Thesis of Process

STUDIES ON SPHERONIZATION PROCESSES BY
ROTARY AND EXTRUSION
GU LI
NATIONAL UNIVERSITY OF SINGAPORE
2005
STUDIES ON SPHERONIZATION PROCESSES BY
ROTARY AND EXTRUSION
GU LI
B.Sc (Pharm)
A THESIS SUBMITTED FOR THE DEGREE OF

DOCTOR OF PHILOSOPHY
DEPARTMENT OF PHARMACY
NATIONAL UNIVERSITY OF SINGAPORE
2005
… ACKNOWLEDGMENTS
ACKNOWLEDGMENTS
I wish to express my deepest and most sincere appreciation to my supervisors,
Associate Professor Paul Heng Wan Sia and Dr. Liew Celine Valeria for their
constant guidance, care and patience throughout the course of my research study. I am
grateful to have them as my teachers, as what I have learnt from them will benefit me
throughout my whole life.
I am grateful to the GEA-NUS Pharmaceutical Processing Research
Laboratory, Department of Pharmacy for the use of research facilities, as well as to
the National University of Singapore for providing the postgraduate research
scholarship.
My gratitude and thanks also goes to Associate Professor Chan Lai Wah for
her care and Teresa, Mei Yin and Peter for their technical assistance. The wonderful
company and help came from all in the laboratory, especially for the enlightening
lunch time discussions with Chin Chiat, Liang Theng, Kang Teng and Sze Nam. I
wish to specially thank Sze Nam, Josephine and Lene for various help.
Last but not least, I wish to express my deep appreciation for the support from
my family, especially my husband Sun Jinhui, parents and parents-in-law.
Gu Li
December, 2005
i
… TABLE OF CONTENTS
TABLE OF CONTENTS
Page
ACKNOWLEDGEMENTS i
TABLE OF CONTENTS ii
SUMMARY vi
LIST OF TABLES viii
LIST OF FIGURES x
I. INTRODUCTION 1
A. Historical background and terms 1
B. Advantages of pellets 2
C. Formation and growth of pellets 4
C1 Bonding forces 4
C2 Mechanism for agglomerate formation and growth 6
D. Pelletization by extrusion spheronization and rotary processing 12
D1 Extrusion spheronization 12
D1.1 Equipment used 13
D1.2 Formulation variables 15
D1.2.1 MCC acting as spheronization aid 16
D1.2.2 Substitute for MCC as spheronization aid 18
D1.2.3 Additives 23
D1.2.4 Moistening liquid 28
D1.2.5 Particle size of filler 29
D1.3 Process variables 29
D2 Rotary processing 31
D2.1 Equipment used 31
D2.2 Formulation and process variables 39
ii
D2.2.1 Type and content of MCC 40
D2.2.2 Type and content of moistening liquid 42
D2.2.3 Particle size of filler 43
D2.2.4 Material loading methods 44
D2.2.5 Speed of frictional plate 45
D2.2.6 Spheronization time 46
D2.2.7 Moistening liquid addition rate 47
D2.2.8 Atomizing and gap air pressures 48
D2.2.9 Load size 49
D2.2.10 End point monitoring 49
II. OBJECTIVES 51
III. EXPERIMENTAL 53
A. Materials 53
A1 Lactose 53
A2 Microcrystalline cellulose 54
A3 Crospovidone 54
B. Physical characterization of starting materials 55
B1 Particle size and size distribution 55
B2 Specific surface area 55
B3 Flowability 56
B4 Moisture content 56
B5 Bulk and tapped densities 57
C. Methods of preparing pellets 57
C1 Rotary processing 57
C2 Extrusion spheronization 61
C2.1 Small scale 61
iii
C2.2 Large scale 61
D. Characterization of pellets 62
D1 Mean size, size distribution, oversized fraction, fines and yield 62
D2 Shape 63
D3 Bulk and tapped densities 64
D4 Friability 65
D5 Moisture content 65
D6 Porosity 65
E. Rotary processing and extrusion spheronization studies 67
E1 Influence of operational variables in rotary processing 67
E2 Effect of frictional plate design in rotary processing 69
E2.1 Characterization of teardrop studded frictional plates 69
E2.2 Preparation and characterization of pellets prepared by rotary 72

processing
E3 Feasibility of eliminating of pre-mixing in rotary processing 73
E4 Effect of lactose particle size in spheronization processes 75
E5 Functionality of crospovidone as a spheronization aid in extrusion 77

spheronization
E5.1 Torque rheological properties 77
E5.2 Preparation of pellets by small and large scale extrusion 78

spheronization
IV. RESULTS AND DISCUSSION 83
A. Influence of operational variables in rotary processing 83
B. Effect of frictional plate design in rotary processing 88
B1 Loading 88
B2 Adhesion 89
B3 Mean size, size distribution, oversized fraction and fines 91
iv
B4 Shape 96
B5 Density and friability 98
B6 Porosity 99
B7 Between batch variability 102
C. Feasibility of eliminating pre-mixing in rotary processing 103
D. Effect of lactose particle size in spheronization processes 109
D1 Studies in rotary processing 111
D2 Studies in extrusion spheronization 126
D3 Choice of lactose grades in spheronization processes 130
E. Functionality of crospovidone as a new spheronization aid in extrusion 130

spheronization
E1 Postulated mechanism of pellet formation with crospovidone 131
E2 Performance of various crospovidone grades in small scale extrusion 134

spheronization
E3 Effects of operating variables in large scale extrusion spheronization 136
E3.1 Reproducibility of the process 136
E3.2 Effects of operating variables on pellet quality 140
E3.3 Comparison of crospovidone-lactose pellets with MCC-lactose pellets 143
V. CONCLUSION 145
VI. REFERENCES 149
VII. PUBLICATIONS 170
v
… SUMMARY
SUMMARY
Pellets were prepared with two pelletization processes of rotary processing and
extrusion spheronization. The effects of various equipment design, formulation and
process variables on the quality of final products were investigated.
The two variables, amount of water added and frictional plate speed during
tumbling stage were identified as important variables for producing high quality
pellets in rotary processing. Newly designed teardrop shaped studs on the frictional
plates were investigated for pelletization in rotary processing. Differences in the
dimension of studs on the plates influenced the magnitude of forces imparted by the
rotating plate to the starting powder mass for the pellet production. Hence, pellets of
different physical properties resulted. Plate with medium height studs was
demonstrated to achieve the best overall reproducibility and minimal material
adhesion.
In rotary processing, the feasibility of eliminating the pre-mixing step for
making pellets was explored. Three loading configurations were used to load without
pre-mixing starting materials of microcrystalline cellulose (MCC) and lactose.
Physical properties of the pellets without pre-mixing were compared against those
prepared using a blend prepared in a separate mixer prior to loading. No significant
difference in pellet properties could be attributed to the effect of pre-mixing and the
different loading configurations. This study demonstrated that homogeneous powder
blends are not required for the production of pellets since the tumbling action of the
powders at the start of rotary processing is sufficient to ensure adequate powder
mixing.
The effect of lactose particle size was investigated in two spheronization
processes. In rotary processing, lactose 100M produced more uniform pellets with
vi
… SUMMARY
less oversized fraction and a better robustness of the process indicated by low
sensitivity to water content variation in pellet mean size and yield. Lactose 450M
gave pellets of high sphericity. Lactose 200M provided a compromise by showing all
desirable pellet and process attributes in rotary processing. In extrusion
spheronization, lactose 450M worked very well in producing uniform pellets with
high yield and good sphericity. The process robustness is also best for lactose 450M
with less sensitivity to variation of water content and wider range of water to produce
high yield. Hence, for both the processes, the choice of lactose grades depended
which properties were more highly sought for by the formulator.
Three grades of crospovidone were evaluated for their abilities to function as
spheronization aids in extrusion spheronization. Crospovidone was believed to behave
like a liquid repository in its interaction with water during extrusion spheronization
although its binding ability was weaker than that of MCC. Spherical pellets of narrow
size distribution could be made from the finer crospovidone grades with higher water
levels than weight equivalent MCC based formulations. Crospovidone pellets were of
equivalent quality to those prepared with MCC, especially in the shape, size and yield.
The potential of crospovidone was investigated and demonstrated to be a competent
alternative to MCC in the production of pellets by extrusion spheronization.
vii
… LIST OF TABLES
LIST OF TABLES
Page
Table 1 Physical properties of lactose grades used. 53
Table 2 Physical properties of crospovidone powders. 54
Table 3 Operational variables and levels for orthogonal design. 67
Table 4 Orthogonal design – matrix L34 68
Table 5 Characteristics of teardrop studs on three frictional plates. 72
Table 6 Pellet preparation conditions for evaluating the feasibility of 75

eliminating pre-mixing in rotary processing.
Table 7 Amount of water used to prepare pellets in rotary processing and 76

extrusion spheronization.
Table 8 Experimental matrix of the Box-Behnken design. 80
Table 9 Properties of pellets resulted from the orthogonal design 83

experiment.
Table 10 T-test for the four variables. 85
Table 11 Observations of material adhesion during rotary processing with 90

the three teardrop studded frictional plates.
Table 12 Physical characteristics of pellets produced using the three 99

teardrop studded frictional plates.
Table 13 Median pore diameter of pellets prepared using the three teardrop 100
studded frictional plates.
Table 14 Coefficient of variance of the properties of pellets produced using 103

Table 15 Physical characteristics of pellets prepared under condition A. 104
Table 16 Coefficient of variance (%) for the pellet mass median diameter. 104
Table 17 Physical characteristics of pellets prepared under condition B. 105
Table 18 Physical characteristics of pellets prepared under condition C. 106
Table 19 Trendline equations for the three lactose grades. 113
Table 20 Process reproducibility (physical properties of pellets). 140
viii
… LIST OF TABLES
Table 21 Physical properties of pellets prepared with XL-10 and lactose 141
200M.
Table 22 Physical properties of pellet prepared with MCC and lactose 144
200M.
ix
… LIST OF FIGURES
LIST OF FIGURES
Page
Figure 1 Changes in states of liquid saturation caused by (A) addition of 5

binder liquid or (B) densification of the agglomerate.
Figure 2 Schematic of agglomeration process – traditional view. 7
Figure 3 Schematic of agglomeration process – alternative approach. 9
Figure 4 The nucleation formation mechanism (A) Distribution 10

mechanism; (B) Immersion mechanism.
Figure 5 Depiction of frictional plates with different designs of surfaces 15

for extrusion spheronization.
Figure 6 Schematic diagram representing proposed mechanism for pellet 33

formation and growth during rotary processing.
Figure 7 Schematic diagram of designs of rotary processors (a) single 35

chamber; (b) double chamber.
Figure 8 Depiction of frictional plates with different surface designs in 37

rotary processor.
Figure 9 Diagram of multi-purpose system (MP-1) with the rotary 58

processor insert.
Figure 10 Diagram depicting the double chamber design of the rotary 58

processor.
Figure 11 Diagram of pellet formation in rotary processor. 59
Figure 12 Photographs of plates with teardrop-shaped studs of different 70

dimensions. (A) Plate Short with shortest studs, (B) Plate Medium
with medium height studs, (C) Plate Tall with tallest studs.
Figure 13 Schematic diagram of a frictional plate with teardrop studs. 71
Figure 14 Schematic diagram depicting the four material loading methods. 74
Figure 15 Effect of the four variables on pellet size, size distribution and 84
oversized fraction.
Figure 16 Recovered product obtained from rotary processing runs using 92

Figure 17 Mass median diameter and span of pellets prepared using the 93
three teardrop studded frictional plates.
x
… LIST OF FIGURES
Figure 18 Oversized fraction and fines prepared using the three teardrop 95
Figure 19 Shape factors of pellets prepared using the three teardrop studded 97
frictional plates.
Figure 20 Porosity of pellets prepared using the three teardrop studded 101
frictional plates.
Figure 21 Moisture content of the pellets produced by rotary processing 110

(open) and extrusion spheronization (closed). Moisture content of
extrudates produced by extrusion spheronization.
Figure 22 Mass median diameter of pellets prepared by rotary processing 112

(open) and extrusion spheronization (closed).
Figure 23 Span of pellets prepared by rotary processing (open) and 115

extrusion spheronization (closed).
Figure 24 Oversized fraction of products prepared by rotary processing. 116
Figure 25 Yield of pellets prepared by rotary processing (open) and 117

Figure 26 Circularity of pellets prepared by rotary processing (open) and 120

Figure 27 Aspect ratio of pellets prepared by rotary processing (open) and 121
Figure 28 eR of pellets prepared by rotary processing (open) and extrusion 122

spheronization (closed).
Figure 29 Porosity of pellets prepared by rotary processing (open) and 124

Figure 30 Median pore diameter of pellets prepared by rotary processing 125

(open) and extrusion spheronization (closed).
Figure 31 Effect of added water levels and mixing times on the torque 133
profiles of MCC-lactose, XL-10-lactose, and INF-10-lactose
powder mixtures. Torque values in [Nm] Newton meter.
Figure 32 Mean size of pellets prepared using small scale extrusion 137
spheronization (A) XL-10 and (B) INF-10.
Figure 33 Span of pellets prepared using small scale extrusion 138

xi
… LIST OF FIGURES
Figure 34 Oversized fraction of pellets prepared using small scale extrusion 139
xii
… INTRODUCTION
I. INTRODUCTION
A. Historical background and terms
The granulation process of size enlargement used within the pharmaceutical
industry has its roots in ancient times. The term “granulated” material is derived from
the Latin word “granulatum” meaning grained (Parikh, 1997). Nowadays, the
granulation process is used in many industries, coal mining, agrochemical and
pharmaceutical. Pharmaceutical granulations are commonly used for the preparation of
feed materials for tabletting and precursors to the encapsulation processes.
The development of pharmaceutical granulation was driven by the invention of
the tablet press in 1843. The demands on high quality granulated materials were
further increased in the 1970s when high speed tablet machines with automated
controls were introduced. With the advent of controlled release technology, also in the
1970s, interest in spherical particles increased as they are best suited for a coating to
produce multi-particulate dosage forms.
Granulation, also known as agglomeration, is a size enlargement process during
which fine powders or particles are aggregated into small, free-flowing, spherical
and/or semi-spherical units that are referred to as granules or agglomerates (Ghebre-
Sellassie, 1989a). The term pelletization is used when highly spherical agglomerates of
narrow size distributions are produced. For pharmaceutical purposes, useful
agglomerates are in the size range from about 0.5 to 1.5 mm as they are usually
intended for oral administration.
The general terms “granulation” and “pelletization” are sometimes used
synonymously and no clear distinction is made between them. Generally, if a size
enlargement process produced agglomerates of a wide size distribution, within the
1
… INTRODUCTION
range of 0.1 to 2 mm, the process may be called granulation. Pelletization is often
referred to as a size enlargement process that involves the manufacture of
agglomerates with a relatively narrow size range, usually with mean size from 0.5 to 2
mm (Schæfer et al., 1992). Spheronization is a type of pelletization and a more specific
term usually associated with spherical units formed by a size enlargement process
which includes a spheronization step where extrudates or agglomerates are rounded as
they tumble on a frictional plate. Due to the spheronization step, the resultant products
normally have optimal mean size, uniform size distribution and highly spherical shape
when compared with granules obtained from other agglomerate processes (Vervaet et
al., 1995).
B. Advantages of pellets
Pellets are suitable for use as the final product or for further processing by
coating. The highly spherical shape of pellets confers various technological
advantages.
a) Good flowability. The uniform size and spherical shape of pellets allows
accurate capsule filling with minimal unit dose variation.
b) High physical integrity. Pellets flow with minimal friction and dust generation
during processing as compared to flow of other powders or conventional granules.
c) Superior qualities for coating application. Due to spherical shape, low surface
area to volume ratio, smooth surface, and ability to withstand mechanical stresses,
pellets are very suitable for coating and designed as coated drug delivery systems.
Pellets have become more popular in the pharmaceutical industry as a result of
increased interest in multi-particulate dosage forms for controlled drug delivery
(Niskanen et al., 1990a; Porter, 1994). Controlled release oral solid dosage forms
2
… INTRODUCTION
usually contain drugs intended for delivery either at a specific site within the
gastrointestinal tract or over an extended period of time. For controlled release pellets,
the desired goals mentioned can be achieved through the application of a drug release
limiting coat or by the formulation of matrix pellets. Multi-particulate drug delivery
systems can be prepared by blending pellets that contain chemically incompatible
drugs, or the same drug but with different release rates in an appropriate ratio to
achieve the desired overall drug release profile. These delivery systems may affect
drug release at the same site or at different sites within the gastrointestinal tract.
Modified release multi-particulate dosage forms prepared using pellets have several
therapeutic advantages over single unit dosage forms such as tablet or powder-filled
capsule dosage forms (Bechgaard and Nielson, 1978). Some examples of therapeutic
advantages are listed below:
a) Pellets can disperse freely throughout an area of the gastrointestinal tract after
ingestion. The drug will be released over a wider area. Drug absorption is maximized
as a large gastrointestinal surface can be involved in the absorption process, assuming
uniform drug absorption throughout the gastrointestinal tract.
b) Peak plasma level of the drug can be reduced by the use of pellets with
different release rates. Potential side effects are minimized without markedly lower
drug bioavailability.
c) The wide distribution of pellets in the gastrointestinal tract limits localized
build up of the drug. Dangers of mucosa lining damage caused by certain irritant drugs
can be alleviated.
d) Modified release multi-particulate delivery systems are less susceptible to dose
dumping than single unit dosage forms (Ghebre-Sellassie, 1989a; Ghebre-Sellassie and
Knoch, 1995).
3
… INTRODUCTION
C. Formation and growth of pellets
C1 Bonding forces
The composition of pharmaceutical dosage forms is heterogeneous, comprising
drug and excipient powders. Bonds between particles in agglomerates need to be
sufficiently strong to prevent breakdown of agglomerates on drying as well as
subsequent handling and processing (Augsburger and Vuppala, 1997). A few
mechanisms (attractive forces between solid particles, interfacial forces and capillary
pressure in mobile liquid surfaces, adhesional and cohesional forces in immobile
bonding bridges and solid bridges) were identified for the forces operating during and
after agglomeration (Rumpf, 1962).
Attractive forces are short-range forces that cause solid particles to stick to
each other when the inter-particle distance is small enough. However, in the wet
agglomeration process, these attractive forces can only initially hold and orientate the
particles in a contact region. These forces do not play a significant role in determining
the final strength of the agglomerates. The reason is that attractive forces only work
over very short distances and the magnitude of these forces decrease with an increase
in particle size. The attractive forces involved in particle bonding include molecular
(Valence and Van der Waals) and electrostatic forces.
The process of agglomerate formation is identical in the wet pelletization
process, requiring the use of a moistening liquid. The surface energy in a three-phase
system of solid, liquid and gas tends to be reduced by the formation of liquid bridges
between particles whenever a particulate solid is mixed with a liquid which wets the
solid surfaces (Kristensen et al., 1984; Kristensen, 1995). The states of liquid bridging
depend on the liquid saturation of the agglomerate expressed as the ratio of pore
4
… INTRODUCTION
volume occupied by liquid to the total volume of pores within the agglomerate. Liquid
saturation is affected by the amount of binder liquid presented and the porosity within
aggregates. Liquid saturation can be classified into four stages, namely, pendular,
funicular, capillary and droplet stages (Newitt and Conway-Jones, 1958; Rumpf,
1962). A state of liquid saturation can be brought about by continuous addition of
liquid and/or the densification of wet agglomerate during process (Figure 1) (Schæfer,
1996). Densification of agglomerates could occur simultaneously when the shear
forces are involved. Thus, high shear granulation needs less binding liquid than low
shear processes.
(A)
Pendular Funicular Capillary Droplet
(B)
Pendular Funicular Capillary Droplet
Figure 1. Changes in states of liquid saturation caused by (A) addition of binder liquid
or (B) densification of the agglomerate ( Air, Liquid, Solid).
5
… INTRODUCTION
Besides mobile liquid bridges, bonding forces can also be supplied by
immobile liquid bridges. These bridges are formed with viscous binders or with thin
adsorption layers (Rumpf, 1962). Strong bonds can be generated when highly viscous
binders adhere to the surface of solid particles. These bonds are similar to those that
exist due to solid bridges. The shape of the particle surface is not changed because the
bridges are immobile and a constant liquid pressure associated with freely movable
bridges cannot be formed.
Although the forces of attraction, particularly liquid bridges, contribute to the
formation of agglomerates from the solid particles at the initial stage of agglomeration,
the permanent integrity of the agglomerate is ultimately dependent on solid bridges.
Cohesive forces due to liquid bridges exist only in the presence of the moistening
liquid. Their effects tend to be eliminated with the evaporation of liquid upon drying.
Solid bridges can be built up in several ways, such as crystallization of dissolved
binder substances, hardening binders, solidification of melted components and
chemical reaction.
C2 Mechanism for agglomerate formation and growth
Agglomeration behavior has been traditionally described by a number of
mechanisms (Figure 2, adapted from Iveson et al., 2001). The starting materials need
to be wetted with the moistening liquid (commonly water or binder solution) before
agglomeration takes place. The differences between these agglomeration mechanisms
depend on the relative size of agglomerates and non-agglomerate materials. These
mechanisms may collectively be considered as cases of coalescence and/or breakage.
6
… INTRODUCTION
Nucleation
Coating/Layering/Snow-balling/Onion-skinning
Coalescence
Abrasion Transfer
+ +
Crushing and Layering
+ +
Figure 2. Schematic of agglomeration process – traditional view. ( represent

wetted powder or aggregate)
7
… INTRODUCTION
An alternative mechanistic approach was proposed to view agglomeration as a
combination of three sets of rate processes which are wetting and nucleation,
consolidation and growth, attrition and breakage (Butensky and Hyman, 1971; Ennis
and Litster, 1997; Tardos et al., 1997) (Figure 3, adapted from Iveson et al., 2001).
a) Wetting and Nucleation. The liquid binder is distributed finely over the dry
powder bed and each sizable droplet initiates the formation of a nucleus.
b) Consolidation and Growth. Collisions between two agglomerates, agglomerate
and primary particle or agglomerate with equipment surface result in compaction and
the possibility of growth by coalescence.
c) Attrition and Breakage. Wet or dry agglomerates break due to impact, wear or
compaction during the agglomeration process or subsequent product handling.
Generally, the agglomeration process starts from a nucleation regime during
which primary particles with wetted surfaces adhere together. During this initial phase,
small agglomerates (nuclei) of a loose structure are formed. There are two mechanisms
of agglomerate formation which could be referred as distribution and immersion
mechanisms, depending on the comparative dimension of droplet of binder liquid and
the size of primary particles (Figure 4, adapted from Iveson et al., 2001). When the
droplets of binder liquid are smaller than the solid particles or of the same order of
size, a distribution mechanism takes place. The binding liquid is well distributed on the
surface of solid particles. Subsequently, nuclei are formed by coalescence between the
wetted particles. The immersion mechanism takes place when the binder droplet is
much larger than the primary particle size and particles surround and are immersed
into the large droplet.
8
… INTRODUCTION
Wetting and Nucleation

Moistening Liquid
Solid Particles
Consolidation and Coalescence
Attrition and Breakage
Figure 3. Schematic of agglomeration process – alternative approach.
9
… INTRODUCTION
(A)
Solid Particles Spray Droplet Distribution Coalescence
(B)
Solid Particles Spray Droplet Immersion
Figure 4. The nucleation formation mechanisms (A) Distribution mechanism; (B)

