OF COHESIVE