Er ZLD

A STUDY ON BOTTOM-SPRAY GRANULATION AND
ITS POTENTIAL APPLICATIONS
ER ZHI LIN DAWN
NATIONAL UNIVERSITY OF SINGAPORE
2010
A STUDY ON BOTTOM-SPRAY GRANULATION AND
ITS POTENTIAL APPLICATIONS
ER ZHI LIN DAWN

B.Sc. (Pharm.) Hons., NUS
A THESIS SUBMITTED
FOR THE DEGREE OF DOCTOR OF PHILOSOPHY
DEPARTMENT OF PHARMACY
NATIONAL UNIVERSITY OF SINGAPORE
2010
ACKNOWLEDGEMENTS
I would like to express my heartfelt thanks to my supervisors, Asst. Prof Celine Liew and A/P
Paul Heng for their guidance and the opportunities they have given me to learn and grow
during the course of my study.
I am indebted to NUS for providing me with a research scholarship to fund this higher degree,
and to the Department of Pharmacy and its administrators for the facility and support during
my candidature.
I also wish to thank A/P Chan Lai Wah for her concern and advice throughout my candidature.
Special thanks to Mrs Teresa Ang, Mr Peter Leong and Ms Wong Mei Yin, the laboratory
technologists during my course of study for their technical assistance.
I am fortunate to have been in the company of a group of supportive and helpful fellow
postgraduates in GEA-NUS PPRL. They have made the laboratory a very pleasant and
conducive place to work in. I would like to especially thank Elaine, Zhihui, Sook Mun, Yihui,
Atul, Likun, Stephanie, Wun Chyi and Christine for their invaluable friendship.
Finally, my deepest gratitude belongs to my dear family and friends, especially to my parents,
for their faith and belief in me. I am grateful to my beloved husband, Dale, for his loving
support and patience during this work. I will also like to thank my best friend, Serena, for her
constant encouragement.
Dawn, 2010
ii
DEDICATION
For my parents, Chin Lam and Hwee Kiang
iii
Table of contents
TABLE OF CONTENTS
ACKNOWLEDGEMENTS ...........................................................................................ii
DEDICATION ............................................................................................................. iii
TABLE OF CONTENTS .............................................................................................. iv
SUMMARY ................................................................................................................... x
LIST OF TABLES .......................................................................................................xii
LIST OF FIGURES .................................................................................................... xiv
LIST OF SYMBOLS .................................................................................................xvii
I. INTRODUCTION ............................................................................................... 2
A. BACKGROUND .............................................................................................. 2
A1. Significance of granulation ......................................................................... 2
A2. Types of granulation ................................................................................... 4
A2.1. Dry granulation processes ................................................................... 4
A2.2. Wet granulation processes ................................................................... 5
B. FLUIDIZED BED GRANULATION ............................................................... 9
B1. Techniques of spray .................................................................................. 11
B2. Advantages and challenges ....................................................................... 14
B3. Parameters influencing the process and granule quality ........................... 16
B3.1. Material related factors ...................................................................... 17
B3.2. Process related factors during the liquid binder addition
phase ............................................................................................... 20
B3.3. Process related factors during the drying phase ................................ 22
C. RECENT ADVANCES IN FLUIDIZED BED GRANULATION ................ 25
C1. Process analytical technology (PAT) in fluidized bed granulation ........... 25
C1.1. Moisture content ................................................................................ 26
iv
Table of contents
C1.2. Particle size ........................................................................................ 27
C1.3. Composition of bed material ............................................................. 28
C1.4. Solid state transformations ................................................................ 28
C2. Fluidized bed granulation methods ........................................................... 29
C2.1. Fluidized bed melt granulation .......................................................... 29
C2.2. Fluidized bed binderless granulation ................................................. 31
C2.3. Bottom-spray granulation .................................................................. 32
II. HYPOTHESIS AND OBJECTIVES .............................................................. 40
A. HYPOTHESIS ................................................................................................ 40
B. OBJECTIVES ................................................................................................. 41
III. EXPERIMENTAL ......................................................................................... 44
A. MATERIALS .................................................................................................. 44
A1. Feed material ............................................................................................. 44
A2. Liquid binder ............................................................................................. 44
A3. Model drugs .............................................................................................. 44
A4. Tablet excipients ....................................................................................... 45
A5. Chemicals for dissolution media preparation and high
performance liquid chromatography (HPLC) analyses ............................. 46
B. METHODS ..................................................................................................... 47
B1. Feed material ............................................................................................. 47
B1.1. Blending of powder ........................................................................... 48
B1.2. Determination of powder particle size ............................................... 48
B1.3. Determination of powder flow with angle of repose ......................... 48
B2. Liquid binder ............................................................................................. 49
B2.1. Micronization of HCT ....................................................................... 49
v
Table of contents
B2.2. Determination of particle size of micronized HCT ........................... 50
B2.3. Preparation of HCT-incorporated liquid binder ................................ 50
B3. Granulation process ................................................................................... 50
B3.1. Real-time measurement of process conditions .................................. 52
B3.2. Determination of process drying efficiency ...................................... 54
B3.3. Determination of granule bed temperature profiles ........................... 54
B3.4. Determination of capacity for moisture removal ............................... 55
B3.5. Determination of granule bed moisture content profiles ................... 55
B3.6. Determination of air velocity within partition column ...................... 56
B3.7. Determination of process yield .......................................................... 56
B4. Characterization of granules...................................................................... 57
B4.1. Granule size ....................................................................................... 57
B4.2. Granule shape .................................................................................... 57
B4.3. Granule surface morphology ............................................................. 58
B4.4. Granule flow ...................................................................................... 58
B4.5. Granule porosity ................................................................................ 59
B4.6. Granule friability ............................................................................... 59
B4.7. Content determination of HCT in granules ....................................... 60
B4.8. Dissolution of HCT from granules .................................................... 61
B4.9. Amount of ASA degradation ............................................................. 61
B5. Compaction process .................................................................................. 63
B5.1. Heckel plot analysis ........................................................................... 64
B6. Characterization of tablets ......................................................................... 65
B6.1. Tablet surface morphology and roughness ........................................ 65