Immersion mechanism.
10
… INTRODUCTION
In wet agglomeration by high shear pelletization (Holm et al, 1983, 1984,
1985a-b) and rotary processing (Wan et al., 1995; Holm, 1996a-b; Holm et al., 1996),
the distribution mechanism dominates because droplets of the binding liquid were
comminuted by atomizing air and well distributed by the shear and centrifugal forces.
For a well controlled nucleation, a uniform distribution of the binding liquid is
necessary. Therefore, it is advantageous that the binding liquid is atomized and
gradually added in order to avoid the formation of lumps (Wan et al., 1994).
The nuclei grow in size by either capturing unagglomerated particles or by
coalescence with other nuclei. During the nucleation phase, the tendency for
coalescence between initial particles, or between an initial particle and a nucleus will
be larger than the tendency for coalescence between two nuclei. On the basis of the
fundamental work of Rumpf (1962), the agglomerate strength is inversely proportional
to the particle size. Therefore, nucleation is characterized by a disappearance of fines.
After formation, the nuclei are densified and gain strength to resist the mechanical
forces acting in the process. Thereafter, agglomerate growth by coalescence between
nuclei is able to occur.
Normally, the end point of agglomeration process is not in the nucleation
phase, agglomerate growth will proceed by coalescence to achieve a larger
agglomerate size. During agglomeration processes, nuclei will collide into each other
under the shear force or centrifugal forces. The weaker agglomerates will be crushed,
leaving the fragments to enter into new agglomerates formed by coalescence. Thus, the
agglomerate growth was determined by the balance between crushing and coalescence.
When coalescence dominated the process, the agglomerate grows in size.
11
… INTRODUCTION
D. Pelletization with extrusion spheronization and rotary processing
Several manufacturing techniques are used for agglomeration like agitated wet
agglomeration using high shear granulation/pelletization, fluid bed granulation,
solution or powder layering, spray drying and spray congealing, tumbling melt
granulation (Ghebre-Sellassie, 1989a; Ghebre-Sellassie and Knoch, 1995; Parikh,
1997). Extrusion spheronization and rotary processing are two methods employed
currently for producing highly spherical pellets due to the spheronization process
involved.
D1 Extrusion spheronization
Extrusion spheronization is a multi-step pelletization process involving dry
mixing, wet massing/granulation, extrusion, spheronization and drying (Hicks and
Freese, 1989; Nesbitt, 1994; Vervaet et al., 1995). Briefly, dry powders are first mixed
to attain a homogeneous mixture followed by the addition of moistening liquid to the
powder mix to prepare the wet mass during the granulation stage (Hellén et al., 1992a;
Baert and Remon, 1993). The wet mass is then extruded to form cylindrical noodle-
like extrudates. Subsequently, these extrudates are rounded into spherical pellets.
Pellets obtained by spheronization are then subjected to drying. The ease of process
and pellet quality depend on complex interactions between equipment design,
formulation and process variables during extrusion spheronization (Kristensen, 1988;
Schwartz, 1988; Kristensen and Schæfer, 1993; Baert et al., 1993a; Shah et al., 1995;
Sonaglio et al., 1995a-b; Vervaet et al., 1995).
12
… INTRODUCTION
D1.1 Equipment used
Multiple equipments were needed to prepare pellets in extrusion
spheronization. Mixer, granulator, extruder, spheronizer and drying equipment are
needed corresponding to the various process steps.
In extrusion spheronization, a homogeneous mixture of dry powders could be
attained with various types of mixers/granulators. Planetary mixer, sigma blade mixer,
high shear mixer and continuous granulator may be used for dry mixing and
granulation, among which the planetary mixer is among the more commonly used type
(Vervaet et al., 1995). Subsequently, granulating liquid is added to moisten the powder
in the granulator. A homogeneous liquid distribution in the wet mass is desirable and
the evaporation of the moistening liquid should be restricted or be limited to a
controlled loss. For example, cooling of the granulation bowl was applied to offset the
evaporation of liquid in a high shear mixer (Baert et al., 1991). In some processes, wet
granulation was followed by extrusion with a short interval between these two stages
(Hellén et al., 1992b; 1993a-d; Hellén and Yliruusi, 1993). Attempts were made to
keep the wet mass sealed in a plastic bag overnight or for at least twelve hours to allow
liquid equilibration (Fielden et al., 1989, 1992a-c, 1993; Bains et al., 1991; Newton et
al., 1992, 1995a; Pinto et al., 1992; Jerwanska et al., 1995).
Due to variations in design of the different extruders, the extrudates formed
using a similar formulation but with different extruders may not be of equivalent
quality (Fielden et al., 1992c; Baert et al., 1993b; Newton et al., 1995b). There are
several types of extruders available commercially (Sherrington and Oliver, 1981;
Hicks and Freese, 1989; Vervaet et al., 1995). There are four main types of extruders:
screw, sieve and basket, roll and ram extruders. Screw extruders can differ as either
single screw extruder or twin screw extruder. Extruders can also be classified
13
… INTRODUCTION
according to their feed mechanism of the plastic wet mass to the extrusion screen, by
means of screws (axial and radial) or by means of gravitational forces (rotary cylinder,
rotary gear and ram extruders) (Vervaet et al., 1995; Pišek et al., 2001). The degree of
the compaction forces varies depending on the extruder type (Sherrington and Oliver,
1981; Shah et al., 1994).
During spheronization, the centrifugal force imparted by the frictional plate
causes the extrudates to travel in a rope-like tumbling motion (O’Connor and
Schwartz, 1989; Rowe, 1994). The edge of the segments will be removed or remodeled
by the tumbling motion of the materials on the frictional plate, transforming the
extrudates into pellets.
The frictional plates usually have grooves in a cross-hatch or a radial pattern
(Vervaet et al., 1995). The cross-hatch pattern (Figure 5a), where grooves vertically
intersect each other, is a common plate design as they can be fabricated more
economically. The pattern will affect the time and speed needed to produce pellets. It
was observed that although the plate surface pattern may not influence the extrudates
of good quality significantly, it may affect the spheronization of more sensitive
formulations (Newton et al., 1995b). For plates with grooves arranged in a radial
pattern (Figure 5b), radiating grooves move outwards from the center with increasing
distances between them. The manufacture of these radial patterned frictional plates is
technically more difficult and costs more. However, it is claimed that the application of
frictional forces from a radial patterned frictional plate is more uniform over the
rotating powder mass and energy transfer is greater (Hicks and Freese, 1989). This
may be especially important when different loads are used in the spheronizer.
14
… INTRODUCTION
(a) Studs in cross-hatch pattern (b) Studs in radial pattern
Figure 5. Depiction of frictional plates with different designs of surfaces for extrusion
spheronization.
After spheronization, the pellets are discharged from the spheronizer for drying
in a hot air oven, fluid bed, microwave oven or freeze dryer (Vervaet et al., 1995).
Pellet characteristics vary between different drying methods due to the drying rates
(Bataille et al., 1993; Dyer et al., 1994).
D1.2 Formulation variables
The basic formulations for extrusion spheronization consist of spheronization
aid, moistening liquid, active drug, filler/diluent and additives (e.g. lubricants and pH
modifiers). The most common formulations for making placebo pellets generally
included only microcrystalline cellulose (MCC) and lactose. In order to prepare high
quality pellets, the wetted mass must fulfill certain conditions (Chatlapalli and Rohera,
1998). During extrusion, the wetted powder material must be able to form a cohesive
yet plastic mass that remains homogeneous through out the extrusion process. For
spheronization, a precise balance between brittleness and plasticity of the extrudates is
15
… INTRODUCTION
needed to ensure the break up and rounding of extrudates. Generally, the drug and
filler materials do not possess the requisite attributes and may necessitate the inclusion
of another material to confer these properties. The most commonly used excipient to
aid aqueous extrusion spheronization is MCC. MCC is added to alter the rheological
properties of the wetted mass to achieve the condition for the successful pellet
formation.
D1.2.1 MCC acting as spheronization aid
MCC possesses almost incomparable efficiency in producing pellets of
appropriate properties. Pellets produced with MCC often have a narrow size
distribution, high sphericity and desirable mechanical properties. There are two models
explaining the mechanisms of MCC acting as a spheronization aid.
The MCC was described as a “molecular sponge” which has high water
absorption and retention properties and is also capable of readily releasing water
during evaporation (Fielden et al., 1988). It controls the movement and distribution of
water in wet powder masses and impedes phase separation during extrusion and
spheronization when the masses and extrudates are subjected to strong forces. The
cellulose particles provide the ability to hold water as a “sponge”. During extrusion,
the “sponge” is compressed until water is squeezed out and lubricates the particles
flowing through the extruder. This explains why the formulation in a broader range of
water content could be used to make pellets (Bains et al., 1991; Ek and Newton, 1998).
The unsurpassed efficiency of MCC in extrusion spheronization has been attributed to
its high internal porosity and large surface area, enabling the moistened mass to retain
a large amount of usable moisture for lubrication during extrusion (Shah et al., 1995;
Heng and Koo, 2001). This moisture then plasticizes the surface of the extrudates for
16
… INTRODUCTION
remodeling their shape into pellets during spheronization. Additionally, the ability of
MCC to bind together the components of the wetted powder mass is critical to its
performance during extrusion spheronization.
Another model is the crystallite-gel-model presented by Kleinebudde (1997). It
is proposed that a gel is formed during extrusion with MCC. In the presence of a
liquid, especially water, the MCC particles will break down to smaller subunits due to
shear during granulation and extrusion. With increasing shear stress, this process will
be more or less complete; finally single crystallites of colloidal size may occur. These
single particles are able to form a crystallite-gel and immobilize the liquid. The
crystallites or their agglomerates can form a framework by cross-linking with
hydrogen bonds at the amorphous ends. Single crystallites will result in a delicate
network. The viscosity of the gel depends on the particle size of the resulting
components and the liquid content. With increasing liquid content, the fraction of
gelling agent decreases and deformability increases (Kleinebudde, 1997). Kleinebudde
et al (2000) investigated the effect of the degree of polymerization of cellulose
materials on the behavior of MCC and powdered cellulose during homogenization and
extrusion spheronization processes. It is postulated that the sponge model is more
appropriate for the cellulose type with high degree of polymerization (Powdered
cellulose), whereas the gel model is more applicable to cellulose types with lower
degree of polymerization (MCC).
The type and amount of MCC in spheronization has influence on the
performance of process and quality of resultant pellets (Newton et al., 1992; Pinto et
al., 1992; Hileman et al., 1993a-b; Kleinebudde et al., 1994; Heng et al., 1995;
Sonaglio et al., 1995a; Basit et al., 1999). The amount of water for successful
production of pellets may be described as a function relative to the amount of MCC
17
… INTRODUCTION
(Bains et al., 1991; Elbers et al., 1992). Formulations with higher proportions of MCC
have higher moisture requirements and the sphericity of the pellets is enhanced. The
process of high drug loading formulation is more sensitive to the moisture content due
to the reduced content of MCC (Bains et al., 1991). The working range of moisture
content narrowed with decreased quantity of MCC.
Different types and grades of MCC are available commercially. Differences in
the properties of MCC may arise from variation in the source of raw material (wood
pulp) and manufacturing conditions by different suppliers. Conditions of manufacture
processes include pulping parameters (e.g. acidic or alkaline treatment, degree of
degradation and bleaching sequence), mechanical processes (e.g. milling and spray-
drying) and chemical processes (e.g. hydrolysis conditions). Thus, MCC grades may
differ in particle size, moisture content, degree of crystallinity and other
physicochemical properties (Rowe and Sadeghnejad, 1987; Staniforth et al., 1988;
Parker et al., 1989, 1992; Parker and Rowe, 1991; Landin et al., 1993a-b; Rowe et al.,
1994; Sonaglio et al., 1995a; Heng and Koo, 2001; Soh et al., 2004). Hence, studies
needed to be carried out to develop better MCCs or find alternative equivalents.
D1.2.2 Substitutes for MCC as spheronization aid
A wide range of materials have been investigated as substitutes for MCC in
extrusion spheronization. These included hydroxypropyl methylcellulose,
hydroxyethyl cellulose, powdered cellulose, chitosan, β-cyclodextrin, maize starch,
pectinic acid and κ-carrageenan. The properties of these materials and the quality of
the pellets formed were compared with those of MCC.
Two cellulose ethers, hydroxypropyl methylcellulose and hydroxyethyl
cellulose have been evaluated as substitutes for MCC for spheronization (Chatlapalli
18
… INTRODUCTION
and Rohera, 1998). Isopropyl alcohol was used as the moistening liquid as these
polymers are water soluble but practically insoluble in isopropyl alcohol.
Hydroxypropyl cellulose was employed as the binding agent and effectively lowered
pellet friability. MCC pellets were also prepared as control. The formulations were
hydroxypropyl methylcellulose, hydroxyethyl cellulose or MCC (95%), hydroxypropyl
cellulose (5%) and isopropyl alcohol (q.s). Hydroxypropyl methylcellulose can
produce pellets with comparable quality as those of MCC. In dissolution testing with
water as medium, hydroxypropyl methylcellulose pellets absorbed water and formed a
single viscous gel matrix that slowly dissolved. Hydroxyethyl cellulose pellets were
swollen but intact and slowly eroded, whereas MCC pellets stayed intact without
dissolution or erosion. The findings indicate that hydroxypropyl methylcellulose could
find possible application in pellet formulations of water-sensitive drugs. It will be a
good choice as a pelletization aid when complete water-solubility of all the
formulation excipient is desired. However, production stability and process robustness
issues need to be addressed.
Powdered cellulose has a chemical structure similar to that of MCC but it differ
in its swelling behavior (Lindner and Kleinebudde, 1994; Alvarez et al., 2003). In a
study, pellets were prepared with powdered cellulose and furosemide (25 or 50%)
without other additives (Alvarez et al., 2003). MCC pellets were prepared for
comparison. Pellets prepared with powdered cellulose showed smaller mean size,
broader particle size distribution, greater surface roughness, higher friability but
similar sphericity to pellets made with MCC. Hence, it could be noted that the
mechanical properties, size and size distribution of pellets prepared with powdered
cellulose were less ideal than those of MCC. The release of furosemide from powdered
cellulose pellets was markedly more rapid than from MCC pellets. It was attributed to
19
… INTRODUCTION
the higher micropore volume of powdered cellulose pellets. Hence, powdered cellulose
is potentially advantageous as an alternative to MCC for making rapid drug release
pellets of highly cohesive but poorly water-soluble drugs. The lower consistency
profile of the wet mass (containing powdered cellulose and furosemide) was obtained
using mixer torque rheometer and it indicated lower binding properties of powdered
cellulose (Alvarez et al., 2003). Hence this necessitated the incorporation of an
additional binder. In another study, the formulation used consisted of powdered
cellulose/MCC, paracetamol, sodium carboxymeththylcellulose and colloidal silicon
dioxide (Lindner and Kleinebudde, 1994). MCC pellets showed superior physical and
mechanical properties with lower friability. Powdered cellulose pellets were smaller
with a broader size distribution and higher surface roughness. Pellets prepared with
powdered cellulose exhibited a faster drug release during dissolution and did not
disintegrate during testing. Powdered cellulose and MCC showed different behaviors
during the drying of the wet pellets. The evaporating water left pores in powdered
cellulose pellets resulting in higher porosity.
Chitosan is soluble in acidic media and insoluble in neutral and alkaline
aqueous solutions (Steckel and Mindermann-Nogly, 2004). Chitosan is structurally
similar to cellulose except that the hydroxyl groups at carbon-2 are replaced by amino
or acetamido groups in chitosan. It was also used to produce pellets without MCC
(Agrawal et al., 2004). Chitosan was found to absorb a large quantity of water and
acted as an extrusion-spheronization aid in as low as 20% w/w to produce pellets.
However, the pellets were friable and rough, necessitating the inclusion of an adhesive
binder. Hydroxypropyl methylcellulose (5-10% w/w) was included in the formulation
to produce pellets with friability of less than 2%. The chitosan content, hydroxypropyl
methylcellulose content, water content, extruder speed and spheronizer speed were
20
… INTRODUCTION
shown to affect pellet quality. In another study, plain chitosan pellets (100% w/w)
were produced using diluted acetic acid (Steckel and Mindermann-Nogly, 2004).
β-cyclodextrin was used to prepare pellets using small amounts of MCC
(Gazzaniga et al., 1998). The mixture used contained 8 parts β-cyclodextrin to 1 part
MCC. Substitution of MCC by β-cyclodextrin led to a consequent decrease in the
amount of water needed to obtain good quality extrudates. Increasing the content of β-
cyclodextrin also resulted in higher pellet friability. Pellets containing triamcinolone
acetonide were produced with MCC–β-cyclodextrin–triamcinolone acetonide (5:90:5)
(Villar-López et al., 1999). The pellets had high sphericity, retained their integrity in
dissolution medium and released drug rapidly.
In one study, maize starch was used to prepare pellets of indomethacin 20%
and maize starch/MCC 80% with gelatin solution as the binding liquid. The quality of
the resultant pellets containing maize starch was comparable to that of MCC
(Eerikäinen and Lindqvist, 1991).
Starch and dextrins were evaluated as substitutes of MCC (Prieto et al., 2005).
Drug was not included in the formulation and distilled water was used as the wetting
agent. It was found that starch only as a principal excipient could prepare pellets with
acceptable physical characteristics. The mixture, starch (corn or wheat): white dextrin
(80:20 w/w), gave high quality pellets of good size and shape distributions.
The pectin derivative, pectinic acid (degree of methoxylation <10%) has lower
solubility in water than pectin. Pectinic acid or MCC as extrusion aid had been
compared in formulations of pectin acid or MCC to drug in the ratio of 99-20%:1-80%
(Tho et al., 2003). Three drugs were selected as models, riboflavin as drug of very low
water solubility, paracetamol and theophylline as drugs with high water-solubility.
Pectinic acid was found to be well suited as an extrusion aid excipient in pellet
21
… INTRODUCTION
preparation by extrusion spheronization (Tho et al., 2002; 2003). It had a high drug
loading capacity and produced disintegrating pellets that were well suited for fast
delivery of drugs with a low water-solubility. An elevated temperature of 45 ºC during
spheronization was needed to achieve optimal shape of the pellets. Compared with
MCC, pectinic acid was found to require less water for pellet formation and was more
sensitive against changes in water content. Pectinic acid was found to be sensitive to
the type and amount of drug and, consequently, its universality of application is lower
than MCC. Pectinic acid pellets were rougher with surface cracks but were not as
strong as MCC pellets. The great advantage of pectinic acid lies in its pellet
disintegrating properties after a short period of exposure to liquid and hence, a rapid
drug release was obtained.
Carrageenan was investigated for its suitability as a novel extrusion aid
(Bornhöft et al., 2005). κ-carrageenan is insoluble and swells in cold water. This
material depicted suitable plastic and brittle properties for spheronization.
Formulations contain 5-98% κ-carrageenan, α-monohydrate lactose 93-0% and
antipyrine at 2% produced pellets in the whole ratio range. When κ-carrageenan was
compared with MCC, another formulation of κ-carrageenan/MCC: lactose at 10:90%
was used. Due to its higher water binding property, κ-carrageenan required higher
water content and a broader optimal range for the formation of pellets, which indicated
improved robustness of the pelletization process. The pellets made from κ-carrageenan
possessed comparable quality in terms of shape and size as those of MCC.
Most of these materials possess some form of physical similarities to MCC,
such as very poor water/alcohol solubility. However, many of these excipients lack the
binding ability of MCC and necessitate the inclusion of binders to the formulation
before pellets of good quality could be successfully formed. Furthermore, when these
22
… INTRODUCTION
excipients were used, the quality of their pellets was often reported to be inferior to
those prepared with MCC, in spite of the efforts expended in optimization and process
control.
From the findings from various researchers, it appeared that a superior
spheronization aid must possess the following attributes in order to produce pellets of
comparable or even higher quality as those prepared using MCC. These desirable
attributes are: a) insolubility in the moistening liquid used or water insolubility since
water was most commonly used as moistening liquid; b) large water absorption and
retention capacity (liquid repository) to achieve an optimal rheological condition for
extrusion and spheronization; c) sufficient binding properties; d) sufficiently large
surface area for interaction with water and the constituent ingredients present in the
formulation, and e) ability to modify drug release.
D1.2.3 Additives
A wide range of materials has been investigated as additives to improve ease of
processing, physical properties of the final pellets or for modifying the drug release
profile (sustained release or fast release). For example, the incorporation of a binder
could help the formation of pellets with high drug levels (Funck et al., 1991). Binders
evaluated include carbomer, sodium carboxymeththylcellulose,
hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone and pregelatinized
starch. The binder (2%) together with MCC (18%) could produce pellets with 80%
drug (anhydrous theophylline) loading. Pellets formed had lower friability. Drug
dissolution profiles were not dramatically affected by the low binder levels. However,
pellet behavior during dissolution varied with the binder selected. Pellets with starch,
23
… INTRODUCTION
polyvinylpyrrolidone and sodium carboxymeththylcellulose disintegrated as did the
control (MCC and drug only).
MCC products containing sodium carboxymethylcellulose were found to be
particularly useful in preparing high dose pellets (Hileman et al., 1993a). Avicel PH-
101 appeared to be an ideal matrix material for the preparation of pellets with low drug
loading while Avicel RC 581 seemed more applicable for preparing pellets with high
drug dose by improving binding properties and plasticity (Ghali et al., 1989; Elbers et
al., 1992). Hydrophilic polymers such as sodium carboxymethylcellulose,
hydroxypropylmethyl cellulose, hydroxypropyl cellulose and polyvinylpyrrolidone
worked as adhesive binder in association with MCC to improve pellet yield and
sphericity (Law and Deasy, 1998). They also help make the process more tolerant to
minor alterations in the two key variables: moisture content and spheronizer speed.
Hydroxypropyl cellulose and polyvinylpyrrolidone were the most satisfactory among
the polymers examined in this study because of the lower adhesive strength favoring
good yields of highly spherical pellets. Avicel 955 containing 95% MCC and 5%
methylcellulose, aided ease of spheronization, giving acceptable yields of good pellets
with high drug loading of 70% (Gouldson and Deasy, 1997). Avicel 955 was more
tolerant to minor alterations in level of hydration which improved the process
robustness. Among various silicates, kaolin, talc and veegum F provided improved
plasticity for the formation of pellets (Law and Deasy, 1997). They also worked as
cohesive binders by exerting capillary attraction, and affected pellet integrity, eased
extrusion-spheronization and delayed drug release.
Evidence showed that the presence of high levels of glyceryl monostearate
assisted the preparation of pellets when a drug that interacted with MCC and water was
included in the pellet formulation (Basit et al., 1999). Another study investigated the
24
… INTRODUCTION
performance of glyceryl monostearate added to a formulation containing MCC and
model drugs with various solubilities (Chatchawalsaisin et al., 2005). The presence of
glyceryl monostearate reduced the quantity of water required for the process to
function, which could be of benefit where the drug is sensitive to the level of water or
the quantity of heat energy required to evaporate the water. However, glyceryl
monostearate did not retard drug release. Surface active agents, e.g. sodium stearyl
fumarate worked well as additives in a formulation containing high drug level
(acetaminophen 70%) and MCC (Mesiha and Vallés, 1993). It enhanced extrudability
by greatly reducing heat generation and facilitating the exit of the formed wet mass
from the extruder head. It also produced smooth extrudates with a low incidence of
surface defects (shark-skinning) and suitable pellets (Harrison et al., 1985a-b). Wetting
agent such as sodium lauryl sulphate improved sphericity but reduced pellet yield by
favoring agglomeration (Law and Deasy, 1997).
Weak bases and weak acids were examined in the formulation of 20% MCC,
20% trial excipients (weak bases or weak acids) and 60% lactose (Law and Deasy,
1997). Control pellets were prepared with 20% MCC and 80% lactose. Weak bases
such as sodium bicarbonate and weak acids such as fumaric acid aided spheronization
resulting in higher pellet sphericity. The yield of pellets made from formulation
containing fumaric acid was less sensitive to small variations in water content,
indicating a better process robustness. However, citric acid and tartaric acid promoted
unwanted formation of over-sized agglomeration, and the resultant pellets possessed
low sphericity. Collectively, the results showed that it was not possible to predict the
effect of different material on pellet yield and sphericity within the classes of
excipients (Law and Deasy, 1997).
25
… INTRODUCTION
pH modifiers (acids, buffer, salt) were also evaluated in another study
(Bianchini et al., 1992). Basic formula containing d-indobufen, MCC and lactose
(55:30:15 w/w) was used as the reference. Fumaric, tartaric and citric acids and sodium
citrate substituted the soluble filler (lactose). The pH modifiers affected the
microenvironment of drug molecules giving rise to different release profile patterns.
The incorporation of rapidly dissolving salt (sodium citrate) resulted in less
homogeneous pellet growth with a wider size distribution. Eudragit and Aquacoat are
available commercially in liquid form and contain acrylic resin and ethylcellulose
respectively. Acrylic resin (Eudragit RS 30D:RL 30D 50%:50% w/w) or ethylcellulose
(Aquacoat ECD30) was added in the fumaric acid formulation as granulation liquid.
Incorporation of insoluble polymers brought about a homogeneous matrix system that
produced prolonged drug release.
Hydrophobic waxy substances such as hydrogenated caster oil and Precirol
ATO5 improved pellet sphericity but reduced yield by favoring agglomeration (Law
and Deasy, 1997). Wax such as spermaceti, glyceryl palmitostearate, castor wax and
beeswax were included to slow down the release of water soluble drug
chlorpheniramine maleate (Ghali et al., 1989). However, the finished pellets must be
subjected to thermal treatment above the melting point of the waxy material to achieve
this controlled drug release. The melting and resolidification of these waxes due to the
thermal treatment resulted in a redistribution of the wax in the pellets and a possible
change in the pore sizes within the pellets. Inclusion of polyethylene glycols had been
used to enhance drug release (Vervaet et al., 1994). However, the presence of release
modifying agents needs to be considered and evaluated if these agents interfere with
the production process.
26
… INTRODUCTION
Low-substituted hydroxypropylcelluloses are insoluble in both water and
alcohols but swell in water (Kleinebudde, 1993). Low-substituted
hydroxypropylcelluloses were used to produce pellets by acting as a filler instead of
totally substituting MCC to work as a pelletization aid. In comparison to MCC, a
larger amount of water was required for making pellets. The optimal working range of
water was broader with the addition of low-substituted hydroxypropylcelluloses than
that of MCC, indicating a lower sensitivity to moisture content. Pellet quality in terms
of shape was inferior as reflected by higher aspect ratio and lower sphericity values.
Pellets prepared using low-substituted hydroxypropylcelluloses swelled and softened
without disintegration during dissolution, resulting in a faster dissolution of
acetaminophen. Pellets made with low-substituted hydroxypropylcelluloses were more
porous. Low-substituted hydroxypropylcelluloses with smaller particle size improved
pellet sphericity and were more useful as a spheronization aid.
Chitosan and MCC pellets were prepared with MCC at various contents in the
formulation (Steckel and Mindermann-Nogly, 2004). With an increasing amount of
chitosan in the powder mixture, it was necessary to raise the quantity of granulation
liquid to obtain pellets with good sphericity, tight size distribution, low abrasion and
adequate tensile strength. The mass fraction of chitosan within the pellets could be
increased to 100% by using diluted acetic acid for the granulation step. The application
of chitosan as a binder in the production of pellets was investigated by Santos et al.
(2002). Polyvinylpyrrolidone was included as second binder to impart consistency of
the wet masses thus improving pellet yield. The use of chitosan enhanced pellet
strength and produced pellets with acceptable physical characteristics. Pellet density
decreased with an increase of chitosan content in the formulation. Increased chitosan
load resulted in pellets of lower porosity values. This was attributed to the binding
27
… INTRODUCTION
capacity of chitosan leading to more compacted structures. Pellet surfaces also became
rougher as the chitosan load increased. Chitosan was also used to prepare pellets in
combination with Avicel RC-591 (Goskonda and Upadrashta, 1993). The success of
using Avicel RC-591 was attributed to the increased binding ability brought about by
the presence of sodium carboxymethylcellulose (~11%) since the attempt of
combining Avicel PH-101 and chitosan failed to make pellets. Incorporation of higher
viscosity grades of chitosan yielded pellets with decreased pellet sphericity, increased
surface roughness and slower release characteristics when acetaminophen was used as
the model drug. Pellet density decreased with an increase in chitosan content in the
formulation. Dissolution medium affected drug release from chitosan containing
pellets due to the swelling nature of chitosan in acidic media. In water, pellets made of
chitosan exhibited gel-like structure and disintegrated.
D1.2.4 Moistening liquid
Water functions as a moistening and binding agent in the wet massing stage,
acts as a lubricant and plasticizer during the extrusion process, imparting plasticity
during spheronization. It affects the quality of extrudates and their ability to
spheronize. The amount of water was important to the process and the quality of
pellets produced (Vervaet et al., 1995). Water/ethanol mixtures have also been used as
the moistening liquid (Goodhart et al., 1973; Lindberg et al., 1988b; Millili and
Schwartz, 1990; Elbers et al., 1992). Strongly bonded pellets were formed with water
while pellet strength decreased with an increase in the alcoholic content of
water/ethanol mixtures.
28
… INTRODUCTION
D1.2.5 Particle size of filler
Different levels of drug loading require filler/diluent to be added to the
formulation to form the required bulk. The filler could have significant influences on
drug release and can be particularly important when the drug used is poorly soluble in
water (Erikäinen and Lindqvist, 1991; Blanqué et al., 1995). The particle size of the
filler had profound influence on the extrusion characteristics of the wet mass during
processing and final pellet quality (Fielden et al., 1989, 1992b, 1993).
Lactose is commonly used as filler in extrusion spheronization due to its water
solubility and wide availability. Larger lactose particle size was found to have reduced
water requirement to produce pellets (Fielden et al., 1993). There is an inter-
relationship existing between particle size and specific surface area. Sufficient surface
wetting and bonding must be established between particles. Particle size and, hence,
particle surface area determined the amount of moistening liquid required to some
extent.
In another study, variation in the particle size of the lactose used also affected
the size of pellets formed (Wan et al., 1993). A linear relationship was established
between pellet mass median diameter and amount of water used for spheronization
within the range of amount of water investigated using a small laboratory spheronizer.
It was found that larger lactose particle sizes required less water to form pellets with
equivalent mean sizes.
D1.3 Process variables
Process variables in extrusion spheronization may be mainly classified as
extrusion and spheronization variables according to the process steps (Woodruff and
29
… INTRODUCTION
Nuessle, 1972; Malinowski and Smith, 1975; Chariot, et al., 1987; Lovgren et al.,
1989; Ku et al., 1993; Ghebre-Sellassie and Knoch, 1995; Vervaet et al., 1995).
Extrusion speed had been widely studied and the findings were not always
consistent due to the various extruder designs and formulations used. Extrusion rate
effect was not significant (Hasznos et al., 1992) but was found to be related to steady
state flow, passage time and mean residence time (Lindberg et al., 1988a; Kleinebudde
and Lindner, 1993). The extrusion temperature rose following an increase in extrusion
speed (Malinowski and Smith, 1975) but was not considerably affected by extrusion
speed in another study (Kleinebudde and Lindner, 1993). Higher extrusion speeds
caused the occurrence of extrudate surface defects, such as roughness and shark-
skinning, and further affected pellet quality (Gamlen and Eardley, 1986).
The effect of extrusion screen was attributed to the screen size and thickness or
die length (Vervaet et al., 1995). Generally, pellet size was affected by the screen
thickness (die length) and diameter of the screen orifices (Hellén et al., 1992b; 1993a-
b). The cross-sectional area of extrudates was governed by the diameter of the screen
orifices. A small length of the orifice to diameter has been associated with surface
defects on extrudates. An increase in the length usually gave longer, smoother and
denser extrudates, which tended to produce pellets with larger size.
Spheronization speed and residence time play very important roles on pellet
characteristics (Vervaet et al., 1995). In general, higher speeds and longer residence
times tended to increase sphericity and mean size, decrease the amount of fines and
enhance densification. The effect of spheronization load was attributed to contact
between particles themselves and/or that between particles and frictional plate
(Vervaet et al., 1995). More highly spherical pellets may be obtained relatively quickly
30
… INTRODUCTION
with an ideal load when inter-particle contacts and particle-plate contacts were
optimal.
D2 Rotary processing
Another more recent method for producing spherical pellet is rotary processing
which is a one-pot wet spheronization process. The whole cycle of wet spheronization,
drying, and, if desired, coating, can be performed in one closed system (Gajdos, 1984;
Gamlen, 1985; Ghebre-Sellassie et al., 1985; Goodhart, 1989; Robinson and
Hollenbeck, 1991; Niskanen et al., 1990a-b; Niskanen, 1992; Bechard and Leroux,
1992; Parikh et al., 1997; Vecchio et al., 1998).
D2.1 Equipment used
Centrifugal granulator, rotary fluidized bed granulator, rotary fluid bed, rotary
processor and rotor granulator are some of the terms used to describe the equipment
for rotary processing (Holm et al., 1996; Holm, 1996a-b; Vuppala et al., 1997; Rashid
et al., 1998, 1999, 2000, 2001). The rotary processor was modified from the
conventional fluidized bed granulator (Parikh et al., 1997). The basic design of the
equipment includes an air handling system, frictional plate, product chamber,
extension chamber and liquid spray system. There are three better known
manufacturers of rotary processors: GEA-Aeromatic, Glatt Air Technique and
Vector/Freund Corporation (Li et al., 1988). The basic design of these units contains
some different features. The prototype was first developed in the 1970s (Goodhart,
1989). Progressive changes and modifications to the basic design resulted in the rotor
granulator (Glatt), roto-processor (Aeromatic), spir-a-flow (Freund) and centrifugal
granulator (Freund) (Goodhart, 1989). For some designs, drying may not be possible
31
… INTRODUCTION
since the centrifugal-granulators were not enclosed in a fluidized bed system (Nesbitt,
1994). The width of the gap between the frictional plate and chamber wall and the
height of the frictional plate may be adjusted in some models to provide better control
of the air velocity without involving changes in the air volume.
The rotary processor may be used to produce spherical particles via several
processing techniques such as powder layering, solution layering, wet spheronization
as well as coating. In recent years, there have been comparatively more intensive
rotary processing studies on wet spheronization than on powder layering techniques.
Wet spheronization by rotary processing consists basically of three consecutive stages:
liquid addition, tumbling and drying (Figure 6) (Liew et al., 1998). It involves the
conversion of a powder mix into pellets by the spraying of a moistening liquid onto the
powder mass while it moves in a coil-wreath shape or rope-like motion. During rotary
processing, three forces (centrifugal, gravitational and fluidizing) act on the product
from different directions. The centrifugal forces are generated from the revolution of
the frictional plate and tend to push material towards the wall of the processing
chamber at the periphery of the frictional plate (Ghebre-Sellassie and Knoch, 1995).
Incoming air from the gap between the frictional plate and wall aids the upward
movement of material. As the lift velocity exerted by the airflow above the gap
dissipates with distance, the material loses its upward momentum and cascades
downwards and inwards due to gravity force. The centrifugal force is a function of the
rotational speed of the plate while the vertical distance transversed by the particles in
the tumbling mass depends on gap air velocity and bulk volume of the powder mass.
The combined action of the three forces produces a rope-like tumbling motion of the
moistened powder mass on the frictional plate. A rapid turnover production rate is
responsible for the high product efficiency of the equipment.
32
LIQUID ADDTION TUMBLING DRYING
STAGE STAGE STAGE
Breakdown Agglomeration and Agglomeration and

Breakdown spheronization
Breakdow spheronization
MCC:lactose Moisture – Small primary Larger Larger Pellets
aggregates
powder mix quenched chunks aggregates aggregates
Figure 6. Schematic diagram representing proposed mechanism for pellet formation and growth during rotary processing.
… INTRODUCTION
33
… INTRODUCTION
The spray gun is located at the lower portion of the wall such that it is fully
immersed in the powder mass. With a tangential spray mode, spray droplets travel in a
tangential path concurrent to the motion of the material on the frictional plate.
Agglomeration proceeds with the addition of the atomized moistening liquid onto the
revolving material. Dense pellets of narrow size distributions can be prepared by rotary
processing (Leuenberger et al., 1990; Wan et al., 1994; 1995).
The rotary processor can be considered as a hybrid of a fluidized bed and a
spheronizer. There are two basic designs, single and double chamber systems (Figure
7). The single chamber processor is comparatively simpler in design. However, for
drying and coating to take place within a single chamber, the limited drying capacity of
the processor extends the processing time considerably, especially with coating
applications. Some of the single chamber processors have the motor housing separated
from the processor itself. The double chamber design is more complicated but offers
the flexibility of efficient pellet drying and coating. The rotary processor with a double
chamber design consists of an inner metal chamber housed inside a larger outer
chamber. The frictional plate resides within the inner chamber, with a narrow gap
between the frictional plate and inner chamber wall. A perforated metal ring encircles
the circumferential area separating the two chambers (Figure 7b). Fluidizing air may
be introduced through the outer chamber via perforations on the metal ring. Drying of
pellets after preparation may be effected by lifting the inner chamber pneumatically to
present a gap for pellets to move to the outer circumferential area to be dried by the
fluidizing air. The second chamber equipped the rotary processor with a highly
efficient fluidized bed drying capacity.
34
… INTRODUCTION
(a)
Nozzle Frictional plate
Gap air
(b)
Outer chamber
Inner chamber
Perforated metal
ring
Nozzle Frictional plate
Gap air
Fluidizing air
Figure 7. Schematic diagram of designs of rotary processors (a) single chamber; (b)
double chamber.
35
… INTRODUCTION
The frictional plate provides the centrifugal force which propels the pellets
towards the wall of the processing chamber and kinetic force for material movement.
The uniqueness of the rotary processor lies mainly with the frictional plate. In the
absence of specialized tools for mixing and breakdown of agglomerates, material
movement in the processor relies largely on the forces set up by the frictional plate to
bring about liquid distribution and mixing during the liquid addition stage in pellet
production.
The surface of the frictional plate may be specially designed to meet specific
applications. In cases when the rotary processor is used for powder layering with non-
pareil seeds or for coating with core pellets, frictional plates used are those with
smoother surfaces or completely smooth plates instead of plates with protuberances.
The reason for the use of smooth surface plates is that non-pareil seeds and core pellets
generally have better flow properties than fine powders and are able to tumble in a
rope-like motion on plates with smooth surfaces. A smooth plate is also best for
avoiding material adhesion but it does not supply sufficient shear for effective
spheronization (Pišek et al., 2000). Hence, for making pellets, a frictional plate with
protuberances on the surface was required. Protuberances on the plate surface can
supply higher shear and come with different design and distributed in either cross-
hatch or radial pattern. Design of protuberance on the frictional plate is an important
consideration since these protuberances have a greater tendency to cause material
adhesion compared with a smooth plate.
Compared with extrusion spheronization, pellets made in the rotary processor
do not involve an extrusion stage. Therefore, the edges of these protuberances on the
frictional plate need not be angular in rotary processing. Studs with a smooth but
undulating design are desirable as the production of rotary processed pellets starts with
36
… INTRODUCTION
powder starting materials. Studs described as pyramidally shaped elevations (Figure
8a) or square studs with rounded edges positioned in a cross-hatch pattern on the
surface of the frictional plate have been used in pellet production by rotary processing
(Wan et al., 1994, 1995; Holm et al., 1996; Holm, 1996a; Liew et al., 1998, 2000).
With symmetrical studs on the plate, moist materials have a tendency to be trapped in
the valley between two adjacent studs and around the wake region of the stud as the
powder mass slides over.
The frictional plate can be made of stainless steel or polytetrafluoroethylene.
Polytetrafluoroethylene frictional plate produced higher pellet yields compared to
stainless steel frictional plate. However, a stainless steel frictional plate (Figure 8b)
allowed better heat conduction, and consequently gave rise to better drying compared
to a polytetrafluoroethylene frictional plate (Chukwumezie et al., 2002).
(a) Pyramidally shaped studs (b) Smooth surface plate

in cross-hatch pattern with wide spaced baffles
Figure 8. Depiction of frictional plates with different surface designs in rotary