B6.2. Tablet porosity ................................................................................... 66
vi
Table of contents
B6.3. Tablet tensile strength ........................................................................ 67
B6.4. Disintegration of tablets ..................................................................... 67
B6.5. Dissolution of HCT from tablets ....................................................... 67
B7. Statistical analyses..................................................................................... 68
B7.1. Design-of-Experiment and response surface modelling .................... 68
B7.2. Multivariate data analysis .................................................................. 69
B7.3. Regression analyses ........................................................................... 69
B7.4. Other data analyses ............................................................................ 70
B7.5. Level of significance.......................................................................... 70
IV. RESULTS AND DISCUSSION ..................................................................... 72
A. ROLE OF FLUID DYNAMICS AND WETTING ON GRANULE
FORMATION IN PG .................................................................................... 72
A1. Factors influencing air velocity within the partition column .................... 73
A2. Factors influencing characteristics of granule batches ............................. 77
A2.1. Influence of variables on process yield ............................................. 77
A2.2. Influence of variables on granule size and size distribution.............. 85
A2.2.1. Influence of variables on fines ................................................... 85
A2.2.2. Influence of variables on lumps ................................................. 88
A2.2.3. Influence of variables on modal size fraction ............................ 89
A2.2.4. Influence of variables on MMD................................................. 89
A2.2.5. Influence of variables on span ................................................... 91
A2.3. Influence of variables on granule shape ............................................ 91
A2.4. Influence of variables on granule flow .............................................. 95
B. APPLICABILITY OF PG AND TG FOR SPRAY DEPOSITION OF
DRUG DURING GRANULATION ............................................................. 96
vii
Table of contents
B1. Drug content and drug content uniformity of PG and TG granules .......... 96
B2. Impact of particle circulation pattern and fluid dynamics in PG
and TG on granule growth ........................................................................ 99
B2.1. Resultant mode of granule growth in PG and TG ........................... 102
B2.2. Process sensitivity to binder spray rate and the resultant
influences on granule growth ....................................................... 106
B2.3. Process sensitivity to particle size of feed material and the
resultant influences on granule growth ......................................... 112
B3. Drug release properties of PG and TG granules ..................................... 117
B4. Flow properties of PG and TG granules.................................................. 119
C. COMPACTIBILITY STUDY ON PG AND TG GRANULES ................... 120
C1. Compaction behaviour of PG and TG granules ...................................... 120
C1.1. Influence of compactibility of granules on tablet properties ........... 126
C1.2. General relation between granule characteristics, granule
compactibility and tablet properties ............................................. 136
C2. Compaction behaviour of PG and TG granules with tablet
excipients ................................................................................................. 142
C2.1. Influence of compactibility of granules on disintegrant
efficacy ......................................................................................... 145
D. INVESTIGATIVE STUDY ON THE ABILITY OF PG TO
GRANULATE MOISTURE SENSITIVE DRUGS .................................... 150
D1. ASA stability in PG and TG during processing ...................................... 150
D1.1. Impact of particle circulation pattern and fluid dynamics in
PG and TG on ASA stability ........................................................ 155
D1.2. Influence of inlet air temperature and binder spray rate.................. 158
viii
Table of contents
D2. Factors influencing processing conditions and ASA stability in
PG ............................................................................................................ 161
D2.1. Influence of AAI diameter............................................................... 163
D2.2. Influence of inlet air temperature .................................................... 164
D2.3. Influence of binder spray rate .......................................................... 165
V. CONCLUSION ............................................................................................... 168
VI. REFERENCES ............................................................................................. 172
VII. LIST OF PUBLICATIONS ........................................................................ 211
ix
Summary
SUMMARY
The potential of bottom-spray fluidized bed granulation has not been fully realized as
research in this area had been rather limited. However with current advances in
fluidized bed equipment, there is growing interest in using the bottom-spray technique
for granulation. The gap in scientific knowledge and the improved, modified Wurster
system introduced recently, precision granulation, provided the much needed impetus
for this study.
A 33 full factorial design was employed to investigate the role of fluid dynamics and
wetting on granule formation in this process. The three factors investigated include air
accelerator insert, partition gap and binder spray rate. Measured air velocity within the
partition column was found to be largely influenced by the diameter of the air
accelerator insert and dictated granule growth in which a positive correlation to
granule size was exhibited. The partition gap played an important role in transporting
particles into the spray granulation zone, whereas the binder spray rate affected
granule shape. Unlike conventional top-spray granulation, fluid dynamics in the
bottom-spray process can be easily modulated by using different air accelerator
inserts and partition gaps to allow for flexible control of granule size, shape and flow.
The highly ordered particle circulation pattern and unique fluid dynamics in the
bottom-spray bed resulted in the presence of distinct cyclical phases of wetting,
growth and drying during granulation, thereby favouring layered growth. The strong
impact of fluid dynamics on granule growth in the bottom-spray process was observed
to cause relative insensitivity to wetting and a stronger dependence on feed material
characteristics in comparison to the top-spray process. Unlike agglomerate formation
x
Summary
by solidification of liquid bridges with the top-spray technique, layered growth with
the bottom-spray technique was found to cause precise spray deposition of drug
particles onto feed particles during granulation. The bottom-spray granules were
observed to be stronger, more spherical and flowed better than top-spray granules. A
smaller extent of granule rearrangement and slippage occurred during compaction,
and these bottom-spray granules were also found to yield more readily through plastic
deformation under pressure. The resultant tablet properties were found to be generally
similar between the two types of granules.
The highly ordered particle circulation pattern and unique fluid dynamics in bottom-
spray processing were also shown to be more advantageous to the chemical stability
of a moisture sensitive drug in comparison to the top-spray process. This was
attributed to confined, localized granulation within the partition column, with rapid
drying “targeted” at the granules after wetting. A reduction in processing time without
any adverse effect on drug stability was possible with employment of high inlet air
temperature and high binder spray rate using the bottom-spray process, provided that
process drying efficiency was not compromised.
Precision granulation was found to be an attractive alternative to the conventional top-
spray granulation process. The findings in this study were encouraging for they
highlighted the suitability of particle circulation pattern and fluid dynamics in this
process for (i) spray deposition of a micronized drug during granulation and (ii) wet
granulation of a moisture sensitive drug.
xi
List of tables
LIST OF TABLES
Table 1. Compositions of powder blends used as feed material. ................................. 47
Table 2. Formulations of liquid binder used for granulation. ...................................... 49
Table 3. Process variables and their operating conditions in PG and TG.................... 53
Table 4. Factorial design: variables and their defined levels. ...................................... 68
Table 5. Response surface modelling: regression coefficients of effect of