processor.
37
… INTRODUCTION
Several investigators have described the use of polytetrafluoroethylene in high
shear mixers for reducing adhesion of moist material on granulator walls (Ritala et al.,
1988; Schæfer et al., 1990, 1992; Holm et al., 1993; Kristensen and Schæfer, 1993).
Polytetrafluoroethylene was also widely used in lining the product chamber wall to
reduce material adhesion during wet spheronization by rotary processing (Vertommen
et al., 1996a-b, 1997a-b, 1998a-b; Liew et al., 1998, 2000). Without
polytetrafluoroethylene lining, part of the moistened powder mass occasionally formed
stationary layers or cakes which periodically detach from the wall and return to the wet
mass undergoing spheronization. These cakes can become the cores for lump
formation (Liew et al., 1998, 2000). This phenomenon is undesirable as it gives rise to
product yields with wide size distributions. A removable polytetrafluoroethylene film
formed by applying polytetrafluoroethylene tape onto the chamber wall had the
disadvantage of dislodging from the wall after several runs when materials slipped
underneath and loosened the film. A permanent polytetrafluoroethylene coating is thus
preferred when compared to an applied-on tape.
The polytetrafluoroethylene lining influenced the quality of pellets produced
using starting materials of different particle sizes (Liew et al., 1998). The effect of the
polytetrafluoroethylene lining was found marginal for formulations containing lactose
200 mesh. For the coarser 100 mesh lactose, larger pellets were formed at equivalent
moistening levels when the chamber wall was lined with polytetrafluoroethylene tape.
The pellets made from MCC and 100 mesh lactose agglomerates are more fragile than
those made from MCC and 200 mesh lactose. With the softer, low friction and non-
stick properties of the polytetrafluoroethylene lining, pellets made of MCC and lactose
100 mesh were less likely to fragment on collision impact with the chamber surface
and thus were able to grow to a larger mean size.
38
… INTRODUCTION
An agitator blade may be added to a rotary processor to exploit the combined
advantages of high shear mixing and fluidization techniques (Watano et al., 1991,
1992, 1994a-c). The addition of an agitator blade introduces a tumbling and
compacting action to the conventional fluid-bed system. This facilitates the production
of pellets of higher densities due to an increase in the magnitude of shear forces
involved and can also prevent lump formation (Li et al., 1988). Two baffles were
installed to ensure that the powder mass traveled in a tumbling rope-like motion on the
frictional plate (Vecchio et al., 1994; Vertommen et al., 1996a, 1997a). The first baffle
directed the upper part of the powder mass downward to the frictional plate and inward
toward the center of the inner chamber, thus preventing the division of wetted powder
mass into two parts moving at different speeds. The second baffle guided the material
toward the center of the inner bowl. The baffles, together with polytetrafluoroethylene
lining of the inner wall, ensured a coil-wreath shaped movement of the moist mass in
the inner bowl. The idea of using a chopper to prevent localized over-wetting and to
facilitate breakdown of large agglomerates into smaller fragments has been
investigated. The chopper was found to have no significant influence on mean size,
size distribution and amount of agglomerates. The optimal spiral, rope-like movement
of the moistened mass ensured the orderly movement and spread of moistening liquid
over the powder mass, making the use of a chopper superfluous (Vertommen et al.,
1996a).
D2.2 Formulation and process variables
Rotary processing shares many similarities with fluid-bed granulation and with
the spheronization stage of the extrusion spheronization process. Formulation and
processing variables which influenced fluid-bed granulation and spheronization also
39
… INTRODUCTION
affected the process and pellet quality in rotary processing (Gajdos, 1984; Robinson
and Hollenbeck, 1991; Vecchio et al., 1994; Vertommen and Kinger, 1994; Ghebre-
Sellassie and Knoch, 1995; Heng et al., 1996; Holm et al., 1996; Holm, 1996a-b;
Vertommen et al., 1997a-b). Formulation variables in rotary processing consist of type
and content of MCC, type and content of moistening liquid and lactose particle size
could affect the spheronization process and pellet quality. Process variables such as
material loading methods, speed of frictional plate, spheronization time, moistening
liquid addition rate, atomizing and gap air pressures and load size also could influence
the process and end product quality.
D2.2.1 Type and content of MCC
Rotary processing was found to be affected by formulation variables such as
MCC type and content (Vecchio et al., 1994; Heng et al., 1996; Holm et al., 1996;
Vertommen et al, 1997a-b). MCC can be used with or without additional binding
agents. It is available in various powdered and colloidal grades from several suppliers.
Among all types of MCC supplied, Avicel PH 101 is the most commonly used grade
(Watano et al., 1991; Vecchio et al., 1994; Wan et al., 1994, 1995; Vertommen 1996b,
1997b, 1998a-b; Liew et al., 1998, 2000; Vecchio et al., 1998; Pišek et al., 2000, 2001;
Kristensen et al., 2000a, 2000b. Avicel RC-581 and CL-611 grades had been used for
producing pellets but no differences in mean size and size distribution of pellets were
seen between grades (Chukwumezie et al., 2002). Another grade of MCC used for
producing pellets in rotary processing was Emcocel 50M (Heng et al., 1996). Three
grades of MCC were used to prepare theophylline pellets and the effects of differences
of MCC on the formation of pellets and the effects on pellet quality were investigated
(Sienkiewicz et al., 1997). The pellets were characterized by size, density, friability,
40
… INTRODUCTION
drug content and shape. Only minor differences were seen during processing. Avicel
PH 200 was reported to be slightly superior in its ability to successfully form
theophylline pellets (83% success rate) compared to Avicel PH 101 (75% success
rate), and PH 200 was about equal to PH 102 (Sienkiewicz et al., 1997). Holm found
there was no difference in porosities of pellets prepared using different MCC grades
(Holm, 1996b).
The MCC content had the most significant impact on spheronization efficiency.
The amount of MCC required depended on the other components in the formulation
(Holm et al., 1996). The working range of MCC content can be as low as 10% of the
total starting materials (Holm et al., 1996; Sienkiewicz et al., 1997). However, a
controllable spheronization process for producing pellets with consistent and
acceptable characteristics required the content of MCC to be at least 20% (w/w) of the
starting materials (Kristensen et al., 2000b). A decrease in the proportion of MCC
resulted in higher deposition and adhesion of moistened material, formation of large
irregularly shaped lumps and augmentation of electrostatic charges causing material to
stick on the product container (Vecchio et al., 1994). The amount of MCC present was
found to influence the mean size, size distribution, friability and shape of pellets
produced by rotary processing (Robinson and Hollenbeck, 1991; Vertommen et al.,
1997a-b; Chukwumezie et al., 2002). Increased MCC content led to a narrowing of
pellet size distribution, increased mean size and sphericity and decreased pellet
friability (Holm et al., 1996; Holm, 1996b). However, porosity of the final product was
not influenced by the amount of MCC in the formulation (Holm, 1996b). MCC content
was also found to play the most dominant role in determining the overall dissolution
rate of a very slightly water soluble drug administered in low doses (Vertommen et al.,
1996b).
41
… INTRODUCTION
D2.2.2 Type and content of moistening liquid
The most critical and influential variable for pellet growth was the amount of
liquid binder present for wet spheronization (Vervaet et al., 1995). Some studies have
demonstrated the importance of the amount of moistening liquid in controlling size,
size distribution, shape, friability and other physical characteristics of pellets produced
by rotary processing (Wan et al., 1993; Holm et al., 1996; Heng et al., 1996;
Vertommen et al., 1996b, 1997a; Chukwumezie et al., 2002). Water content can be
calculated based on a dry mixture (Watano et al., 1991; Wan et al., 1994, 1995; Liew
et al., 1998, 2000; Chukwumezie et al., 2002) or water/MCC ratio since MCC was
used as the spheronization aid in many studies (Vertommen et al., 1996b, 1997b,
1998a-b). With an increase in the amount of moistening liquid, there was an increase
in the liquid saturation of pellets. More moisture was available for the formation of
bonds between particles. The presence of surface moisture improved particle surface
plasticity and aided the deformation and coalescence of particles during collisions.
Consequently, the moistened particles agglomerate and consolidate to form pellets.
Surface plasticity enhanced deformation, assisting the rounding of pellets (Ghebre-
Sellassie, 1989b; Wan et al., 1994). With the increase in water-MCC ratio, pellet mean
size increased and pellets produced were less friable but of wider size distribution
(Vertommen et al., 1997a-b).
The moisture content of wet mass should be precisely controlled within very
narrow limits to ensure the production of pellets of appropriate size and size
distribution. The amount of moistening liquid added should reach the required level so
that pellets with a suitable mean size can be obtained (Heng et al., 1996). If an
excessively high level of moistening liquid was added, a large amount of undesired
42
… INTRODUCTION
oversize lumps was produced due to localized over-wetting and a less well controlled
agglomeration process. The products had a skewed size distribution. The quantity of
water to be added should take into consideration the moisture contents of the starting
materials which depended on storage conditions prior to usage. During the water
addition phase, a small proportion of the added water will be removed by the gap and
atomization air streams.
Water was the most commonly used moistening liquid for formulations
containing MCC as a spheronization aid in rotary processing (Wan et al., 1994, 1995;
Heng et al., 1996; Liew et al., 1998, 2000). Binders are usually not incorporated as the
addition of MCC provides sufficient adhesive strength for forming agglomerates.
However, researchers had attempted to incorporate various binders in the moistening
liquid in addition to MCC. Aqueous polymer solutions/suspensions containing
Eudragit NE 30D (Pišek et al., 2000), hydroxypropylmethyl cellulose (Chukwumezie
et al., 2002), polyvinylpyrrolidone (Robinsen and Hollenbeck, 1991) and gelatin
(Robinsen and Hollenbeck, 1991) had been used in the moistening liquid.
Polyvinylpyrrolidone was reported to produce pellets of higher sphericity when
compared with gelatin (Robinsen and Hollenbeck, 1991). Hydroxypropylmethyl
cellulose as a binder improved product yield (Chukwumezie et al., 2002).
D2.2.3 Particle size of filler
Generally, fillers were incorporated into the pellets although some formulations
only contained model drug and MCC (Sienkiewicz et al., 1997; Pišek et al., 2000).
Various fillers of different water solubilities were tested for their suitability to be used
in rotary processing. Lactose was shown to be more suitable as a substitute for a
portion of MCC than mannitol or calcium carbonate (Vecchio et al., 1994) to prepare
43
… INTRODUCTION
pellets in a rotary processor. The formulation containing calcium carbonate produced a
wet sticky mass whilst mannitol gave rise to larger granules with a more evident
development of electrostatic charges. The solubility of lactose in the liquid binder
helped in pellet densification and lactose based pellets were less porous than those
prepared with dicalcium phosphate (Holm, 1996a).
The particle size of filler is influential (Holm et al., 1996; Sienkiewicz et al.,
1997; Liew et al., 1998) in rotary processing. The ability of very fine particle to assist
the production of pellets is low due to the strong adhesion of micronized material onto
the interior surfaces of the equipment (Holm et al., 1996). Resultant pellets possessed
wider size distribution and increased amount of lumps. The lowest level of MCC could
be 10% to achieve pelletization with coarser filler. However, for the finest grades of
lactose and dicalcium phosphate, an MCC content of 20% was required in order to
obtain a controllable pelletization process. The pellets formed with coarser lactose 100
mesh particles were inherently weaker in comparison to those formed with finer
lactose 200 mesh particles (Liew et al., 1998). With the same amount of water added,
coarser lactose resulted in larger pellet size and narrower size distribution.
D2.2.4 Material loading methods
Mixing of powder materials often constitutes the first processing stage in the
preparation of solid dosage forms for ensuring a uniform distribution of the constituent
ingredients, facilitating subsequent processing such as pelletization. In the studies
reported thus far, moistening liquid was usually sprayed onto the pre-mixed powder
materials in rotary processor. The starting materials can be pre-mixed in a separate
mixer (Vertommen et al., 1997a; Liew et al., 1998, 2000; Korakianiti et al., 2000) or
mixed manually (Robinson, 1991; Vecchio et al., 1994; Kristensen et al., 2000a,
44
… INTRODUCTION
2000b). The powder blend was then loaded into the rotary processor for making
pellets. The starting material can also be pre-mixed in the rotary processor itself prior
to liquid addition step (Holm et al., 1996; Pišek et al., 2000, 2001). There was no study
showing that this pre-mixing step was required, however, it was generally applied.
D2.2.5 Speed of frictional plate
The speed of the frictional plate can be kept constant during the whole process
run and the speed used affected pellet particle size (Robinsen and Hollenbeck, 1991;
Holm et al., 1996; Vertommen et al., 1996b, 1997a-b; Chukwumezie et al., 2002).
Some studies showed that pellet size increased with an increase in rotating speed (Liew
et al., 2000) but contrary results were also reported (Korakianiti et al., 2000). A
possible explanation for these contradictory findings was attributed to differences in
methods and/or equipment used. For successful spheronization, there has to be a
balance between the agglomeration of powder particles and the break down of large
oversize agglomerates or lumps. Strong centrifugal forces can supply sufficient energy
into the system to bring about coalescence. These forces can concurrently contribute to
size reduction of large opportunistic quenched aggregates brought about by attrition or
breakage. A low-high-low speed variation protocol was developed to produce pellets
with a narrow size distribution and with a minimum amount of oversize particles in the
total product yield (Liew et al., 2000).
Higher speeds were reported to give rise to pellets of narrower size
distributions (Holm et al., 1996), slightly wider size distributions (Vertommen et al.,
1997a), higher sphericities (Vertommen et al., 1997b), lower friabilities (Vertommen
et al., 1997a), smoother surfaces (Vertommen et al., 1997b), reduced pore volumes
45
… INTRODUCTION
(Vertommen et al., 1998a), higher crushing strengths, and greater total pellet yields
(but lower usable yields) (Robinson and Hollenbeck, 1991). When a high frictional
plate speed was used, improved liquid addition reduced lump formation, and thus a
narrow size distribution pellet batch can be produced. In cases where the resultant
pellets were more fragile, high frictional plate speed resulted in increased breakdown
of the pellets and wider size distributions resulted. Lumps were formed at the low
rotating speed during the wet massing phase as wetted material adhered to plate due to
lower centrifugal forces and less impact of the mass (Holm et al., 1996). Rotating
speed was also found to have a major influence on the overall dissolution rate since
overall dissolution rate was linked to pellet size (Vertommen et al., 1996b).
An inter-relationship between the surface of the frictional plate and rotating
speed had also been observed (Korakianiti et al., 2000). With a textured surfaced
frictional plate, an increase in rotational speed produced pellets of smaller size, lower
sphericity and rougher surfaces. Larger, more spherical and smooth surfaced pellets
were produced with an increase in speed when a smooth surfaced frictional plate with
spaced baffles was used.
D2.2.6 Spheronization time
Pellet size was found to be related to spheronization time (Robinson and
Hollenbeck, 1991; Holm et al., 1996; Vertommen et al., 1997a; Liew et al., 2000;
Chukwumezie et al., 2002). Extended spheronization time resulted in pellets with
narrower size distribution (Holm et al., 1996; Vertommen et al., 1997a), higher
sphericity shape (Vertommen et al., 1997a-b), lower friability (Vertommen et al.,
1997a), smoother surface (Vertommen et al., 1997b), reduction in pore volume
46
… INTRODUCTION
(Vertommen et al., 1998a) and higher crushing strength (Robinson and Hollenbeck,
1991).
D2.2.7 Moistening liquid addition rate
It was found that the most critical and influential variable for granule growth
was the amount of moistening liquid present after liquid addition (Robinson and
Hollenbeck, 1991; Vertommen et al., 1996b). A higher binder addition rate increased
pellet crushing strength and “usable” yield (0.25 – 1 mm fraction). It was reported that
the water addition rate had a considerable influence on the size and size distribution of
pellets prepared using a rotary processor (Vecchio et al., 1994; Vertommen et al.,
1997a). Pellet size was found to increase with increased spray rate when atomizing
pressure and amount of moistening liquid delivered were kept constant (Vecchio et al.,
1994; Wan et al., 1995; Holm et al., 1996). If the level of agitation forces in the rotary
processor was insufficient for ensuring a spiral, rope-like material movement, lower
water addition rates enabled sufficient time for adequate spreading of the moistening
liquid (Vertommen et al., 1996a). Inadequate spreading of the water added influenced
the pellet formation process. Regions with excessive amounts of water contributed to
the formation of larger agglomerates. In addition, the influence of water addition rate
on pellet size was compounded by differences in the amount of water removed by the
air streams. Increasing the water addition rate decreased the process time, and less
water would be removed by gap air. Consequently, more water remained in the
formulation at the end of the water addition phase (Wan et al., 1994; Vertommen et al.,
1998b). The amount of water removed from the agglomerating powder mass by the
gap air and nozzle atomizing air can be estimated from the flow rate, temperature and
relative humidity measurements of the air stream and moisture content of the final
47
… INTRODUCTION
product. With a fixed volume of moistening liquid sufficient for spheronization, larger
pellets were produced with increasing liquid addition rates (Wan et al., 1995). With a
constant atomizing air pressure, the atomized droplets became larger and had a wider
size range when liquid addition rate was increased. The amount of oversize
agglomerates was increased and a less uniformly sized yield may be produced with the
use of relatively higher spray rate. However, changes in spray droplet size and size
distribution attributed to variations in water addition rate may be offset by other pellet
parameters. As such, the effect of spray rate had also been found to be comparatively
minor and overshadowed by the prevalent centrifugal forces (Heng et al., 1996).
D2.2.8 Atomizing and gap air pressures
Higher atomizing pressures produced relatively smaller droplets with the same
spray addition rate and the range of droplet sizes tended to be narrower (Wan et al.,
1995). Changes in spray droplet size and atomizing pressure did not appear to greatly
affect mean pellet size (Wan et al., 1995). However, the presence of an atomizing
pressure was necessary and it should be maintained at an optimal level sufficient for
the even dispersion of the moistening liquid to reduce both localized over-wetting
during spheronization and the amount of oversize particles formed. Excessively high
pressures could disrupt material rope-like flow pattern. Small amounts of the material
could also be entrained by an atomizing air if the pressure was too high (Pišek et al.,
2000). At the start of a spheronization run, a positive gap air pressure is required to
prevent powder slippage between the frictional plate and wall of the production
chamber. Higher gap air pressure was reported to result in a greater rate of moisture
loss, increased attrition of pellets and the production of smaller pellets (Wan et al.,
1994; Vertommen et al., 1998b).
48
… INTRODUCTION
D2.2.9 Load size
Depending on the equipment type, various load sizes, from 0.5 to 10 kg, have
been used for pellet production (Korakianiti et al., 2000; Pišek et al., 2000;
Chukwumezie et al., 2002; Kristensen et al., 2000b). For example, in one study, 12-
inch and 19-inch roto inserts were used for 1 kg and 5 or 10 kg loads of starting
materials, respectively (Chukwumezie et al., 2002). An increase in load size from 0.5
to 1 kg improved size distribution, yield, bulk density and shape of pellets produced in
a 3.5 liter rotary processor (Robinson and Hollenbeck, 1991).
D2.2.10 End point monitoring
Identification of the spheronization end point in rotary processing appears to be
critical to the success of the operation (Robinson and Hollenbeck, 1991; Holm et al.,
2001). The moisture content of the product could be controlled in several ways. The
first method attempted was to carefully control all factors influencing the rate of
evaporation during liquid addition, such as product temperature, air flow to process
unit, humidity of inlet air, and moisture content of starting materials (Holm et al.,
1996). The moisture removed by the atomizing air, gap air and fluidizing air should be
considered (Wan et al., 1994). The second method studied involved monitoring the
moisture content with the help of an infrared moisture sensor (Watano et al., 1991).
Another method proposed for determining the end point of wet spheronization in a
rotary process was by measuring the torque and terminating liquid addition once a
certain increase in torque value was obtained (Kristensen et al., 2000a, 2000b). The use
of torque increase measurements was found to be suitable for predicting the stage of
pellet production in rotary processing because the water content of the mass was
49
… INTRODUCTION
reflected by the torque value. Variations in moisture content of the materials being
processed can be compensated for by adding an amount of liquid to reach a certain
level of torque. As torque measurements were found to be influenced by the speed of
the frictional plate and batch size, a correlation was reported between torque increase
and pellet size if other process variables were kept constant (Kristensen et al., 2000b).
Power consumption can also be used to monitor the end-point of liquid addition
(Holm, 1996b; Holm et al., 2001). The level of power consumption after liquid
addition correlated with the mean size of the final product.
The process of converting powder into highly spherical pellets in a single pot
processor is a very efficient and attractive pellet making method. However, for the
process of random opportunistic growth to be harnessed, stringent control in a
predictable manner of all critical variables is needed. When all formulation and
operational variables are well controlled, pellets of high quality can be produced. Of
the many variables, process variables such as the speed of frictional plate and rate of
addition of the moistening liquid can profoundly influence the process and quality of
the end product. The total volume of the moistening liquid added needed to be
precisely controlled, taking into account the moistening liquid lost to the gap air.
50
… OBJECTIVES
II. OBJECTIVES
Extrusion spheronization and rotary processing both possess the capability of
producing highly spherical pellets. Studies were conducted to explore the effects of
various equipment design, formulation and process variables on the processes and
quality of final products. The findings of this research have considerable industrial
relevance and could be used to better understand the science of agglomeration. There
were five major objectives in this study.
A. Influence of operational variables in rotary processing
Four independent variables, frictional plate speed during liquid addition stage,
water addition rate, amount of water added and frictional plate speed during tumbling
stage were studied using an orthogonal design to investigate their effects in rotary
processing. The objective was to identify important variables for better process control
and preparation of high quality pellets.
B. Effect of frictional plate design in rotary processing
The objective was to investigate new frictional plate designs by introducing
teardrop shaped studs arranged in radial pattern and of different stud dimension.
Teardrop shaped studs were smooth protuberances specially designed to examine their
potential for minimizing material adhesion.
C. Feasibility of eliminating pre-mixing in rotary processing
There were various protocols for loading starting material into the rotary
processor with/without pre-mixing. The objective was to examine the possibility of
eliminating the pre-mixing of starting materials to make rotary processing a truly one-
51
… OBJECTIVES
pot process. The effects of bulk powder loading methods were evaluated by varying
process and formulation variables.
D. Effect of lactose particle size in spheronization processes
The objective was to examine the effects of lactose particle size on the
preparation of pellets by rotary processing and extrusion spheronization. Three grades
of lactose (lactose 100M, 200M and 450M in decreasing order of mean particle size)
were investigated to evaluate process robustness and resultant pellet quality. The
mechanism of pellet formation was also elucidated in terms of packing with particles
of different dimensions.
E. Use of crospovidone as a new spheronization aid
The objective was to explore and demonstrate the functionality of cross-linked
polyvinylpyrrolidone (crospovidone) as a spheronization aid and a promising
alternative to MCC in extrusion spheronization. Crospovidone was used to prepare
pellets without involving MCC in the formulation and without additional binder.
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III. EXPERIMENTAL
A. Materials
The materials used were lactose α-monohydrate, microcrystalline cellulose
(MCC) and cross-linked polyvinylpyrrolidone (crospovidone). The materials were
characterized using the methods presented in Section B. They were used as supplied
for pellet production with distilled water as the moistening liquid.
A1 Lactose
Three grades of lactose α-monohydrate, lactose 100M (Pharmatose 100M),
lactose 200M (Pharmatose 200M) and lactose 450M (Pharmatose 450M) from DMV
International (De Melkindustrie Veghel, The Netherlands), were employed as the bulk
materials. The properties of the lactose grades are listed in Table 1.
Table 1. Physical properties of lactose grades used.
Lactose grade 100M 200M 450M
Mean particle size (µm) 155.7 ± 0.4 44.3 ± 0.5 21.7 ± 0.9
Span 1.1 ± 0.0 2.3 ± 0.0 2.4 ± 0.1
2
Specific surface area (m /g) 0.2 ± 0.1 0.5 ± 0.0 0.7 ± 0.0
Angle of repose (º) 38.6 ± 2.7 52.2 ± 3.4 63.8 ± 4.7
Angle of difference (º) 8.3 ± 0.9 14.0 ± 2.0 19.8 ± 1.3
*Mean value ± standard deviation
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A2 Microcrystalline cellulose
Microcrystalline cellulose (MCC) was used as the spheronization aid in most of
the studies. MCC is a purified, partially depolymerised cellulose obtained by acidic
hydrolysis of α-cellulose (Rowe et al., 2003). The MCC used in this study was Avicel
PH 101 (Asahi Chemical, Japan) with mean particle size of powder of 76.5±0.5 µm.
The bulk and tapped densities obtained were 0.31±0.003 g/ml and 0.43±0.003 g/ml
respectively.
A3 Crospovidone
Crospovidone is a synthetic water-insoluble cross-linked homopolymer of N-
vinyl-2-pyrrolidone (Rowe et al., 2003). It is available commercially in several particle
size grades. Crospovidone has been used as a superdisintegrant in solid dosage forms
at concentrations of 2–5% although the smallest particle size grade can also be used to
adsorb gases and toxins in the gastrointestinal tract. Three grades of crospovidone
(Polyplasdone XL, Polyplasdone XL-10 and Polyplasdone INF-10) from International
Specialty Products (USA) were characterized and evaluated for their use as
spheronization aids against a commonly used MCC grade, Avicel PH 101. The
properties of the three crospovidone grades are listed in Table 2.
Table 2. Physical properties of crospovidone powders.
Crospovidone grade XL XL-10 INF-10
Mean particle size (µm) 127.7 ± 8.1 31.3 ± 1.0 19.7 ± 0.2
Span 1.5 ± 0.1 1.7 ± 0.0 1.5 ± 0.1
Bulk density (g/ml) 0.26 ± 0.00 0.28 ± 0.01 0.30 ± 0.02
Tapped density (g/ml) 0.34 ± 0.00 0.43 ± 0.01 0.48 ± 0.02
Carr index (%) 32.5 ± 0.0 50.8 ± 0.8 63.3 ± 2.0
*Mean value ± standard deviation
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B. Physical characterization of starting materials
The methods employed for characterizing starting powder materials are
described below.
B1 Particle size and size distribution
The particle size and size distribution of the powder were determined using the
laser light diffracting particle size analyzer (LS230, Coulter Corporation, USA)
equipped with a dry powder feeder. All measurements were carried out in triplicate
and results averaged. The mean particle size and size distribution were characterized
by mean particle diameter and span respectively. Span was calculated according to the
equation below.
X 90 − X 10
Span = Equation (1)
X 50
where X10, X50 and X90 were the particle diameters at the 10, 50 and 90 percentiles of
the cumulative percent undersize plot, respectively.
B2 Specific surface area
Powder specific surface area was determined using a surface area and pore size
analyzer (Nova 4200e, Quantachrome Instrument, USA). It is based on the Brunauer-
Emmett-Teller (BET) method using nitrogen as the adsorbent gas.
1 1 C-1 P
= + × Equation (2)
W[(Po/P)-1] WmC WmC Po
where W is the weight of gas adsorbed at a relative pressure P/Po, Wm is the weight of
adsorbate constituting a monolayer of surface coverage, and C is BET constant which
is related to the energy of adsorption in the first adsorbed layer and consequently, its
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value is an indication of the magnitude of the adsorbent/adsorbate interactions. All
measurements were in triplicates and results averaged.
B3 Flowability
A powder tester (PT-N, Hosokawa Micron, Japan) was used to determine the
angles of repose and fall, which can indicate the flowability of powder. An appropriate
amount of powders was first passed through a 0.355 mm aperture size sieve and then
poured through a glass funnel in a controlled manner onto an 80 mm diameter
horizontal circular platform until a stable and consistent heap was formed. The angle
of repose was measured as the angle of the slope made with the horizontal powder
heap. Thereafter, a weight was lifted to the upper end of a pole and released three
times to give shocks to the heap. The slope angle of the collapsed heap was determined
as the angle of fall. The difference between the angle of repose and the angle of fall
was calculated and referred to as the angle of difference. All determinations were
carried out in triplicates.
B4 Moisture content
The moisture content of powder was determined with the loss of drying
method. The powder samples (5 g) were first spread in the glass container and dried at
105ºC for 3 h. The dried samples were then cooled in a desiccator under vacuum
overnight. The weights before and after drying were accurately determined. Four
replicates were carried out for each powder sample and results were averaged.
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B5 Bulk and tapped densities
A tapping apparatus (Stampfvolumeter, JEL, Germany) was used for this study.
The powder was sieved lightly into the graduated cylinder with an inner diameter of 28
cm and cut exactly to 100 ml. Excess powder was scraped off carefully with a spatula
and the weight of filled powder was determined. The cylinder with powder was tapped
until no further change in volume was observed. Bulk density (ρb) and tapped density
(ρt) were calculated from their initial and final volumes. Carr index was subsequently
derived according to the methods described previously (Carr, 1965). Five repeats were
carried out and the average value obtained.
ρt − ρb
Carr index = × 100% Equation (3)
ρt
C. Methods for preparing pellets
Pellets were prepared using two pelletization methods, rotary processing and
C1 Rotary processing
The multi-purpose system (MP-1, GEA-Aeromatic, UK) with the rotary
processor insert was used for the preparation of pellets (Figure 9). The rotary processor
has a double chamber design with polytetrafluoroethylene lining on the inner chamber
(Figure 10). A schematic diagram depicting pellet formation in the rotary processor
was presented in Figure 11.
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Air supply
Rotary
processor unit
Figure 9. Diagram of multi-purpose system (MP-1) with the rotary processor insert.
Inner chamber
Polytetrafluoroethylene
Lining
Outer chamber
Frictional plate
Figure 10. Diagram depicting the double chamber design of the rotary processor.
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Moisture
quenched chunks
Liquid addition stage

Agglomerates
Agglomerates
Tumbling stage
Pellets
Drying stage
Figure 11. Diagram of pellet formation in rotary processor.
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Starting materials containing MCC and lactose were first loaded onto the
frictional plate. Water addition and start of frictional plate rotation were carried out
simultaneously and it marked the beginning of the liquid addition stage. Water was
sprayed at a constant rate using a peristaltic pump (504U, Watson Marlow, UK) onto
the rotating powder through a nozzle (inner diameter 0.8 mm) at an atomizing pressure
of 1.2 bar. A gap air pressure of 1.5 bar was applied to prevent material loss through
the gap between the frictional plate and inner chamber wall. The speed of the frictional
plate was varied following a low-high-low speed variation protocol (Liew et al., 2000).
During the liquid addition stage, the frictional plate was rotated at 100 rpm (tip
speed of 86.4 m/min) initially for 20 s, and then increased to 520 rpm (tip speed of
449.3 m/min) and maintained for 2 min. After the powder was wetted, the frictional
plate speed was increased to 1045 rpm (tip speed of 902.8 m/min) until liquid addition
was completed. During the tumbling stage, the frictional plate was rotated for an
additional 20 min at 520 rpm before drying was carried out. The inlet air temperature
was set at 30°C during the liquid addition and tumbling stages, and increased to 60°C
during drying. The drying process was deemed as completed when a constant exhaust
air temperature was attained.
Some variables differed in the different rotary processing studies such as
frictional plate used, load size, method of bulk powder loading, amount of water added
and water addition rate. The parameter details for these variables will be described
subsequently under the relevant studies. Unless otherwise indicated, other parameters
for all the studies were the same as described above.
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C2 Extrusion spheronization
Preparation of MCC-lactose pellets or crospovidone-lactose pellets were
carried out using both small scale and large scale extrusion spheronization equipment.
C2.1 Small scale
Thirty grams of MCC-lactose or crospovidone-lactose blends were mixed by
geometric dilution. Water, calculated as a percentage of the total dry powder weight,
was sprayed into the powder blends and wet massed in a mortar for 10 min. The
moistened mass was manually extruded through a 1.0 mm aperture size mesh.
Spheronization was carried out in a spheronizer (120, Caleva, UK) fitted with a cross-
hatched patterned frictional plate of 120 mm diameter. Extrudates were spheronized at
the designated speeds and times (e.g. 5 min at 1500 rpm or tip speed of 565 m/min, for
MCC-lactose formulations and 5 min at 1250 rpm or tip speed of 471 m/min, for
crospovidone-lactose formulations). The pellets were then oven-dried at 60°C for 8 h.
C2.2 Large scale
MCC-lactose or crospovidone-lactose blends were used as starting materials.
One kg of the starting materials was mixed using a double cone mixer attached to a
main motor (AR 401, Erweka, Germany) for 30 min at 6 rpm. The powder mix was
transferred to a planetary mixer (Kenwood Major, UK). The required amount of water
was gradually added and mixed over 20 min. The resultant wetted mass was extruded
through a radial screw extruder (Nica E140, GEA-Aeromatic, UK) fitted with a screen
of 1 mm thickness and 1 mm circular dies. One kg of the extrudates was spheronized
in a spheronizer (Nica S320, GEA-Aeromatic, UK) with a 320 mm diameter cross-
hatch patterned frictional plate at the designated speeds and times. The spheronization
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speed for MCC-lactose material was 600 rpm (tip speed of 603 m/min). When
crospovidone-lactose was used, the spheronization speed was 410 rpm (tip speed of
412 m/min), 480 rpm (tip speed of 482 m/min) or 550 rpm (tip speed of 553 m/min)
depending on the setting of the experimental design in Section E5. Drying was carried
out at 60°C for 8 h.
D. Characterization of pellets
Pellet characteristics of mean size, size distribution, oversized fraction, yield,
shape, bulk and tapped densities, friability and porosity were characterized using the
methods as described as follows.
D1 Mean size, size distribution, oversized fraction, fines and yield
The recovered product from each run was subdivided into eight random
samples using a spinning riffler (PT, Retsch, Germany). A representative sample was
subjected to size analysis by sieving. A nest of sieves (Endecotts, U.K.) of aperture
sizes range of 0-2.8 mm (0.125 mm, 0.25 mm, 0.355 mm, 0.425 mm, 0.5 mm, 0.6 mm,
0.71 mm, 0.85 mm, 1 mm, 1.4 mm, 1.7 mm, 2 mm and 2.8 mm) was used to separate a
weighed amount of pellets into various size fractions. A sieve shaker (VS1000, Retsch,
Germany) vibrating at 1 mm amplitude for 15 min was used for separating the pellets
into the various size fractions.
Pellets retained on the 2.8 mm aperture size sieve were defined as the oversized
fraction. The fines fraction consisted of particles that passed through the 0.425 mm
aperture size sieve. The percentages of the recovered fractions, oversized fraction and
fines were calculated based on the total recovered product after sieving. Yield was
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defined as particles included in the fractions between 0.71 and 1.4 mm and the modal
class fraction referred to the size fraction with the highest weight of pellets.
The mean size and size distribution of pellets were described using mass
median diameter and span, respectively. Mass median diameter was defined as pellet
size corresponding to the 50th weight percentile mark on the cumulative percent
undersize percent plot. Span was calculated using the equation below.
X 90 − X 10
Span = Equation (4)
X 50
where the X90 and X10 values were the diameters corresponding to the 90th and 10th
weight percentile marks, respectively (Wan et al., 1994b; Wan et al., 1995).
D2 Shape
Unless otherwise stated, at least 100 pellets from each batch were randomly
selected from the modal fraction obtained by sieving for image analysis. The image
analyzer (PC Image 2.2, Foster Findlay Associates, U.K.) consisted of a computer
system connected to a video camera (SSC-M370CE, Sony, Japan) mounted on a
stereomicroscope (SZH, Olympus, Japan). Parameters that could be directly
determined from the digitized images of the pellets were area (A), perimeter (P), length
(L), breadth (B) and mean radius (re). To determine the length, the center of the area
was first found, then the furthest point on the object boundary from this center was
determined. After that, the furthest boundary point from this point was found. Breadth
was the projection of the object onto an axis perpendicular to the length.
Shape factors were derived from the directly measured parameters. Circularity,
aspect ratio and eR were three shape factors selected. Circularity values emphasized the
spherical shape of pellets while the elongation of pellets was described by the aspect
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ratio. For perfectly spherical pellet, these two shape descriptors would bear values of
unity. Another shape factor eR, which took into consideration both deviation of shape
from sphericity and surface irregularities was used to differentiate between more or
less elliptical particles (Podczeck and Newton, 1994, 1995; Podczeck et al., 1999). In
the equation for calculating eR, re was a mean radius determined from all the radii
measured from each of the boundary points to the center of the object. The value f was
a correction factor (Podczeck and Newton, 1995). There was no clear definition of
“round” pellets, however, it was generally agreed that pellets of aspect ratio lower than
1.1 and eR higher than 0.6 were taken as highly spherical (Santos et al., 2002; Bornhöft
et al., 2005).
4πA
Circularity = Equation (5)
P2
L
Aspect ratio = Equation (6)
B
2
2πre B
eR = − 1−   Equation (7)
Pf L
 B Equation (8)
f = 1.008 − 0.2311 − 
 L
D3 Bulk and tapped densities
Pellets were poured gently through a glass funnel into a graduated cylinder
with an inner diameter of 28 mm and cut exactly to 100 ml. Excess pellets were
removed using a spatula. The cylinder was then tapped for 600 times and the packed
volume of pellets was noted. Further tapping of 400 times was carried out with an
observation of the volume after each 100 times tapping to ensure that the pellets were
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tapped to a constant volume. The bulk density, tapped density and Carr index values
were obtained in triplicates.
D4 Friability
An accurately weighed amount of pellets, about 10 g, taken from the modal
class fraction of products was placed in a friability tester (TA20, Erweka, Germany)
and tumbled for 200 revolutions at 25 rpm. Twelve steel balls (diameter 6 mm,
weighing 0.884 g each) were included as attrition agents. After friability testing, the
pellets were sieved through sieves with 0.25, 0.355 and 0.5 mm aperture size
(Endecotts, UK). The friability of pellets was calculated as:
Wi − Wr
Friability = × 100% Equation (9)
Wi
where Wi was the initial weight of pellets before friability testing, and Wr was the total
weight of pellets retained above the three sieves after friability testing.
D5 Moisture content
The moisture was determined using the loss of drying method described
previously in Section B4. Pellet samples were collected after the tumbling stage in
rotary processing and after the spheronization stage in extrusion spheronization.
Extrudates produced in extrusion spheronization process were also tested for their
moisture content. The moisture content determinations were carried out for four
samples and results were averaged.
D6 Porosity
The intraparticulate pores of pellets were determined using mercury intrusion
porosimetry (9320, Micromeritics, USA) at a pressure range of 3–30000 psia (0.02-
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206.93MPa). The operational principle of this process is based on the Washburn
equation,
p ⋅ r = −2 ⋅ γ ⋅ cosθ Equation (10)
where p is the applied pressure, r is the radius of pore into which mercury will intrude,
γ is the surface tension of mercury and θ is the contact angle between mercury and pore
wall. Mercury contact angle, surface tension and density were taken as 130º, 485
dyne/cm and 13.53 g/ml respectively. The sample (2.4 g) was chosen from model
fraction by sieving. Porosity was calculated using the equations as below.
ρe
Porosity = (1 − ) × 100% Equation (11)
ρa
Wsample
ρe = Equation (12)
V penetrometer − V Hg
Wsample
ρa = Equation (13)
V penetrometer − VHg − Vintrusion
where Wsample was the weight of pellet sample, Vpenetrometer was volume of empty
penetrometer which is 6.131 ml including both cell (5 ml) and stem volume (1.131 ml)
of the penetrometer, and VHg was the volume of mercury filled into the penetrometer at
50 µm Hg vacuum. Vintrusion was the volume of mercury intruded under the pressure of
5800 psia (40MPa). Hence, pellet density (ρe) and apparent density (ρa) can be
obtained. Cumulative specific intrusion volume was plotted versus the pore diameter.
Median pore diameter was defined as the pore diameter corresponding to the 50% of
the maximum intruded volume of mercury.
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E. Rotary processing and extrusion spheronization studies conducted
Descriptions of the various studies conducted on rotary processing and
extrusion spheronization are detailed below.
E1 Influence of operational variables in rotary processing
Blends of MCC and lactose 200M (25%:75% w/w) were prepared by pre-
mixing in a 4 L laboratory double cube mixer (J. Engelsmann AG, Germany) rotating
at 50 rpm for 30 min. The pellets were prepared in the rotary processor with frictional
plate which was named as plate Medium (medium studs) and described in greater detail
under a subsequent section. The material load size was 0.6 kg.
Orthogonal design was employed for studying the effect of variables in a
multivariable process (Heng et al., 2000). Frictional plate speed during liquid addition
stage (S-liquid addition), water addition rate (R), amount of water added (W) and
frictional plate speed during tumbling stage (S-tumbling) were the four independent
operational parameters chosen for this design. Orthogonal array L34 was employed with
four variables and three levels for each variable (Tables 3 and 4).
Table 3. Operational variables and levels for orthogonal design.
S-liquid addition R W S-tumbling

(rpm) (ml/min) (%) (rpm)
Level –1 523 24 37.5 313

Level 0 730 30 40.0 523
Level +1 1045 36 42.5 730
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Table 4. Orthogonal design – matrix L34

Run No. S-liquid addition R W S-tumbling
1 -1 -1 +1 0
2 0 -1 -1 -1
3 +1 -1 0 +1
4 -1 0 0 -1
5 0 0 +1 +1
6 +1 0 -1 0
7 -1 +1 -1 +1
8 0 +1 0 0
9 +1 +1 +1 -1
Pellet quality was described using mass median diameter, span and oversized
fraction. The responsive term, K value, was calculated for a quantitative evaluation of
the effects of a single variable. For each pellet characteristic, K was the average of the
corresponding responses of a certain variable at the same level.
Analysis of variance and multiple linear regression were applied to assess the
effects of the individual variables. Statistical software SPSS (Version 10.0) was used
to calculate multiple regression equations. Data obtained from the orthogonal design
were first transformed to index values within 0-1 using the following equation:
X i − X min
Xs = Equation (14)
X max − X min
where Xs was the standardized value, Xi was the actual value being transformed, and
Xmax and Xmin were the maximum and minimum values of each column, respectively.
Since the transferred index value was used to plot the equation, its coefficient
value in the regression equation for each variable indicated their comparative sequence
of importance. The t test results showed whether each variable was significant in
determining the response of pellet property (significance level of P<0.05).
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E2 Effect of frictional plate design in rotary processing
E2.1 Characterization of teardrop studded frictional plates
Three frictional plates with teardrop-shaped studs of different dimensions were
used to prepare pellets in the rotary processor (Figure 12). The teardrop-shaped studs
(n = 140 per plate) were mechanically manufactured and arranged in a similar radial
pattern on all three plates. Measurements of stud height and cross-sectional area were
made with reference to the tallest part of the studs (Figure 13).
For characterizing the surface area of a stud, a flexible transparent film was
used to envelope the stud forming a skin on the stud. The film was then carefully
detached, edges trimmed and surface area determined by spreading the film gently
over graph paper. The measurement was repeated for 10 randomly chosen studs for
each plate.
Next, impression models of the studs were made using clay by carefully fitting
the clay over the studs. The weight of a testing liquid required to fill each impression
model was noted. The testing liquid was a 0.05% polysorbate 85 (Merck, Germany)
aqueous solution. A calibration line of weight against volume of testing liquid was first
plotted. The volume of the stud, i.e., the volume of testing liquid required for filling
the impression model, was determined from the weight of testing liquid used and the
calibration plot. The test was repeated for 10 randomly chosen studs for each plate.
The height at the tallest part of the stud and stud volume were directly
measured from the studs while the cross-sectional area was calculated based on the
width and height at the tallest part of the stud (Figure 13). The characteristics of studs
were tabulated in Table 5.
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(A)
(B)
(C)
Figure 12. Photographs of plates with teardrop-shaped studs of different dimensions.

(A) Plate Short with shortest studs, (B) Plate Medium with medium height studs, (C)
Plate Tall with tallest studs.
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275 mm
57.5 mm
Frictional plate rotation (Clockwise direction)
Width
Top view of
stud
Side view of
Height stud
Cross-sectional area
of stud
Width
Figure 13. Schematic diagram of a frictional plate with teardrop studs.
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Table 5. Characteristics of teardrop studs on three frictional plates.
Cross-sectional
Height Volume Surface area
Plate area
(mm) (mm3) (mm2) (mm2)
Short 0.97 ± 0.07 26.45 ± 6.82 5.30 ± 0.29 93.77 ± 3.42

Medium 1.60 ± 0.14 50.08 ± 7.84 8.11 ± 0.51 111.89 ± 6.06
Tall 2.75 ± 0.14 105.77 ± 11.34 14.65 ± 0.59 132.37 ± 4.69
*Mean value ± standard deviation.
E2.2 Preparation and characterization of pellets prepared by rotary processing
The three frictional plates named as plates Short, Medium and Tall were used to
prepare pellets in rotary processing. MCC-lactose blends (25%:75% w/w) for rotary
processing were first prepared by pre-mixing in a 4 L laboratory double cube mixer (J.
Engelsmann AG, Germany) rotating at 50 rpm for 30 min. Preliminary rotary
processing runs were first carried out using the three frictional plates with MCC-
lactose powder blends of 0.6, 0.8 and 1 kg in order to select a suitable load size for
evaluating the three teardrop studded frictional plates. The load size chosen for
subsequent experiments in this study was 0.6 kg. The amount of water added was fixed
at 37.5% w/w basing on the dry weight of the starting materials. The water addition
rate was 27 g/min. After the completion of each run, the pellets were discharged
carefully from the inner chamber of the rotary processor and collected, leaving the
frictional plate for examination of material adhesion.
For each of the three frictional plates, five processing runs were carried out and
the results averaged. After the completion of each run, the pellets were discharged
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carefully from the inner chamber and collected, leaving the frictional plate for
examination to show evidence of material adhesion. The pellets were characterized in
terms of their mean size, size distribution, bulk and tapped densities and friability. For
shape characterization, 50 pellets were randomly chosen from each run, therefore, 250
pellets were tested for each frictional plate.
E3 Feasibility of eliminating pre-mixing in rotary processing
MCC and lactose powders without pre-mixing were loaded to the rotary
processor using three loading configurations (Figure 14). Configuration I and II
involved the layering of MCC and lactose powders (I: MCC upper layer; II: lactose
upper layer). For these two configurations, the first layer of powder material was
loaded prior to spreading the other powder material uniformly over. For the side by
side loading (III), MCC powder was carefully placed onto the frictional base plate,
occupying about a quadrant before lactose powder was filled onto the remaining space.
For method IV, the MCC and lactose was first mixed using a double cone mixer
attached to a main motor (AR 401, Erweka, Germany) rotating at 6 rpm for 30 min.
The powder blend was then loaded onto the frictional base plate of the rotary
processor.
MCC and lactose powders were loaded into rotary processor using the methods
described above (Figure 14). Then the pelletization process was effected with liquid
addition, tumbling and drying. Load size of the starting materials was 0.6 kg for each
run. Pellets were prepared using the frictional plate with teardrop shaped studs of
medium height (plate Medium).
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MCC Lactose
MCC Lactose
I: Layered loading with MCC on top II: Layered loading with lactose on top
MCC and Lactose

MCC Lactose blend
III: Side by side loading IV: Loading of MCC-lactose mix
Figure 14. Schematic diagram depicting the four material loading methods.
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Three sets of conditions with different formulations and operating parameters
were employed for making pellets (Table 6). These conditions differed in the MCC
concentration, amount of water added, water addition rate and duration of water
addition. The four loading methods were all tested under these conditions. All
experiments were repeated and results averaged.
The pellets obtained from the different runs were characterized in terms of
mean size, size distribution, oversized fraction and shape.
Table 6. Pellet preparation conditions for evaluating the feasibility of eliminating pre-
mixing in rotary processing.
Water Water Number

MCC-Lactose Amount of
addition addition of
Condition proportion water added
time rate replicate
(%) (%) (min) (g/min)
A 25:75 37.5 8.3 27 4

B 15:85 30 8.2 22 3
C 15:85 30 4.2 43 3
E4 Effect of lactose particle size in spheronization processes
Pellets were prepared by both rotary processing and large scale extrusion
spheronization. Three lactose grades (100M, 200M and 450M), differing in mean
particle sizes, were used in this study. One kg blends of MCC-lactose in a ratio of 1:3
was premixed in double cone mixer attached to a main motor (AR 401, Erweka,
Germany) at 6 rpm for 30 min. The range of amounts of water used was chosen for
preparing pellets with mean sizes from approximately 0.6 mm to 2.0 mm (Table 7).
Each lactose and water levels combination was repeated twice and the results
averaged.
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Table 7. Amount of water used to prepare pellets in rotary processing and extrusion
spheronization.
Rotary processing Extrusion spheronization
100M 32%-37% 37%-42%

200M 36%-41% 38%-45%
450M 38%-42% 39%-49%
With a fixed rate for water addition, the duration of time for water addition
varied due to the different amounts of water added. Hence, water evaporation was
tested by determining the moisture contents in the wet pellet batches after the tumbling
stage for rotary processing. In extrusion spheronization, the water evaporation was also
monitored by measuring both the extrudates and wet pellets immediately after
extrusion and spheronization steps respectively.
For rotary processing, the frictional plate used was plate Tall since the other
two plates can not support 1kg load of starting materials. Water was sprayed onto the
tumbling powder mass at 50 g/min. Samples of pellets were obtained after the
tumbling stage in rotary processing for moisture content determinations. The
pelletization process in rotary processing was terminated after the completion of the
tumbling stage. Oven-drying was carried out for the pellets prepared by rotary
processing to ensure that pellets produced by rotary processing and extrusion
spheronization were equivalently treated during the drying phase.
For extrusion spheronization, 1 kg of the extrudates was spheronized at 600
rpm (tip speed of 603 m/min) for 10 min. Samples of extrudates were collected after
extrusion and pellets immediately after the completion of spheronization for moisture
content determination.
76
… EXPERIMENTAL
The dried pellets obtained from rotary processing and extrusion spheronization
were characterized in terms of mean size, size distribution, oversized fraction, yield,
shape and porosity.
E5 Functionality of crospovidone as a new spheronization aid in extrusion
spheronization
Three grades of crospovidone (XL, XL-10 and INF-10) and three grades of
lactose (100M, 200M and 450M) were used as starting materials for preparing pellets.
MCC was used as the reference material to evaluate the function of crospovidone
acting as spheronization aid. Pellets were prepared using both small scale and large
scale extrusion spheronization runs as described previously.
E5.1 Torque rheological properties
Torque rheological properties of powder mixture containing crospovidone-
lactose or MCC-lactose were characterized using the laboratory scale mixer torque
rheometer (Caleva, England). It consisted of a 150 ml capacity jacketed stainless steel
bowl equipped with two mixing blades. Three grades of crospovidone (XL, XL-10 and
INF-10) and MCC together with lactose 200M was evaluated. Binary mixtures (25 g)
consisting of the spheronization aid (crospovidone or MCC) and bulk material (lactose
200M) in the proportion of 25%:75% w/w were prepared by geometric dilution. The
powder mix was loaded into the mixer torque rheometer and the rheological profiles of
the binary mixtures were determined at different water levels.
The amount of water added was expressed as a percentage of the total powder
weight. Added water levels ranged from 45–65 % w/w, 40–55 % w/w and 20–40 %
w/w for XL-10-lactose, INF-10-lactose and MCC-lactose mixtures respectively.
77
… EXPERIMENTAL
Various amounts of water in the range of 20-90% were tried for the XL-lactose
mixture, however the wet mass failed to achieve a sufficiently cohesive texture for any
appreciable torque responses to be generated.
Water was added as a bolus dose after the torque generated for the dry powder
was recorded. All the water was evenly distributed throughout the powder bed while
the blades turned. The mean torque was used as the rheological parameter. The torque
was measured directly from the mixer bowl with the help of a torque arm connected
from the main body of the mixer to a calibrated load transducer. The following
equipment settings were used for all the studies: mixer speed, 50 rpm; sampling rate at
which data were captured during logging periods, 100 Hz; measurement range, 0-5 Nm
and sensitivity, ±0.01 Nm. The mean torque was monitored over 16 min of mixing
during which equilibrium values were attained. At each water level, experiments were
triplicated and average of torque responses was obtained.
E5.2 Preparation of pellets by small and large scale extrusion spheronization
Pellets were prepared using both small scale and large scale extrusion
spheronizers as described previously in Section C2. For the small scale extrusion
spheronization runs, three grades crospovidone (XL, XL-10 and INF-10) and three
grades of lactose (100M, 200M and 450M) were used to prepare crospovidone-lactose
(ratio of 1:3) pellets.
Preliminary studies were carried out using 1500 rpm (tip speed of 565 m/min).
MCC-lactose 200M pellets were obtained with appropriate amounts of water added
(37-40% water). However, the optimal spheronization speed for crospovidone had to
be reduced to 1250 rpm (tip speed of 471 m/min). Although pellets containing
crospovidone could be produced at the start of spheronization at higher speeds (1500
78
… EXPERIMENTAL
rpm), they were not strong enough to remain as integral entities under prolonged
strong shear forces.
For the large scale crospovidone-lactose extrusion spheronization runs, XL-10
and lactose 200M pellets were prepared using formulation and processing parameters
as stipulated in the following experimental design (Table 8). A Box-Behnken
experimental design (Bodea and Leucuta, 1998; Karnachi and Khan, 1996) was
employed to elucidate the effects of the operating variables on the quality of the
crospovidone-lactose pellets (Table 8). At any one time, two variables were varied at
two levels (-1, 1) while the other two remained constant at level zero (Table 8).
Based on the small spheronizer study, the findings for each parameter used
were extrapolated to large scale process to arrive at a set of parameters ranges. The
operating levels for each variable (Table 8) were selected based on the results of the
preliminary studies. The lower limit of XL-10 concentration was set at 20% since a
low amount of spheronization aid did not allow production of high quality pellets.
Water concentration coefficient was adjusted accordingly due to the level of XL-10
concentration to make the pelletization process workable. The spheronization speed in
the small scale spheronizer was 1250 rpm (tip speed of 471 m/min), hence a speed of
480 rpm (tip speed of 482 m/min) was used to provide an approximately similar tip
speed in the large scale spheronizer. The upper limit for spheronization time was 15
min to allow enough tumbling time to produce higher pellet sphericity. In general, the
parameters chosen need to meet three criteria here, (a) equal interval for each level
which is a character of the Box-Behnken design; (b) a workable process for obtaining
high quality pellets; and (c) opportunity for evaluation of the effect of each variable.
79
… EXPERIMENTAL
Table 8. Experimental matrix of the Box-Behnken design.
Coded Values Actual Values

Run
Block Run [C] [W] [S] [T] [C] [W] [S] [T]
Code
(%) (rpm) (min)
1 cw -1 -1 0 0 20 1.4 480 8.5

i 2 Cw 1 -1 0 0 30 1.4 480 8.5
3 cW -1 1 0 0 20 1.6 480 8.5
4 CW 1 1 0 0 30 1.6 480 8.5
5 st 0 0 -1 -1 25 1.5 410 2
ii 6 St 0 0 1 -1 25 1.5 550 2
7 sT 0 0 -1 1 25 1.5 410 15
8 ST 0 0 1 1 25 1.5 550 15
9 cs -1 0 -1 0 20 1.5 410 8.5

iii 10 Cs 1 0 -1 0 30 1.5 410 8.5
11 cS -1 0 1 0 20 1.5 550 8.5
12 CS 1 0 1 0 30 1.5 550 8.5
13 wt 0 -1 0 -1 25 1.4 480 2
iv 14 Wt 0 1 0 -1 25 1.6 480 2
15 wT 0 -1 0 1 25 1.4 480 15
16 WT 0 1 0 1 25 1.6 480 15
17 ct -1 0 0 -1 20 1.5 480 2
v 18 Ct 1 0 0 -1 30 1.5 480 2
19 cT -1 0 0 1 20 1.5 480 15
20 CT 1 0 0 1 30 1.5 480 15
21 ws 0 -1 -1 0 25 1.4 410 8.5

vi 22 Ws 0 1 -1 0 25 1.6 410 8.5
23 wS 0 -1 1 0 25 1.4 550 8.5
24 WS 0 1 1 0 25 1.6 550 8.5
25 0 0 0 0 25 1.5 480 8.5

vii 26 0 0 0 0 25 1.5 480 8.5
27 0 0 0 0 25 1.5 480 8.5
28 CWST 1 1 1 1 30 1.6 550 15
[C]: XL-10 concentration

[W]: Water concentration coefficient
[S]: Spheronization speed
[T]: Spheronization time
80
… EXPERIMENTAL
The four variables investigated were: XL-10 concentration [C,c], water
concentration coefficient [W,w], spheronization speed [S,s] and spheronization time
[T,t]. This allowed the experimental conditions for a particular run to be readily
represented by its respective code. Hence, the code for Run 1 was ‘cw’ since both XL-
10 and water concentrations were low while the other two variables remained at level
zero. Run 4 was coded as ‘CW’ as both parameters were set at the high levels. The
coding system facilitated comparison between the different runs and enabled the
effects of changing levels to be elucidated. The water concentration coefficient relates
to the theoretical amount of water required for spheronization (added water level) and
was calculated based on a linear equation shown below (Wan et al., 1993).
Added water level (%) = a (Percentage of spheronization aid)
+ b (Percentage of lactose) Equation (15)
The coefficient, b, was the amount of water required by lactose and fixed at 0.2
while a, the water concentration coefficient of the spheronization aid was varied
according to the levels stipulated in the matrix of the Box-Behnken design. For these
crospovidone-lactose formulations, the formulation and processing parameters during
spheronization were as indicated in the experimental design (Table 8).
For comparison, pellets were similarly prepared with MCC and lactose 200M
in a ratio of 1:3 using large scale extrusion spheronization (spheronization speed of
600 rpm, tip speed of 603 m/min, for 10 min). The water levels were varied from 38 to
45% of the total powder weight. The equivalent water coefficient values were
calculated from the above equation.
81
… EXPERIMENTAL
For the pellets produced by small scale extrusion spheronization, mean size,
size distribution and oversized fraction were evaluated. For the large scale process, the
pellets were characterized in terms of mean size, size distribution, oversized fraction,
yield, shape and friability.
82
… RESULTS AND DISCUSSION
IV. RESULTS AND DISCUSSION
The properties of products obtained from the orthogonal design experiment are
presented in Table 9. K values which indicated the effect of each variable were
calculated and shown in Figure 15. As can be seen from Figure 15, the higher amount
of water added (W) resulted in a larger mean pellet size and higher oversized fraction.
For frictional plate speed during tumbling stage (S-tumbling), a higher speed led to
larger mass median diameter as well as a smaller span value.
Table 9. Properties of pellets resulted from the orthogonal design experiment.
Mass median Oversized

Run S-liquid S-
R W diameter Span fraction
No. addition tumbling
(mm) (%)
1 -1 -1 1 0 1.786 0.664 4.654

2 0 -1 -1 -1 0.410 0.750 1.504
3 1 -1 0 1 1.011 0.431 0.438
4 -1 0 0 -1 0.785 1.054 4.875
5 0 0 1 1 3.324 0.393 36.547
6 1 0 -1 0 0.543 0.711 0.287
7 -1 1 -1 1 0.719 0.515 2.314
8 0 1 0 0 1.237 0.566 0.315
9 1 1 1 -1 1.427 0.914 2.613
S-liquid addition – Frictional plate speed during liquid addition stage

R – Water addition rate
W – Amount of water added
S-tumbling – Frictional plate speed during tumbling stage
83
K-mass median diameter (mm)

2.5
1.5
0.5
0
S-liquid R W S-tumbling
addition
Level -1 Level 0 Level +1
0.8
0.6
K-span
0.4
0.2
0
addition
15
K-oversized fraction (%)
12
0
addition
Figure 15. Effect of the four variables on pellet size, size distribution and oversized
fraction.
84
Multiple regression was employed to construct models for pellet size and size
distribution (Equations 16-18). From the equations shown below, W and S-tumbling
possessed higher coefficient for contributing to the mass median diameter, span and
oversized fraction values. The two variables, amount of water added (W) and
frictional plate speed during tumbling stage (S-tumbling) played significant roles in
affecting pellet size and size distribution respectively (Table 10). Combining the
findings from K values (Figure 15), multiple regression equation and t-test analysis
(Table 10), the variables W and S-tumbling were identified as more important
variables affecting pellet quality.
Mass median diameter = 0.556*[W] + 0.278*[S-tumbling] - 0.0353*[S-liquid
addition] + 0.02033*[R] - 0.122 (R2=0.776, F=3.458, p=0.128)
Equation (16)
Span = - 0.695*[S-tumbling] - 0.09*[S-liquid addition] + 0.075*[R] - 0.00233*[W] +
0.770 (R2=0.850, F=5.646, p=0.061) Equation (17)
Oversized fraction = 0.365*[W] + 0.278*[S-tumbling] - 0.0783*[S-liquid addition] -
0.0123*[R] - 0.12 (R2=0.397, F=0.658, p=0.653) Equation (18)
Table 10. T-test for the four variables.

Mass median Span Oversized fraction
diameter (mm) (%)
t Sig. t Sig. t Sig.
S-liquid addition -0.211 0.843 -0.607 0.577 -0.273 0.798

R 0.121 0.909 0.505 0.640 -0.043 0.968
W 3.320 0.029 -0.016 0.988 1.271 0.273
S-tumbling 1.659 0.172 -4.686 0.009 0.970 0.387
85
In rotary processing, pellets were formed directly from a powder mix by
agglomeration. During the liquid addition phase of pellet production, water was
sprayed onto the powder mass moving with the frictional plate. The powder mass
became increasingly moistened as it moved repeatedly across the liquid spray zone.
Due to the mixing action effected by the tumbling motion of the powder mass,
moisture tended to equilibrate from the wet region to the less wet region. The
moisture added to the powder mass effected the formation of bonds between the
powder particles. The presence of surface moisture increased surface plasticity which
aided the deformation and coalescence of particles during collision. Consequently, the
moistened particles agglomerated and consolidated to form pellets. After the liquid
addition phase, pellet continued to grow rapidly as the rotational movement of the
frictional plate enhanced the tumbling motion of the wetted mass during the tumbling
stage and supplied energy to the system to allow the wetted mass to be subjected to
further agglomeration.
For runs where low amount of water was used, the available surface moisture
may not be sufficient to effect pellet growth. The higher amount of water added
increased the wetting of the starting material powder surface and further assisted the
liquid saturation of the aggregates. Hence, larger pellets were produced when higher
amounts of water were added in experiments numbered Runs 1, 5 and 9 (Table 9).
However, oversized pellets tend to form with the addition of excessive moisture.
Higher level of frictional plate speed supplied more energy to the system to
produce pellets with larger mean size. Low tumbling speed did not supply sufficient
energy for uniform mixing and growth, which was evident from Runs 2, 4 and 9
(Table 9).
86
From previous literature, it was observed that there was a linear relationship
between pellet size and liquid spray rate (Wan et al., 1995). However, in this study, a
larger pellet size was obtained using a medium frictional plate speed during liquid
addition stage (S-liquid addition) for medium spray rate (R) (Figure 15). For this run,
the influence of spray rate was overshadowed by the effect of variables W and S-
tumbling. The combination of high water level (W) and high frictional plate speed
during tumbling stage (S-tumbling) augmented the agglomeration process (Run 5,
Table 9).
Besides supplying the energy input for effecting agglomeration
spheronization, the frictional plate speed during liquid addition (S-liquid addition)
also influenced the uniformity of liquid distribution in the powder mass. However, the
extent of the effect of S-liquid addition was not significant compared with the other
two variables: W and S-tumbling.
On their own, none of these four variables can impart significant effect on the
oversized fraction of the final product (Table 10). However, the interaction of W and
S-tumbling played an obvious role by producing a large amount of oversized fraction
(Run 5, Table 9). Larger amount of water led to the production of large pellets whose
movements were out of the rope-like pattern under the strong shear forces imparted
by the high S-tumbling, indicating that the process was out of control. Although the
higher speed during tumbling stage resulted in better size distribution (Figure 15), the
combination of higher amount of water and higher level of S-tumbling should be
avoided to reduce the formation of undesired lumps (oversized particles).
Therefore, it can be concluded that among the four variables, the influence of
the amount of water added (W) and frictional plate speed during tumbling stage (S-
tumbling) were identified as important variables. For producing high quality pellets,
87
these two variables should be carefully controlled and maintained at an optimal level.
Three frictional plates with teardrop shaped studs were available for
investigation. The studs of same number were arranged in a similar radial pattern on
each plate. The difference between plates lies in the properties of studs on their
surface. The characteristics of the studs on the frictional plate included height,
volume, cross-sectional area and surface area (Table 5). Since these characteristics
correlate with each other, stud height was used to represent the frictional plate in the
following discussion. The three frictional plates were named as plate Short, Medium
and Tall based on the sequence of the height of studs on their surface. For example,
plate Short represented the plate with shortest studs.
B1 Loading
From preliminary investigations, it was found that the load size of bulk
powder that could result in successful rotary processing was influenced by the plate
chosen, i.e. the stud property. During the liquid addition stage, water wetted the
powder particles and the starting materials moved under the combined action of
centrifugal and kinetic forces, gravity and gap air. It was found that the powder mass
could not move freely if excessive starting material was loaded onto the frictional
plate. Overloading resulted in only the bottom layer of starting materials on the
frictional plate moving while the upper layer of powder remained relatively
stationary. Under such circumstances, the continued addition of water caused over-
wetting of the powder mixture in the vicinity of the spray nozzle, leaving the
remaining fraction of starting materials under-wetted. The localized over-wetting
88
caused the formation of lumps which was undesirable for pellet production.
Moreover, powder which was not sufficiently wetted could not proceed further to
form agglomerates. This heterogeneous distribution of water did not assist pellet
formation and led to an uncontrollable agglomeration process.
Starting materials of 0.6, 0.8 and 1 kg were tested for suitability as load size
for these three frictional plates. With similar formulations and processing conditions,
it was observed that plate Short was only effective for the 0.6 kg load but not a higher
load of 0.8 kg. Plate Medium, with studs of medium height, was effective for both the
0.6 and 0.8 kg loads. Plate Tall was found to be able to drive the starting materials
moving at all three load sizes effectively. Therefore, the 0.6 kg load was chosen for
the purpose of comparing these three frictional plates.
B2 Adhesion
Due to the lining of polytetrafluoroethylene tape on the wall of inner chamber,
there was very little adhesion on the wall throughout the spheronization run. Visual
observations made on material adhesion to the plate surfaces showed that plate Short
had very low level of moist powder adhesion (Table 11). Only a thin powder film
layer was found on the surface of plate Short. Plate Medium had more material
adhesion than plate Short but less adhesion compared to plate Tall. The amount of
material adhesion on the studs of plate Medium consisted mainly of some moist
material lodged adjacent to the heads of the teardrop shaped studs. Plate Tall had
comparatively the heaviest amount of material adhesion. It could be observed that the
adhered mass comprised not only moist powder but also some pellets. More adhesion
was observed in the valley area next to the stud head, where stud height and stud
width were at their tallest and broadest dimensions, respectively. With an increase
89
in stud height, the depth of the valley at the stud head increased correspondingly.
Hence, this led to a greater tendency for the entrapment of moist material at the valley
areas adjacent to the stud heads during the liquid addition stage of the rotary
processing run. Moist pellets formed may also be caught onto the adhered moist
powder layer as they tumbled on the frictional plate thereby increasing the amount of
material adhesion on the plate surface.
Table 11. Observations of material adhesion during rotary processing with the three
Plate Observations
Short Slight adhesion, in the form of a thin film layer of powder.
More adhesion than plate Short but less adhesion than plate Tall. Only
Medium
some wetted powder was caught around the stud heads.
Heavy adhesion on plate and some pellets were found stuck onto the
Tall
adhered material at the areas around the stud heads.
In previous studies, studs on the frictional plates used were symmetrical (Liew
et al., 1998, 2000a; Holm P., 1996; Wan et al., 1994, 1995). Hence, moist material
had a tendency to be trapped in the valley encircling the whole stud. In this present
study, with a broad head tapering to a tail, the height and width of the teardrop studs
decreased from the stud head towards the tail end. The rotation of the frictional plate
was in a clockwise direction following the streamline nature of the studs, from the tail
end moving forward towards the head of the stud (Figure 13). Due to their
asymmetrical, streamline and tapering nature, adhesion on these teardrop studs can be
reduced by limiting adhesion to the valley area at the stud head where stud height and
width were at their largest dimensions as observed in this study.
90
From Figure 16, the amount of recovered product after each experiment
decreased with an increase in the height of the studs on the frictional plate. There was
significant difference between the recovered amounts of product obtained with plate
Short and those with plate Tall (ANOVA, P<0.05). The decrease in the amount of
recovered product could be attributed to the material adhesion on the frictional plate.
With a fixed load of starting material, greater adhesion corresponded to a lower
amount of recovered product. This effect became more critical with smaller loads of
starting material.
B3 Mean size, size distribution, oversized fraction and fines
In pellet production, it is ideal for the recovered pellets to have the desired
mean size and a narrow size distribution. Span values reflected the degree of
homogeneity in pellet size distribution. A smaller value indicated a narrower and
tighter size distribution with a lower “within batch” variability. Oversized fractions
which could be irregularly shaped lumps or big balls were undesirable and should be
minimized as their presence in the recovered product was often an indication that the
agglomeration process proceeded in a less stable and less predictable manner. The
formulation and processing conditions used in this study were chosen to produce
pellets with a desired mean size of about 1 mm for all three frictional plates.
When these three plates were used, trends of increasing pellet size and
decreasing size distribution were observed with increase in stud height (Figure 17).
Differences between mass median diameter of pellets from plate Tall and those of
pellets formed with the other two plates were found to be significant (ANOVA,
P<0.05).
91
100
99
98
97
Plate Short
Plate Medium
Recovered product (%)
96
Plate Tall
95
94
93
92
91
90
0.5 1 1.5 2 2.5 3
Stud height (mm)
Figure 16. Recovered product obtained from rotary processing runs using the three
92
1.2 1
0.9
1
Mass median diameter (mm)
Plate Short 0.8
Span
0.8 Plate Tall
Plate Medium
0.7
0.6
0.6
0.4 0.5
0.5 1 1.5 2 2.5 3
Stud height (mm)
Figure 17. Mass median diameter (●) and span (○) of pellets prepared using the three
93
For span, significant differences existed between pellets produced by plate
Short and pellets produced using the other two plates (ANOVA, P<0.05). The amount
of oversized fraction in the product obtained from plate Short was significantly larger
(ANOVA, P<0.05) than the amounts obtained with the other two plates (Figure 18).
The fines resulted from plate Short was also greater than those from the other two
plates. There was a positive and significant correlation (Pearson correlation, P<0.05)
between the mass median diameter of the resultant pellets and the height of studs.
Since all the operational conditions for the processes with three frictional
plates were similar, the differences in pellet properties could be attributed to the effect
of the teardrop studs. Following an increase in stud height, the increase in surface area
increased the frictional contact area between the plate and the spheronizing material.
With taller studs, the increased elevation in the vertical plane also resulted in material
being propelled up a slope with a steeper gradient. The material moving on the
frictional plate was also confronted by a larger overall vertical area and volume as
indicated by the larger stud cross-sectional area and volume. When the plates were
rotated at the same speed, the powder mass on the frictional plate with taller studs
therefore generated more chances for moist agglomerates to collide with each other
and with the chamber wall and the surface of frictional plate.
In the production of pellets, the wetted powder underwent wetting, nucleation,
consolidation and coalescence. Loose aggregates (nuclei) formed after powder was
wetted with water, and then further grew to a larger size by coalescence. The higher
forces generated by the taller teardrop studs enhanced the consolidation of moist
aggregates, increasing liquid saturation. The increased surface liquid could lead to a
higher extent of coalescence resulting in the formation of pellets with comparatively
larger mean size.
94
2 6
1.5
4
Oversized fraction (%)
Fines (%)
1
Plate Short
0.5
Plate Tall
Plate Medium
0 0
0.5 1 1.5 2 2.5 3
Stud height (mm)
Figure 18. Oversized fraction (●) and fines (о) prepared using the three teardrop
95
Besides the higher consolidation effect, the frictional force intensified the
mixing action of the moistened powder mass, improving the water distribution. With
poor water distribution, localized over-wetting will result in the formation of lumps
which will form the oversized fraction of final product. With the addition of a fixed
amount of water, localized over-wetting also gave a correspondingly underwetted
wetted fraction that can lead to the production of fines. A more homogeneous liquid
distribution was obtained with a decrease in the tendency for over-wetting and a
reduction in the occurrence of lumps and fines in the final product as can be observed
from comparing plate Short with plates Medium and Tall (Figure 18). Consequently,
the size distributions of the pellet batches were reduced by using plates with taller
studs.
B4 Shape
Three shape factors, circularity, aspect ratio and eR, were used to examine
pellet shape. It can be seen from Figure 19 that both circularity and eR value increased
and aspect ratio decreased when stud height increased from plate Short to Tall.
Nevertheless, for circularity, eR and aspect ratio, there were significant differences
among all of the three plates (ANOVA, P<0.05). A positive and significant
correlation (Pearson correlation, P<0.05) was observed between eR and the height of
stud on the plates.
A higher value of circularity, eR and lower aspect ratio showed a higher degree
of sphericity of pellets. Hence, it should be noted that plate Tall was related to the
production of more highly spherical pellets followed by plates Medium and Short.
96
0.95 Plate Medium
Circularity
0.9 Plate Tall
0.85 Plate Short
0.8
0 0.5 1 1.5 2 2.5 3
Stud height (mm)
1.3
1.25
1.2
Aspect ratio
Plate Short Plate Tall

1.15
Plate Medium
1.1
1.05
1
0 0.5 1 1.5 2 2.5 3
Stud height (mm)
0.75
0.7
0.65
0.6 Plate Medium
0.55
eR
0.5
Plate Tall
0.45
Plate Short
0.4
0.35
0.3
0 0.5 1 1.5 2 2.5 3
Stud height (mm)
Figure 19. Shape factors of pellets prepared using the three teardrop studded
frictional plates.
97
The rolling motion of pellets on the frictional plate and the inner wall
supported the smoothening of pellet surfaces. This tumbling rope-like movement
removes irregularities or protrusions on pellet surfaces mainly by collisions between
pellets forming on the frictional plate surface and the chamber wall. Longer tumbling
time was reported to have a smoothening effect on pellets (Wan et al., 1994). As
discussed in the previous section, a higher force increased consolidation and liquid
saturation. An increased surface liquid improved the plasticity and deformability of
moist aggregates. Moreover, with the same base plate rotational speed, the powder
mass on the plate with taller studs was expected to experience greater frictional forces
which propel the pellets towards the wall of the processing chamber and kinetic forces
for material movement. The higher shear forces increased the impact forces of
collision and enhanced the roundening process.
B5 Density and friability
From the results presented in Table 12, it can be seen that all the bulk density
values of the pellets prepared with the three frictional plates varied between 0.82 and
0.84 g/ml and the tapped density values between 0.86 and 0.87 g/ml. High Carr index
values were indicative of increased cohesion between particles and therefore poorer
flow. Hence, the low values of Carr index (3.34-3.95%) of the pellet batches indicated
good flow properties of these pellets. Due to the high degree of sphericity, good
flowability and narrow size distribution of pellets, the weight variation of pellet-
packed capsules by volumetric measures is expected to be small.
Investigations on pellet friability showed that there was minimal weight loss
after friability testing as pellets formed by rotary processing were spherical, dense and
smooth with minimal protruding surfaces. Nevertheless, the friability values obtained
98
for plate Short and plate Tall were significantly different (ANOVA, P<0.05). Pellets
produced with plate Tall were significantly less friable compared to those produced
using plate Short (Table 12). Pellet friability can also be used to give an indication of
pellet strength, with a lower friability reflecting greater pellet strength. From these
findings, it could be extrapolated that pellets prepared with plate Tall, as compared to
those produced using plate Short, were densified to a greater extent, giving relatively
stronger agglomerates.
Table 12. Physical characteristics of pellets produced using the three teardrop studded
frictional plates.
Plate Bulk density Tapped density Carr index Friability

(g/ml) (g/ml) (%) (%)
Short 0.83±0.01 0.86±0.00 3.60±0.71 0.72±0.37

Medium 0.84±0.02 0.87±0.01 3.34±0.55 0.54±0.22
Tall 0.82±0.02 0.86 ±0.02 3.95±0.74 0.33±0.14
*Mean values ± standard deviation
B6 Porosity
The dimension of the teardrop studs on the frictional plate was found to have a
marked effect on pellet densification (Figure 20). It was found that pellet porosity
decreased with increasing stud height. Pellets produced with the tallest studs were the
densest. The porosity of pellets produced using the shortest studs were significantly
different (ANOVA, P<0.05) from those of pellets formed using taller studs.
With similar starting materials and processing conditions, the powder mass on
the plate with taller studs was expected to experience greater shearing and impact
forces. The higher shear forces improved material movement and increased the impact
99
forces of collisions among the moist agglomerates and with the chamber wall. Thus,
the agglomerates underwent greater degree of densification as evidenced by the lower
porosity. Similarly, it has been reported that pellets produced in a rotary processor
were denser with high rotary speeds and long spheronization times which reduced
pore volume (Vertommen et al., 1998). Hence, porosity can be correlated with the
different extent of densification imparted by various degrees of shear forces.
Median pore size, obtained from the cumulative intrusion volume curve
plotted versus pore diameter, also gave an indication of the overall dimension of the
pores in pellets (Table 13). There was no significant difference (ANOVA, P<0.05) in
the median pore diameters of pellets prepared with the three frictional plates.
Table 13. Median pore diameter of pellets prepared using the three teardrop studded
frictional plates.
Plate design Plate Short Plate Medium Plate Tall
Median pore diameter (µm) 1.36±0.03 1.26±0.06 1.26±0.08

*Mean values ± standard deviation
100
17
16
15 Plate Short
14
Porosity (%)
13
Plate Medium
12 Plate Tall
11
10
8
0 0.5 1 1.5 2 2.5 3
Stud height (mm)
Figure 20. Porosity of pellets prepared using the three teardrop studded frictional
plates.
101
B7 Between batch variability
For a one-pot step pellet production by rotary processing, it is essential to
ensure that each run produces a high yield of pellets with the desired mean size within
a narrow size distribution. Besides “within batch” variability, “between batch”
variability of the pellet batches was investigated for process reproducibility of the
three different base plates. For each plate, a larger deviation from the mean value of
each pellet parameter obtained from five pellet batches would indicate a greater
“between batch” variability and therefore poorer process reproducibility.
On the whole, among the three frictional plates, the largest “between batch”
variabilities for mass median diameter, span, fines and circularity were observed with
plate Short (Table 14). In particular, the deviations from the mean values of fines
reduced markedly when stud height increased in the order from plates Short to
Medium then Tall. For amount of recovered product and eR value, all three plates had
rather similar “between batch” variabilities. For mass median diameter and span of
pellets, the deviation for plate Medium was smaller than for plate Tall. For circularity
and porosity, the deviation for plate Tall was smaller than for plate Medium.
These findings implied that, in general, pellet production using plate Short,
with greater variability between batches, was comparatively less stable and less
reproducible than pellet production using plates Medium and Tall. Hence, under the
similar formulation and processing conditions used in this study, plate Medium was
concluded as the most suitable with less material adhesion. However, if higher loads
are to be used, plate Tall may be more suitable as it was shown to be able to support
higher loads. When larger loads are used, the amount of material loss attributed to
adhesion of moist material onto the frictional plate also becomes comparatively less
102
critical as it accounts for a smaller percentage of the total load used for pellet
production.
Table 14. Coefficient of variance (%) of the properties of pellets produced using the
three teardrop studded frictional plates.
Coefficient of variance (%)

plate Short plate Medium plate Tall
Yield (%) 0.78 0.83 0.62

Mass median diameter (mm) 16.14 7.00 8.90
Span 11.97 7.15 11.79
Oversized fraction (%) 38.98 30.43 59.38
Fines (%) 140.61 58.33 40.00
Circularity 3.14 1.50 1.16
Aspect ratio 1.57 2.14 2.04
eR 24.32 23.24 21.18
Porosity (%) 4.95 6.85 0.34
C. Feasibility of eliminating of pre-mixing in rotary processing
For pelletization in the rotary processor, starting materials were generally pre-
mixed by different methods before the liquid addition step. There was no study
showing if this pre-mixing step was essential to rotary processing. However, it was
generally applied by most researchers. The feasibility of eliminating the pre-mixing
step was investigated in this study. Three different loading configurations of MCC
and lactose powders were evaluated and compared against a pre-mixed MCC-lactose
blend, (pre-mixing carried out separately prior to pelletization) using the properties of
their resultant pellets as comparators. The effects of loading configuration on pellet
quality can be assessed by comparing the pellets prepared by methods I, II and III (see
experimental, section S3).
Under condition A (Table 15), all four loading methods allowed pellets to be
103
produced in a controlled manner. The physical properties of pellets prepared under
condition A were presented in Table 15. Pellet characteristics were found to be similar
in terms of mean size, span, oversized fraction and shape. No significant difference in
these physical properties (ANOVA, p<0.05) could be attributed to the loading
methods of MCC and lactose powders. Starting materials loaded with methods I, II
and III gave rise to pellets with comparable quality and process reproducibility (from
coefficient of variance values) as those prepared with method IV (Table 16).
Table 15. Physical characteristics of pellets prepared under condition A.
Loading configurations
I II III IV
Mass median diameter 0.721±0.072 0.786±0.080 0.768±0.098 0.755±0.106
(mm)
Span 0.674±0.079 0.677±0.038 0.662±0.014 0.650±0.009
Oversized fraction (%) 1.236±1.058 1.290±0.956 1.091±0.447 0.874±0.587
Circularity 0.936±0.010 0.947±0.005 0.946±0.013 0.949±0.011

Aspect ratio 1.174±0.022 1.149±0.015 1.149±0.036 1.135±0.026
eR 0.508±0.028 0.540±0.023 0.539±0.046 0.555±0.037
*Mean ± standard deviation
Table 16. Coefficient of variance (%) for the pellet mass median diameter.
Condition
I II III IV
A 10.04 10.17 12.70 14.01

B 14.88 14.80 15.17 5.43
C 36.42 36.30 44.87 16.81
104
As the MCC proportion (15%) was lower in conditions B and C, the amount
of water added was reduced accordingly. For condition B, the water addition rate was
adjusted to maintain the same duration for water addition as that for condition A.
Under condition B, the pellet characteristics were similar in mean size, span, oversized
fraction and shape as well (Table 17). Once again, no significant difference (ANOVA,
p<0.05) in the pellet properties could be attributed to the loading method. However, a
lower coefficient of variance for pellet mass median diameter for method IV indicated
better process reproducibility (Table 16). Compared with pellets prepared under
condition A, the span and oversized fraction of pellets prepared under condition B
doubled. This demonstrated the deterioration in pellet quality.
Table 17. Physical characteristics of pellets prepared under condition B.
I II III IV
Mass median diameter 0.763±0.113 0.796±0.118 0.799±0.121 0.801±0.044
(mm)
Span 1.165±0.245 1.438±0.638 1.316±0.377 1.298±0.275
Oversized fraction (%) 2.868±0.560 3.591±1.274 3.094±1.398 3.164±0.477
Circularity 0.944±0.012 0.939±0.010 0.938±0.015 0.948±0.004

Aspect ratio 1.150±0.004 1.173±0.023 1.172±0.008 1.156±0.007
eR 0.527±0.010 0.512±0.025 0.513±0.018 0.527±0.004
Coupled with a reduced MCC content, the pelletization process was further
challenged by doubling the water addition rate and halving the duration allowed for
water addition (Condition C). Under condition C, the mean pellet size from the first
three loading methods increased to approximately 1.0 mm, which was larger than
those pellets prepared with method IV. Additionally, a wider pellet size distribution
105
(up to 1.7) and a larger oversized fraction were also obtained (Table 18). The
maximum oversized fraction in methods I, II and III reached 8%, doubling that of
method IV (Table 18). Significant differences between the mass median diameter and
oversized fraction of method IV (pre-mixed) and methods I, II and III (no pre-mixing)
were observed (ANOVA, p<0.05). No obvious difference in pellet shape was noted
between the four loading methods (Table 18). The coefficient of variance values for
pellet mass median diameter in method IV was much lower than the other three
methods which showed similar coefficient of variance values (Table 16). Compared
to conditions A and B, the quality of pellets prepared under condition C were inferior
as reflected in their wider span and higher oversized fractions (Tables 15, 17 and 18).
Process reproducibility for the mass median diameter was also poorer for methods I, II
and III under condition C (Table 16).
Table 18. Physical characteristics of pellets prepared under condition C.
I II III IV
Mass median 0.996±0.363 1.034±0.375 0.948±0.425 0.729±0.122
diameter (mm)
Span 1.487±0.106 1.676±0.436 1.520±0.169 1.557±0.443
Oversized 7.620±3.473 10.046±6.858 7.312±4.680 4.296±2.173
fraction (%)
Circularity 0.942±0.004 0.952±0.003 0.939±0.013 0.921±0.028

Aspect ratio 1.154±0.014 1.136±0.019 1.177±0.059 1.179±0.051
eR 0.534±0.014 0.559±0.023 0.515±0.051 0.498±0.054
106
MCC is an important excipient for the formation of pellets in a rotary
processor due to its unparallel efficiency as a spheronization aid. Without being
distributed to a certain extent, MCC cannot perform its function as spheronization aid
for the formation of pellets. When MCC and lactose were loaded into the rotary
processor with three configurations (I, II and III), no pre-mixing was carried out. MCC
had limited opportunities for mixing during the tumbling stage following liquid
addition as pellets have already been formed. Hence, MCC only had the chance to be
distributed into the powder mass during the liquid addition stage. Compared with
method IV, the formation of pellets with comparable properties showed that the MCC
could be distributed to a sufficient extent where it was able to perform its function as a
spheronization aid. For the two layered loadings (I and II), mixing had to be effected
by the up and down exchanges of materials. The more favorable production of pellets
with side by side (III) loading of MCC and lactose powders implied that the materials
in the rotary processor did not undergo vertical exchanges as efficiently as a more
complicated behavior of material mixing existed due to the rope-like material
movements.
Compared to condition A, pellet quality from condition B were inferior as
reflected by the wider size distribution and oversized fraction of the pellets. This was
due to the lower MCC content used in condition B. As MCC was present in lower
quantities, it was comparatively more difficult to achieve a homogeneous mixing with
lactose during the liquid addition stage. If the MCC was not well distributed, its
performance as a spheronization aid may inevitably be more markedly reduced and
noticed. However, unlike condition C, the longer duration for water addition under
condition B gave the materials greater opportunity for mixing with each other during
the liquid addition stage. This was further facilitated by the lower water addition rate
107
which gave rise to a compensatory effect by delivering a lesser amount of water per
unit time. This allowed for better moisture distribution and less likelihood for
localized over-wetting, especially in regions low with MCC.
With the introduction of water by spraying, the powder was wetted gradually
during the liquid addition stage. In the unwetted state, dry powders flow relatively
better and this assisted material mixing especially with the rope-like movement on the
frictional base plate. Once wetted, the materials had fewer propensities to be mixed
due to reduced flowability. With higher water addition rates, an increased amount of
water was added to the powder mass per unit time. The larger amount of water wetted
the powders at the spray zone very quickly, hence reducing the mixing efficiency.
This poor mixing efficiency was further exacerbated by the short duration time for
water distribution which was important for even distribution of the added water.
Moreover, the combined effect of high water addition rate and short duration
increased the likelihood of localized over-wetting.
However, these three conditions were created to examine the effects of four
loading methods. Pellets of reasonably similar physical properties can be produced
regardless of whether mixed starting materials were used or not when the
spheronization aid, MCC, was sufficient. The loading configuration of MCC and
lactose powders also did not impose significant effects. Hence, these findings
demonstrated the feasibility of omitting the pre-mixing step of MCC and lactose for
the production of pellets with desired size and shape properties in rotary processing.
However, for formulations with low levels of the spheronization aid or short
processing times, it is prudent that pre-mixed powders are used.
108
The influence of lactose particle size on pellet formation by rotary processing
and extrusion spheronization was investigated with lactose grades and amount of
water added as the formulation variables. Firstly, moisture evaporation in two
spheronization processes was monitored. In rotary processing, when 40% water was
added to the powder mass, it could be seen that the determined moisture content of the
wet pellets was about 32% which meant that approximately 8% water was lost during
the liquid addition and tumbling stages in rotary processor (Figure 21). Considering a
load size of 1 kg, this water loss equaled to 80 g water. As the rotary processor was a
one-pot process in a closed system, there was no water loss due to material transfer
between equipment. However, various air sources, fluidizing air, gap air and
atomizing air, were introduced to the rotary processor and contributed to the
evaporation of moisture from the wetted mass. This accounted for nett loss of
moisture from the mass incorporated by water addition through the spray nozzle.
In extrusion spheronization, approximately 7% water was lost during
granulation and extrusion, and about 1% water evaporated during spheronization.
Overall, slightly more moisture was left in the wet pellets after they were made by
extrusion spheronization. Extrusion spheronization was a multiple-step process.
Hence, the loss of water to the environment mainly occurred during the transfer of the
moistened mass between equipments and during the pelletization process. No
fluidizing air, gap air and atomizing air were involved in pellet production by
109
50
48
46
44
Reference line
42 y=x
Moisture content in pellets (%)
40
38
36
34
32
30
28
26
24
22
20
30 32 34 36 38 40 42 44 46 48 50
Amount of water added (%)
Figure 21. Moisture content of the pellets produced by rotary processing (open) and
extrusion spheronization (closed) (Lactose grades ∆▲100M, ○● 200M, □■ 450M);
Moisture content of extrudates (Lactose grades ×100 M, +200M, -450 M) by
110
From Figure 21, the trendline of determined water content of
pellets/extrudates against the amount of water added paralleled the reference line y=x.
In extrusion spheronization, the process duration was kept constant regardless of the
amount of water used. For rotary processing, the time of water addition varied slightly
(6.4 – 8.4 min) since different amounts of water were sprayed at the same water
addition rate. The amount of water lost during the spheronization processes was
approximately the same irrespective of the total amount of water added to the system.
No obvious difference in moisture loss was also noted between the different lactose
grades. Hence, the amount of water added can be used to reflect the moisture content
available in the wet mass for pellet formation.
D1 Studies in rotary processing
The three lactose grades generally displayed similar trends of increasing pellet
size with higher amounts of water added for pelletization (Figure 22). As pellet size is
an important characteristic, other pellet properties were plotted against mass median
diameter of pellets to examine the overall effects on pellet quality. Regression lines of
pellet size versus amount of water added were generated for each lactose grade and
presented in Table 19. The sequence of the slope values in decreasing order was
lactose 450M>200M>100M (Table 19). The three lactose grades showed different
water requirements for pellet formation. Under the current production conditions,
coarse lactose 100M needed less water for forming pellets with equivalent mean size.
For example, for achieving mean pellet size of 1 mm, the amounts of water required
were approximately 35.5%, 38.5% and 39.5% moving from lactose 100M to lactose
450M (Figure 22).
111
0.4
0.3
0.2
Log 10 [Mass median diameter (mm)]
0.1
-0.1
-0.2
-0.3
-0.4
30 32 34 36 38 40 42 44 46 48 50
Amount of water added (%)
Figure 22. Mass median diameter of pellets prepared by rotary processing (open) and
extrusion spheronization (closed) (Lactose grades ∆▲ 100M, ○● 200M, □■ 450M).
112
Table 19. Trendline equations for the three lactose grades.
Lactose
Rotary processing Extrusion spheronization
grade
100M Y=0.0677X-2.3950 (R2=0.9059) Y=0.0911X-3.5694 (R2=0.9583)
200M Y=0.0900X-3.5216 (R2=0.9940) Y=0.0555X-2.3252 (R2=0.9874)
450M Y=0.1445X-5.7703 (R2=0.9795) Y=0.0354X-1.5684 (R2=0.9143)
Y represents logarithm (base of 10) mass median diameter of pellets.
X represents amount of water added.
The slope of the regression line, i.e. change in mean pellet size with amount of
moistening liquid, can be used to depict the sensitivity of the pelletization process to
variations in the water content of the wetted powder mass (Table 19). A gentler slope
indicated higher process robustness with lower sensitivity to water. It is an advantage
for the process to be less sensitive, as measured by the change in mean size of the
resultant pellets, and able to tolerate anticipated variations in the water content of the
wetted powder mass during pelletization.
Lactose 100M with lower specific surface area was more easily wetted with
water. Therefore, less water was needed for producing pellets of the same size when
compared to fine lactose 450M. However, its lower specific surface area also
possessed reduced number of binding points which made the aggregates more
susceptible to fragmentation and breakdown. In dynamic pellet formation and growth
by rotary processing, the formation and breakdown of aggregates occur
simultaneously. For an increase in pellet size, forces supporting aggregate formation
and growth should be dominating during the pelletization process. For lactose 100M,
the nett effect was a relatively smaller change in mean pellet size with amount of
moistening liquid, i.e. a smaller slope value, indicating that the mean size of the
113
resultant pellets prepared by rotary processing using lactose 100M was less sensitive
to variations in the moisture content of its wetted powder masses.
Generally, increasing the amount of added water resulted in pellets with
decreased span values for all three lactose grades (Figure 23). The combination of
lactose 450M with low amounts of water produced much higher span values
indicating wider pellet size distribution. Pellets prepared with lactose 100M had much
lower span values even at low water amounts. In order to achieve mean pellet size
around 1 mm, lactose 450M displayed a span value which was about three times that
of the lactose 100M (Figure 23). The oversized fraction retained above the 2.8 mm
aperture size sieve during size analysis by sieving was mainly made up of lumps. It
was obvious that lactose 100M had the least propensity to produce lumps while
lactose 450M led to the production of an oversized fraction as high as 5% (Figure 24).
Since usable yield was defined as the fraction of pellets within a size range of
0.71 to 1.4 mm, higher yield values were achieved when a suitable amount water was
used which could produce pellets with mean size around 1 mm (Figure 25). A wider
range of amounts of water existed for achieving yields above 80% for lactose 100M.
This observation suggested that it had better process robustness. For lactose 450M,
the wider size distribution gave rise to limited amounts of pellets within the 0.71-1.4
mm size fraction and relatively low usable yields.
In rotary processing, the atomized water was continuously added through the
spray nozzle to the moving powder bed. In general, it is more difficult to distribute a
small amount of water uniformly into a powder mass than to provide good
distribution of a larger amount. Consequently, the higher span values corresponding
to pellet batches with relatively lower amounts of added water could be attributed to
this less uniform water distribution.
114
3 3
2.5 2.5
2 2
1.5 1.5
Span
Span
1 1
0.5 0.5
0 0
30 32 34 36 38 40 42 44 46 48 50 0 0.5 1 1.5 2 2.5
Amount of water added (%) Mass median diameter (mm)
115
Figure 23. Span of pellets prepared by rotary processing (open) and extrusion spheronization (closed) (Lactose grades
∆▲ 100M, ○● 200M, □■ 450M).
6 6
5 5
4 4
3 3

2

2
1 1
0 0
30 32 34 36 38 40 42 44 46 48 50 0 0.5 1 1.5 2 2.5
Amount of water added (%) Mass meidan diameter (mm)
116
Figure 24. Oversized fraction of products prepared by rotary processing (Lactose grades ∆ 100M, ○ 200M, □ 450M).
100 100
80 80
60 60
Yield (%)
Yield (%)
40 40
20 20
0 0
30 32 34 36 38 40 42 44 46 48 50 0 0.5 1 1.5 2 2.5
Figure 25. Yield of pellets prepared by rotary processing (open) and extrusion spheronization (closed) (Lactose grades
117
∆▲ 100M, ○● 200M, □■ 450M).
For pellet formation, nucleation is the first step for forming small aggregates
after wetting. There are two proposed mechanisms for nuclei formation (distribution
and immersion mechanisms) depending on the relative size of the water droplets to
the size of the primary particles (Schaefer and Mathiesen, 1996; Iveson et al., 2001).
When the liquid droplets are smaller than the solid particles or of the same order of
size, the distribution mechanism takes precedence. The liquid is well-distributed on
the surface of solid particles. Subsequently, nuclei are formed by coalescence between
the wetted particles. The immersion mechanism takes place when the liquid droplet is
much larger than the primary particles.
During rotary processing, the atomized water droplets were distributed by the
centrifugal forces imparted by the frictional base plate (Wan et al., 1995). The
distribution mechanism dominates due to the small size of the atomized water
droplets. Especially for lactose 100M, the distribution mechanism was likely to
dominate during the wetting stage, enhancing water distribution. Coarse lactose also
possessed good flowability, allowing the deposited surface water to redistribute
rapidly to other particles due to the presence of a water gradient and good surface
wetting properties of adjacent particles in this hydrophilic powder blend.
For lactose 450M, the immersion mechanism may predominate alongside the
distribution mechanism due to its relatively smaller lactose particle size. Its small size
enhanced its tendency of being dissolved and improved the establishment of a binding
liquid saturated with dissolved lactose especially with the immersion mechanism. The
dissolved lactose increased the adhesive property of the binding liquid and powder
mass and exacerbated the situation of poorer flowability of the MCC-lactose 450M
blend. Lactose 450M possessed cohesive properties which restricted the ease of
spreading water to the other drier parts of the powder. The inherent poor flowability
118
and cohesiveness of lactose 450M did not contribute to improving mass exchanges of
material undergoing agglomeration and this further hampered the distribution of local
water deposited, causing localized over-wetting of materials. Conversely, with a fixed
amount of water, localized over-wetting can also give rise to under-wetting in some
parts of the powder mass leading to the occurrence of fines being present. The
existence of lumps and fines within a product batch clearly indicated less desirable
conditions as a less uniform size distribution of pellets would be seen.
Lumps may also be produced by adhesion of moistened powder to the
processor surfaces, particularly on the frictional plate surfaces. When the adhered
masses became detached, they would contribute to the oversized fraction population
in the final product. The amounts of moisture used for this study was not excessive
and, hence, the level of over-wetting was largely avoided and mainly localized.
Lump formation (consequence of excessive amounts of water used) or
inadequate agglomeration (insufficient water added) did not augur well in producing
high yields since their resultant product did not fall within the defined usable size
range. Lactose 450M was much more sensitive to the amount of water added, and
only one water level used could result in yields higher than 80%. Thus, this clearly
indicated that the particle size of materials to be used for pellet production had to be
kept at a range to provide both flow and binding for optimized pellet production by
rotary processing.
Generally, lactose 200M and 450M gave more spherical pellets as indicated by
higher circularity, eR and lower aspect ratio values (Figures 26-28). In particular,
pellets made with 450M were highly spherical (Circularity >0.93; Aspect ratio <1.1;
eR >0.6).
119
1 1
0.98 0.98
0.96 0.96
0.94 0.94
0.92 0.92
Circularity
Circularity
0.9 0.9
0.88 0.88
0.86 0.86
0.84 0.84
30 32 34 36 38 40 42 44 46 48 50 0 0.5 1 1.5 2 2.5
120
Figure 26. Circularity of pellets prepared by rotary processing (open) and extrusion spheronization (closed) (Lactose grades
∆▲ 100M, ○● 200M, □■ 450M).
1.3 1.3
1.25 1.25
1.2 1.2
1.15 1.15
Aspect ratio
Aspect ratio
1.1 1.1
1.05 1.05
1 1
30 32 34 36 38 40 42 44 46 48 50 0 0.5 1 1.5 2 2.5
121
Figure 27. Aspect ratio of pellets prepared by rotary processing (open) and extrusion spheronization (closed) (Lactose
grades ∆▲ 100M, ○● 200M, □■ 450M).
0.75 0.75
0.7 0.7
0.65 0.65
0.6 0.6
0.55 0.55
eR
eR
0.5 0.5
0.45 0.45
0.4 0.4
0.35 0.35
0.3 0.3
30 32 34 36 38 40 42 44 46 48 50 0 0.5 1 1.5 2 2.5
Figure 28. eR of pellets prepared by rotary processing (open) and extrusion spheronization (closed) (Lactose grades ∆▲
122
100M, ○● 200M, □■ 450M).
Porosity values of pellets prepared in rotary processing were between 3-13%
denoting dense pellets (Figure 29). Among the three lactose grades, coarse lactose
100M showed much higher values for median pore size (Figure 30). In general,
comparatively less dense pellets (higher porosity and larger median pore diameter)
were obtained with the use of lactose 100M.
In rotary processing, the tumbling motion on the frictional plate helped in
spheronizing the pellets. The presence of surface moisture on primary particles
imparted plasticity to the aggregates and assisted deformation during collisions,
producing pellets with higher sphericity. In this study, the range of water used
produced similar sized pellets for all three lactose grades. Rotary processing is a
dynamic pelletization process with nuclei formed from primary particles, which
allowed a sequential packing of component particles. In comparison to lactose 100M,
pellets of a similar dimension prepared with lactose 450M consisted of a larger
number of primary particles. The higher number of particles enhanced packing during
rotary processing as it is easier for smaller particles to rearrange themselves and fill
up spaces between protrusions on pellet surfaces.
In the presence of water, the capillary forces pulled solid particles together and
aided aggregate consolidation. With the addition of more water, the resultant higher
plasticity and deformability of the aggregates worked against frictional forces
between primary particles. Densification of aggregates was enhanced. Moreover,
increased surface moisture provided a lubricative function which assisted particle
rearrangement and packing during consolidation.
123
14 14
12 12
10 10
8 8
6 6
Porosity (%)
Porosity (%)
4 4
2 2
0 0
30 32 34 36 38 40 42 44 46 48 50 0 0.5 1 1.5 2 2.5
124
Figure 29. Porosity of pellets prepared by rotary processing (open) and extrusion spheronization (closed) (Lactose
grades ∆▲ 100M, ○● 200M, □■ 450M).
6 6
5 5
4 4
3 3
2 2
Median pore diameter (µm)

Median pore diameter (µm)
1 1
0
0
30 32 34 36 38 40 42 44 46 48 50
0 0.5 1 1.5 2 2.5
Figure 30. Median pore diameter of pellets prepared by rotary processing (open) and extrusion spheronization (closed)
125
(Lactose grades ∆▲ 100M, ○● 200M, □■ 450M).
A smaller median pore diameter indicated closer packing of primary particles.
The median pore size was mainly dependent on the lactose grades used. With larger
particle size, the packing of lactose 100M particles tend to leave larger interval
between each other due to the lack of fine component particles filling the space.
Compared with the effect of increased amounts of water, lactose particle size was a
more evident factor in affecting the packing of the primary constituent materials in the
pellets. It was also found that the porosity of pellets prepared using lactose 450M was
lower. A contribution to porosity was also the amount of dissolved solids in the
binding liquid. For lactose 450M, its smaller particle size caused the dissolution of
lactose into the binding liquid. Thus, on drying, more of this dissolved lactose was
deposited, contributing to decreased pellet porosity.
D2 Studies in extrusion spheronization
A trend of increasing pellet size with increasing amounts of added water was
also noted for all three lactose grades in extrusion spheronization. However, for
extrusion spheronization, the sequence of slope values was 100M>200M>450M,
opposite to that found for rotary processing (Table 19). For 450M lactose, a plateau
was observed, indicating a very small nett change in mean pellet size against amount
of water added (Figure 22). Similar to rotary processing, finer lactose grades showed
higher water requirements for achieving pellets with equivalent mean size.
In extrusion spheronization, water addition was carried out in a mixer under
constant agitation and kneading with an impeller. The wetted mass was forced
through dies and preformed into cylindrical noodle-like extrudates during the
extrusion step. Consequently, a uniform water distribution within the wetted mass
could be achieved regardless of the lactose grade used. However, since lactose 100M
126
possessed lower specific surface area, it was easier to achieve liquid saturation and
surface plasticity to assist coalescence. Hence, lactose 100M showed a larger
increment in pellet size with same amount of water. This explained the slope sequence
of the regression lines: 100M>200M>450M (Table 19).
Lactose 450M with higher specific surface area required more water for
wetting. This condition imparted a cushioning effect on the water addition resulting in
an overall smaller increase in pellet size against amount of water added. With its
relatively lower slope value, fine lactose possessed better process robustness in
extrusion spheronization due to its lower sensitivity to variation in water content.
The three lactose grades resulted in very similar span values and behaved
rather similarly with increasing moisture addition (Figure 23). There existed a
minimum value for span which corresponded to mean pellet size around 1 mm.
Oversized fractions were not found in these products within the range of water used in
this study. The maximum yields achieved were very high reaching 100% (Figure 25).
With fine lactose, a wider range of water could produce high yields. For lactose
100M, only two water levels resulted in yields higher than 80%. This high yield
corresponded to mean pellet size around 1 mm (Figure 25).
In extrusion spheronization, uniform water distribution during the wet massing
step prevented the formation of over-wetted regions which favored lump formation.
During spheronization, a precise balance between brittleness and plasticity of the
extrudates was necessary for the production of high quality pellets. With insufficient
water (just barely enough for pellet formation), extrudates were brittle and
considerable amounts of fines resulted during spheronization caused by collisions
against the frictional plate. On the other hand, over-wetting presented excessive
amounts of water on the surfaces of particles and agglomerates favoring coalescence,
127
and resulted in the formation of lumps. The production of lumps and fines also led to
the production of pellets with wider size distribution. With appropriate amounts of
water, production of lumps and fines can be limited or even non-existent. Hence, a
narrow span value existed corresponding to the amount of water required to produce
pellets around 1 mm. As there were two additional steps of wet massing and
extrusion, the impact of various lactose particle sizes was not obvious.
High yields seen in Figure 25 corresponded to usage of appropriate amounts of
water for extrusion spheronization. Insufficient or excessive amounts of water did not
produce pellets with mean size within the usable range of 0.71 and 1.4 mm. For
lactose 200M and 450M, high yields were obtained within wide water ranges showing
more robust processes.
The most spherical pellets prepared by extrusion spheronization were with
lactose 450M (Figures 26-28). With lactose 200M, 41% water produced highly
spherical pellets (Circularity >0.93, Aspect ratio <1.1 and eR>0.6) of about 1 mm
mean pellet size, while a range of water (42-46%) existed for lactose 450M to achieve
pellets of similar quality. Lactose 100M did not favor the production of highly
spherical pellets. As rotary processing, dense pellets with porosity values of 5-14%
were similarly produced in extrusion spheronization (Figure 29). A much larger
median pore diameter of pellets prepared with lactose 100M indicated more porous
pellets (Figure 30).
Fine lactose particles were necessary for the rounding process in pelletization
and, thus, the fine lactose 450M made pellets that were more spherical. A similar
explanation based on the number of particles required to form each aggregate, as for
rotary processing, could also be applied for extrusion spheronization. The lactose
solubility effect was more evident in extrusion spheronization than in rotary
128
processing because of the relatively longer process time. During the granulation and
extrusion steps, materials packed closely as a consequence of kneading and extrusion
further assisted the lactose powder to dissolve in water. For lactose 450M, it would
readily dissolve in water especially when large amounts of water were present. These
particles could then recrystallize especially on the surface of pellets during drying and
may contribute in part to the rounding of pellets.
As explained before, the precise balance of brittleness and plasticity of
extrudates assisted the rounding process on the frictional plate during spheronization.
Pellets with the highest sphericity had mean size around 1 mm since the die diameter
in this study was 1 mm. The time for each spheronization run was fixed at 10 min.
Less time would be allocated to round the formed pellets if coalescence was occurring
at the same time, hence the lower sphericity of larger pellets. Theoretically, if enough
time were allowed for spheronization of extrudates produced with high amounts of
water, higher sphericity should be achieved.
Fine lactose 450M resulted in dense pellets with low porosity especially when
sufficient amount of water was provided (Figures 29 and 30). The highest porosity
values observed in pellets prepared from lactose 100M could be attributed to the large
particle size of the primary particles. These large particle encountered more difficulty
in rearrangement within pellets. The lack of small particles to fill up cavities in
between the coarse lactose particles produced a relatively less dense packing of
primary particles, giving pellets with relatively higher porosity and larger median pore
size. The deposition of the dissolved lactose 450M also contribute to the lower
porosity.
129
D3 Choice of lactose grades in spheronization processes
In rotary processing, coarse lactose particles produced more uniform pellets
(narrow size distribution) and fewer lumps (low oversized fraction) with better
process robustness (lower sensitivity to water content variation in pellet mean size and
yield). However, finer lactose should be used to achieve high sphericity in pellets. It
appeared that none of the three lactose grades used possessed all these advantages at
the same time for pellet production by rotary processing. Hence, the choice of lactose
grades depended on which properties were more highly sought for by the formulator.
In extrusion spheronization, finer lactose worked very well in producing uniform
pellets with high yield and sphericity. The process robustness was also best for fine
lactose grades with less sensitivity to variation in water content and a comparatively
wider range of water could be used to produce high pellet yields.
E. Functionality of crospovidone as a new spheronization aid in extrusion
spheronization
MCC is the most commonly-used spheronization aid to alter the rheological
properties of wetted masses to achieve the desired properties for pellet formation.
Examination of the physical properties of crospovidone showed many of the
necessary features present as required for a good spheronization aid. Thus, it was of
interest to further examine the use of crospovidone. The functionality and possible
mechanism of action for crospovidone as a spheronization aid was investigated using
both a small and large scale spheronizer in the extrusion spheronization process.
Effects of processing variables on the quality of pellets formed in large scale
extrusion spheronization were evaluated using a Box-Behnken experimental design.
Results from selected runs obtained from this experimental design were compared to
130
those from extrusion spheronization using a standard grade of MCC to evaluate the
potential and feasibility of crospovidone as a possible substitute for MCC.
E1 Postulated mechanism of pellet formation with crospovidone
For an excipient to function effectively as a spheronization aid, the amount of
water added must be adequate for surface hydration and saturation of its internal pore
spaces. The saturated pores are analogous to a reservoir that can control the uptake
and release of water under certain pressure conditions such as during extrusion and
spheronization. While many excipients are able to hydrate in the presence of water,
they lack an internal water store of adequate rigidity that could be utilized to modulate
the amount of water released under pressure for lubrication during extrusion and for
surface plasticization during spheronization. By far, MCC is the ideal excipient that
can achieve this precise control and balance of water movement in and out of the
pores during extrusion spheronization. Two models have been proposed to explain the
role of MCC in extrusion spheronization where it has been likened to a sponge
(Fielden et al., 1988) and a crystallite-gel (Kleinebudde, 1997).
In this study, crospovidone was found to possess similar abilities to control the
distribution and release of water during extrusion spheronization. It was believed that
crospovidone possesses an internal reservoir of water that could be mobilized under
appropriate pressure ranges. The water holding and controlling capability of
crospovidone was possibly related to its cross-linked arrangement which could form a
mesh-like structure around the internal water reservoir. The mesh-like structure
possesses both rigidity and flexibility to allow the absorption-release-reabsorption of
water during wet massing (moistening), extrusion (lubrication and moistening) and
131
spheronization (surface plasticity). In this respect, it is similar to the sponge model
proposed by Fielden et al. (1988) for MCC.
Mixer torque rheometer can be used to assess the mixing resistance of
moistened powder masses in granulation studies (Chatlapalli and Rohera, 1998).
Functionality and performance of a spheronization aid hinge strongly on its
interaction with water which will in turn, be reflected in the consistency of the wetted
mass containing the spheronization aid. The relationship between the torque
rheological characteristics of wetted masses (containing MCC) and their eventual
ability to be spheronized had been reported (Soh et al., 2004). Thus, it is likely that a
moistened mass that possesses rheological properties like that of MCC will have
similar effectiveness or efficiency as the latter in facilitating spheronization.
Irrespective of the amounts of water added, the moistened XL-lactose mixture
failed to achieve a sufficiently cohesive state for any appreciable torque responses to
be generated. There was no observable increase in cohesion or integration with the
addition of water to the powder mass. The mixer blades of the mixer torque rheometer
were able to rotate within the bulk material with minimal resistance. Therefore, only
the torque profiles of the other two crospovidone-lactose mixtures were presented
together with that of the MCC-lactose mixture in Figure 31.
Torque rheological behaviors for the moistened crospovidone-lactose mixtures
gave valuable insights on the interaction of crospovidone with water during wet
massing (Figure 31). Compared to the MCC-lactose mixture, larger amounts of water
had to be added before the crospovidone-lactose powder mixtures can produce
cohesiveness to provide resistance during mixing in the mixer torque rheometer which
was then reflected as torque responses.
132
Figure 31. Effect of added water levels and mixing times on the torque profiles of MCC-lactose, XL-10-lactose, and INF-10-
lactose powder mixtures. Torque values in [Nm] Newton meter.
133
This observation suggested that the capacity of crospovidone for moisture was
high but appreciable binding only occurred at higher water contents than was seen for
MCC. Moreover, the magnitude of torque responses generated with crospovidone-
lactose mixtures were lower than those of MCC-lactose mixture and this meant that
the consistencies of their moistened masses were not equivalent. This signified the
possibility that pellets could also be prepared using crospovidone as the
spheronization aid provided that sufficient water was available.
Disparities between the binding properties of MCC and crospovidone were
also manifested as differences in processing variables and water requirements during
pellet production. The working range of added water levels for pellet production was
higher for the crospovidone grades (from the small scale extrusion spheronization
experiments), reflecting larger amounts of moisture required to quench the internal
pores. This gave rise to the much wetter appearance of its moistened masses and
subsequently forming extrudates that were longer and smoother. The reduced
spheronization speed using crospovidone containing formulation also indicated the
comparatively lower binding properties.
E2 Performance of various crospovidone grades in small scale extrusion
spheronization
The wetted crospovidone-lactose mixtures appeared to possess much higher
surface wetness than the MCC-lactose mixtures at equivalent water levels for
obtaining pellets with a mean size of 1 mm. The former were also mixed and extruded
with greater ease. Their extrudates were continuous, long and smooth, without the
characteristic shark-skinned appearance of extrudates prepared with MCC. This
observation was also noted in the large scale extrusion spheronization experiments.
134
Of the three crospovidone grades evaluated, only the large particle size grade,
XL, failed to exhibit spheronization aid properties regardless of the lactose grade and
spheronization conditions employed. To provide a plausible explanation of this
phenomenon, its physical properties and rheological behavior were examined.
Firstly, its large particle size reduced the surface area for effective contact and
interaction with the other constituent ingredients (added water and lactose) in the
powder mass. Its sheer size also made it more difficult for the entrapped water (deep
within the core of the particles) to participate in the toggling between moisture
release/absorption during spheronization. This poor interaction was also demonstrated
by the unappreciable torque responses generated for the XL-lactose mixture,
irrespective of the amount of water added in the experiments.
The strong binding of moistened masses containing MCC is provided by the
hydrogen bonding forces contributed by MCC surfaces. Likewise for crospovidone,
its ability to participate in hydrogen bonding enabled it to be a substitute for MCC.
For such interactions, surface area is crucial but the large particle size of XL
effectively reduced the surface area for hydrogen bonding; thus the minimal binding
strength of the XL-lactose mixtures.
Contrary to XL, pellets were prepared with the other two crospovidone grades.
Between XL-10 and INF-10, the coarser XL-10 required a higher amount of water to
produce pellets of comparable sizes (Figure 32). This was because smaller sized
particles had larger surface area for hydrogen bonding and interaction with bulk
material to contribute to the spheronization aid function. Thus, pellets could be
formed at a lower water level when the finer crospovidone grades were used as
spheronization aids.
At very low water levels, the crospovidone particles were not sufficiently
135
hydrated to perform its binding function in facilitating spheronization efficiently.
Consequently, a considerable portion of the powder mixture appeared brittle and dry,
and could not be rounded effectively into pellets. As the added water level increased,
size distribution of the pellets began to narrow, owing to better wetting and more
effective spheronization (Figure 33).
For both XL-10 and INF-10, the span values of their pellets reached a
minimum at 60% and 55% water respectively. These water levels could be regarded
as the optimal levels for attaining pellets with the narrowest size distribution,
corresponding to a mean pellet size of approximately 1.2 mm. Further increase in
added water levels resulted in an overwetted state where uncontrolled coalescence of
pellets occurred reflected by the increased oversized fraction (Figure 34). Some of the
overwetted extrudates adhered onto the spheronizer wall or the frictional plate instead
of flowing with the bulk in a rope-like motion as they were being spheronized.
Evidently, pellet batches containing XL-10 and INF-10 as the spheronization aid
could be prepared with high yields within the desirable size fraction with water level
range of 40–60 %. Furthermore, pellet growth rate was reproducible and predictable
with increases in water levels.
E3 Effects of operating variables in large scale extrusion spheronization
E3.1 Reproducibility of the process
Firstly, the process reproducibility was assessed from the properties of pellets
prepared from Runs 25, 26 and 27. It can be seen from Table 20 that all the variables
in these 3 runs were set at level zero which corresponded to the central value for each
of these variables. As these three runs were identical in operating parameters, their
pellet properties would represent the reproducibility of this process.
136
1.6 1.6
A B
1.4 1.4
1.2 1.2
1 1
0.8 0.8
0.6 0.6

0.4 0.4
0.2 0.2
0 0
35 40 45 50 55 60 65 70 35 40 45 50 55 60 65 70
Added water level (%) Added water level (%)
Figure 32. Mean size of pellets prepared using small scale extrusion spheronization (A) XL-10 and (B) INF-10.
(Lactose grades ∆ 100M, ● 200M, □ 450M).
137
1.2 1.2
A B
A
1 1
0.8 0.8
0.6 0.6
Span
Span
0.4 0.4
0.2 0.2
0 0
35 40 45 50 55 60 65 70 35 40 45 50 55 60 65 70
Figure 33. Span of pellets prepared using small scale extrusion spheronization (A) XL-10 and (B) INF-10.
138
70 70
A B
60 60
50 50
40 40
30 30

20 20
10 10
0 0
35 40 45 50 55 60 65 70 35 40 45 50 55 60 65 70
Figure 34. Oversized fraction of pellets prepared using small scale extrusion spheronization (A) XL-10 and (B) INF-10.
139
Variations between Runs 25, 26 and 27 were found to be very small for most
of the factors evaluated as indicated by the very small coefficient of variance values
(Table 20). These results established the excellent reproducibility of this experimental
design, thus eliminating the need for replicates for the other runs stipulated in the
matrix. At the same time, these conditions were proven to be satisfactory for pellet
production, albeit all variables at level zero.
Table 20. Process reproducibility (physical properties of pellets).
Mean Oversized Aspect

Span Yield Circularity eR Friability
Run size fraction ratio
(mm) (%) (%) (%)
25 1.10 0.21 98.53 0.02 0.93 1.21 0.46 1.62

26 1.09 0.21 97.75 0.15 0.92 1.25 0.40 1.50
27 1.10 0.23 97.86 0.14 0.92 1.25 0.40 1.56
Average 1.10 0.21 98.05 0.10 0.92 1.24 0.42 1.56
Standard
0.00 0.01 0.42 0.01 0.00 0.03 0.03 0.06
deviation
Coefficient
0.38 5.19 0.43 66.71 0.46 2.23 7.64 3.85
of variance
E3.2 Effects of operating variables on pellet quality
Physical properties of pellets from each experiment of the Box-Behnken
design were tabulated in Table 21. Pellets in Blocks ii, iv, vi and vii were prepared
when the spheronization aid concentration was set at 25%. This makes them useful for
comparison with the MCC pellets (to be discussed in the following section) which
were also prepared with 25% MCC or MCC-lactose ratio of 1:3.
140
Table 21. Physical properties of pellets prepared with XL-10 and lactose 200M.
Run Mean Oversized Aspect

Block Run Span Yield Circularity eR Friability
code size fraction ratio
(mm) (%) (%) (%)
1 cw 1.13 0.26 98.26 0.10 0.92 1.21 0.45 1.92

i 2 Cw 1.08 0.17 97.11 0.11 0.90 1.27 0.40 2.46
3 cW 1.26 0.24 93.49 0.62 0.93 1.16 0.50 2.04
4 CW 1.10 0.23 97.41 0.47 0.92 1.25 0.42 6.16
5 st 1.06 0.22 97.48 0.14 0.85 1.43 0.29 2.79

ii 6 St 1.24 0.41 89.80 1.08 0.85 1.23 0.40 4.34
7 sT 1.07 0.19 99.24 0.00 0.92 1.32 0.38 1.38
8 ST / / / / / / / /
9 cs 1.07 0.18 98.42 0.19 0.90 1.34 0.36 2.03

iii 10 Cs 1.06 0.22 98.31 0.01 0.89 1.40 0.33 1.60
11 cS / / / / / / / /
12 CS / / / / / / / /
13 wt 1.06 0.24 94.97 0.14 0.87 1.32 0.35 3.54

iv 14 Wt 1.08 0.22 96.14 0.58 0.89 1.25 0.41 1.89
15 wT 1.13 0.28 97.93 0.12 0.93 1.22 0.44 1.64
16 WT 1.24 0.26 95.88 0.39 0.94 1.19 0.47 1.37
17 ct 1.07 0.24 95.34 0.26 0.92 1.25 0.40 2.25

v 18 Ct 1.07 0.21 96.35 0.29 0.86 1.32 0.34 2.90
19 cT / / / / / / / /
20 CT 1.27 0.17 91.68 1.38 0.93 1.20 0.45 0.95
21 ws 1.06 0.21 98.17 0.10 0.88 1.37 0.34 1.86

vi 22 Ws 1.08 0.19 97.18 0.28 0.90 1.41 0.32 1.71
23 wS / / / / / / / /
24 WS / / / / / / / /
CW
vii 28 ST 1.31 0.27 73.84 0.62 0.95 1.11 0.57 0.29
141
Within these four blocks, only Runs 8, 23 and 24 failed to produce pellets
successfully. Inspection of their operating parameters showed that high spheronization
speeds were employed in these three runs, despite variations in the spheronization
time (Run 8) and added water level (Runs 23 and 24). Excessive lump formation and
wall adhesion occurred in many runs when a high spheronization speed was employed
(Runs 8, 11, 12, 23 and 24) unless the spheronization time was short (Runs 5 and 6) or
when the XL-10 concentration and water levels were high (Run 28).
Elevated levels of spheronization speed and/or time could result in excessively
high shear forces that the extrudates were unable to withstand. The inability to
withstand strong shear forces was indicative of weak cohesive and binding properties
of the extrudates. Clearly, a balanced system of supplied mechanical energy,
residence time and added water level is critical for the extrudates to attain the precise
equilibrium between cohesiveness and surface plasticity so that they can remain as
integrated entities and be spheronized.
On the whole, the runs in Block i yielded pellets with more favorable
properties (Table 21). In particular, the shape factors of pellets in these runs were
superior. As spheronization speed and time were kept constant, runs in this block
represented the interaction between XL-10 concentration and water level. This
suggested that these two variables and their interaction were most influential in the
formation of good quality pellets.
The ability and performance of XL-10 as a spheronization aid is inevitably
associated with the concentration of water present. With adequate water levels, XL-10
was able to modify the rheological properties of the wetted mass so as to produce a
plastic yet cohesive mass suitable for successful pellet formation. During wet
massing, water served to moisten and bind the wetted masses containing XL-10.
142
Thereafter, it aided in the lubrication and plasticization of the wetted mass during
extrusion and spheronization with XL-10 acting as a repository for excess moisture.
Since XL-10 absorbs water more readily than lactose, a larger amount of water
was needed when the concentration of the former was increased. When XL-10
concentration was kept constant, higher water levels tended to produce larger pellets
with an accompanying increase in the % oversized fraction. This was due to
coalescence of overwetted agglomerates, leading to a snow-balling effect.
Nevertheless, spherical pellets with a comparatively narrow size distribution and good
yield could be obtained by modulating the levels of XL-10 concentration and water
only.
Pellets with the most favorable shape factors were formed in Run 28 where all
the variables were set at the high level (Table 21), suggesting that this was the most
promising combination for producing highly spherical pellets in the current study.
More notably, such high quality pellets were produced even though existing
conditions were not be fully optimized.
E3.3 Comparison of crospovidone-lactose pellets with MCC-lactose pellets
For MCC, pellets with the most favorable shape factors (Table 22) were
prepared with 41% and 43% water (corresponding to water coefficient values of 1.04
and 1.12) whereas pellets from Run 28 (Table 21) were chosen to represent the
performance of crospovidone (as exemplified by XL-10).
143
Table 22. Physical properties of pellet prepared with MCC and lactose 200M.
Added
Mean Oversized Aspect
water W Span Yield Circularity eR Friability
size fraction ratio
level
(%) (mm) (%) (%) (%)
39 0.96 0.71 0.57 38.87 0.00 0.94 1.11 0.58 0.45

41 1.04 0.91 0.27 84.45 0.00 0.95 1.09 0.60 0.46
43 1.12 1.10 0.27 99.78 0.00 0.94 1.12 0.58 0.13
45 1.2 1.57 0.31 88.60 0.00 0.93 1.11 0.57 0.09
[W]: Water concentration coefficient
Crospovidone–lactose pellets compared very favorably to those of MCC-
lactose, especially in their shape factors. Though larger pellets were produced with
crospovidone, they were of a narrow size distribution with very little oversized
fraction and an acceptable yield. The friability of pellets was also comparable to that
of MCC pellets indicating good mechanical property. Due to their differences in the
moisture holding ability, crospovidone required higher amounts of added water. As
there is relatively lower overall cohesiveness, less aggressive formation conditions
(longer spheronization at reduced speeds) are required to avoid high shear induced
attrition. Elevated water levels ensured sufficient liquid saturation in crospovidone to
allow its binding properties to be demonstrated while the longer spheronization times
compensated for the reduced speed. This is because it is imperative that the overall
supplied energy is adequate for spherical pellets to be produced.
144
… CONCLUSION
V. CONCLUSION
Four independent variables, frictional plate speed during liquid addition stage,
water addition rate, amount of water added and frictional plate speed during tumbling
stage, were evaluated for their influence on the quality of pellets using an orthogonal
design. The higher amount of water added resulted in a larger mean pellet size and
higher oversized fraction. For frictional plate speed during the tumbling stage, a
higher speed led to larger mass median diameter as well as a smaller span value. The
two variables, amount of water added and frictional plate speed during the tumbling
stage, played significant roles in affecting pellet size and size distribution
respectively, hence were identified as more important variables in affecting pellet
quality. Due to the interaction of amount of water added and frictional plate speed
during tumbling stage, the combination of setting these two parameters at higher
levels should be avoided to reduce the formation of undesired lumps. For producing
high quality pellets, these two variables should be carefully controlled and maintained
at an optimal level.
Differences in the dimension of studs on the plates influenced the magnitude
of forces imparted by the frictional plate to the starting powder mass in rotary
processing. Consequently, the resultant pellets varied in pellet properties such as size,
size distribution, shape, friability and porosities. The forces set up by the frictional
plate must be sufficient for promoting homogeneous liquid distribution, powder mass
mixing and pellet formation without excessive coalescence and uncontrollable growth
145
… CONCLUSION
while minimizing adhesion on the plate. Short studs produced more porous pellets.
This concurred well with the expected lower shear forces that shorter studs can
impart. Plates Medium and Tall both gave pellets with better “within batch” pellet
characteristics than plate Short. Plate Medium with studs of medium height was also
demonstrated to give the best overall reproducibility in this study. A balance between
good reproducibility and “within batch” pellet characteristics with minimal material
adhesion could be achieved with plate Medium. Hence, under the similar formulation
and processing conditions used in this study, plate Medium was concluded as the most
suitable among three plates with teardrop studs. However, if higher loads are to be
used, plate Tall may be more suitable as it was shown to be able to support higher
loads. When larger loads are used, the amount of material loss attributed to adhesion
of moist material onto the rotating frictional base plate also becomes less critical as it
accounts for a smaller percentage of the total load used for pellet production.
C. Feasibility of eliminating of pre-mixing in rotary processing
Pellets prepared with and without pre-mixing using four loading methods of
starting materials were compared and no significant difference could be attributed to
the effect of pre-mixing. Among the three loading configurations without pre-mixing,
there was no obvious advantage of one configuration over the others in terms of pellet
quality. Comparing pellets prepared in three conditions, it was clear that the best
pellets were obtained under optimal formulation and process conditions, regardless of
whether pre-mixed starting materials were used or not. The good mixing efficiency of
the frictional rotating plate in the rotary processor enabled pellets of comparable
quality to be produced even in the absence of pre-mixing. These finding suggested
that pre-mixing of the starting materials could be eliminated for pellet production in a
146
… CONCLUSION
rotary processor. Without the pre-mixing step, considerable time could be saved and
this would undoubtedly increase the throughput of pellet production in rotary
processing. However, it may be judicious to co-feed the different powders to achieve
some preliminary mixing during loading under extreme processing conditions.
Effect of lactose particle size was studied for their performance in preparing
pellets using rotary processing and extrusion spheronization. In rotary processing,
coarse lactose 100M produced more uniform pellets with less oversized fraction and a
better robustness of the process indicated by low sensitivity to water content variation
in pellet mean size and yield. Fine lactose 450M gave pellets of high sphericity.
Lactose 200M provided a compromise by showing all desirable pellet and process
attributes in rotary processing. In extrusion spheronization, lactose 450M worked very
well in producing uniform pellets with high yield and good sphericity. The process
robustness was also best for lactose 450M with less sensitivity to variation of water
content and wider range of water to produce high yield. Hence, the choice of lactose
grade depended on which properties were of greater concern to the formulator.
E. Functionality of crospovidone as a new spheronization aid in extrusion
spheronization
Three grades of crospovidone were evaluated for their abilities to function as
spheronization aids in extrusion-spheronization; of which the two finer crospovidone
grades, XL-10 and INF-10, showed great potential in functioning as effective
spheronization aids. The mechanism of pellet formation using crospovidone as a
spheronization aid has been postulated as such: added water is readily taken up by
147
… CONCLUSION
crospovidone, forming a hydration layer around the particles. With increasing water
levels, its internal pores are gradually filled and saturated. The cross-linked structure
of crospovidone behaves as a mesh to prevent the loss of water trapped within the
internal pores; thus providing a repository for water, like a reservoir. In these aspects,
its mechanism of action resembled the sponge model proposed for MCC. Although
both crospovidone and MCC are capable of hydrogen bonding, the binding ability of
crospovidone was comparatively lower. This gave rise to compensatory increases in
water requirements before crospovidone could demonstrate appreciable binding
properties. The weaker binding capability of crospovidone was demonstrated in its
torque rheological properties, greater ease of mixing and extrusion, as well as the
inability of its pellets to withstand high spheronization speeds.
Crospovidone concentration and water level were deemed to be most critical
in obtaining pellets of desirable quality. The best pellets were produced when all the
variables were set at the higher operating level and were of comparable quality to
those prepared with MCC. Most significantly, these pellets could be produced under a
relatively broad range of conditions that have yet to be fully optimized.
These findings proved that a robust pelletization process is possible with the
finer crospovidone grades which served to aid pellet formation in extrusion-
spheronization. In contrast to most of the previously proposed materials, crospovidone
does not require the addition of binders before it can perform its functions as a
spheronization aid. Like MCC, it is able to yield high quality pellets as a single
functional excipient in the formulation. With more extensive studies and further
material optimization, there is tremendous potential for crospovidone to serve as a
competent alternative to MCC in extrusion spheronization.
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… PUBLICATIONS
VII. PUBLICATIONS
Publications in Journals
1. Gu, L., Liew, C.V., Soh, J.L.P., Heng, P.W.S., 2005. Feasibility of eliminating
pre-mixing for the production of pellets in a rotary processor. Pharm. Dev.
Tech. In Process.
2. Liew, C.V., Gu, L., Soh, J.L.P., Heng, P.W.S., 2005. Functionality of cross-
linked polyvinylpyrrolidone as a spheronization aid: A promising alternative to
microcrystalline cellulose. Pharm. Res. 22, 1387-1398.
3. Gu, L., Liew, C.V., Heng, P.W.S., 2004. Wet spheronization by rotary
processing - A multi-stage single-pot process for producing spheroids. Drug
Dev. Ind. Pharm. 30, 111-123.
4. Liew, C.V., Gu, L., Heng, P.W.S., 2002.The influence of operational variables
on mean size and size distribution of spheroids produced by rotary
spheronization using teardrop studs. Int. J. Pharm. 242, 345-348.
5. Heng, P.W.S., Liew, C.V., Gu, L. 2002. Influence of teardrop studs on rotating
frictional base plate on spheroid quality in rotary spheronization. Int. J. Pharm.
241, 173-184.
Conference/Poster Presentation
1. Liew, C.V., Gu, L., Jakobsen, L.S., Heng, P.W.S. Comparison of water
requirement with lactose of different size in the rotary processing and
extrusion-spheronization, American Association Pharmaceutical Sciences
(AAPS) Annual Meeting and Exposition, October 2003 (Salt Lake city/USA).
2. Heng, P.W.S., Liew, C.V., Gu, L. Influence of the type of teardrop-shaped

studs on the packing properties of rotary processed spheroids. American
Association Pharmaceutical Sciences (AAPS) Annual Meeting and Exposition,
November 10-14, 2002 (Toronto/Canada), pp. 146. Poster Number W5317.
3. Gu, L., Liew, C.V., Heng, P.W.S. The influence of four selected variables on
mean size and size distribution of spheroids produced by rotary spheronization,
13th International Symposium on Microencapsulation, September 5-7, 2001
(Angers/France), pp. 027.
4. Liew, C.V., Gu, L., Heng, P.W.S. Influence of teardrop studs on frictional plate
on spheroid quality in rotary spheronization, 10th International Pharmaceutical
Technology Symposium — Development and Delivery Challenges of the next
Generation of Drugs, September 2000 (Istanbul / Turkey), pp. 195-196.
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STUDIES ON SPHERONIZATION PROCESSES BY

ROTARY AND EXTRUSION

NATIONAL UNIVERSITY OF SINGAPORE

A THESIS SUBMITTED FOR THE DEGREE OF

I wish to express my deepest and most sincere appreciation to my supervisors,

throughout my whole life.

I am grateful to the GEA-NUS Pharmaceutical Processing Research

Laboratory, Department of Pharmacy for the use of research facilities, as well as to

the National University of Singapore for providing the postgraduate research

my family, especially my husband Sun Jinhui, parents and parents-in-law.

LIST OF TABLES viii

A. Historical background and terms 1

C. Formation and growth of pellets 4

C2 Mechanism for agglomerate formation and growth 6

D. Pelletization by extrusion spheronization and rotary processing 12

D1.1 Equipment used 13

D1.2 Formulation variables 15

D1.2.1 MCC acting as spheronization aid 16

D1.2.2 Substitute for MCC as spheronization aid 18

D1.2.4 Moistening liquid 28

D1.2.5 Particle size of filler 29

D1.3 Process variables 29

D2.1 Equipment used 31

D2.2 Formulation and process variables 39

D2.2.1 Type and content of MCC 40

D2.2.2 Type and content of moistening liquid 42

D2.2.3 Particle size of filler 43

D2.2.4 Material loading methods 44

D2.2.5 Speed of frictional plate 45

D2.2.6 Spheronization time 46

D2.2.7 Moistening liquid addition rate 47

D2.2.8 Atomizing and gap air pressures 48

D2.2.9 Load size 49

D2.2.10 End point monitoring 49

B. Physical characterization of starting materials 55

B1 Particle size and size distribution 55

B2 Specific surface area 55

B5 Bulk and tapped densities 57

C. Methods of preparing pellets 57

C2.1 Small scale 61

C2.2 Large scale 61

D1 Mean size, size distribution, oversized fraction, fines and yield 62

D3 Bulk and tapped densities 64

E. Rotary processing and extrusion spheronization studies 67

E1 Influence of operational variables in rotary processing 67

E2 Effect of frictional plate design in rotary processing 69

E2.1 Characterization of teardrop studded frictional plates 69

E2.2 Preparation and characterization of pellets prepared by rotary 72

E3 Feasibility of eliminating of pre-mixing in rotary processing 73

E4 Effect of lactose particle size in spheronization processes 75

E5 Functionality of crospovidone as a spheronization aid in extrusion 77

E5.1 Torque rheological properties 77

E5.2 Preparation of pellets by small and large scale extrusion 78

IV. RESULTS AND DISCUSSION 83

A. Influence of operational variables in rotary processing 83

B. Effect of frictional plate design in rotary processing 88

B3 Mean size, size distribution, oversized fraction and fines 91

B5 Density and friability 98