variables on characteristics of the granule batches. ..................................... 79
Table 6. Effect of variables on characteristics of granule batches. .............................. 80
Table 7. Analysis of variance of effect of variables on characteristics of the

granule batches. ............................................................................................. 82
Table 8. Influence of binder spray rate on PG and TG granule properties. ............... 108
Table 9. MMD, span and angle of repose of the various lactose blends. .................. 113
Table 10. Influence of lactose powder blend on PG and TG granule properties.

................................................................................................................... 116
Table 11. Influence of binder spray rate on drug release (in deionized water)
from PG and TG granules. ......................................................................... 118
Table 12. Characteristics of PG and TG granules in size fraction 355 to 500

µm. ............................................................................................................. 120
Table 13. Heckel plot parameters and properties of tablets formed from PG
and TG granules. ....................................................................................... 123
Table 14. Pearson’s coefficients of correlated variables. .......................................... 140
Table 15. Size and dissolution properties of PG and TG granules used to

prepare tablets for disintegration and dissolution studies. ........................ 143
Table 16. Heckel plot parameters of PG and TG tablets with different

disintegrants incorporated. ....................................................................... 144
Table 17. Disintegration and drug release properties of PG and TG tablets

with different disintegrants incorporated. ................................................. 146
Table 18. Processing conditions and granule properties in PG and TG. ................... 152
Table 19. Influence of variables on processing conditions, granule properties

and amount of ASA degradation in PG. .................................................... 162
xii
List of tables
Table 20. Influence of AAI diameter on air velocity and transit time. ...................... 163
xiii
List of figures
LIST OF FIGURES
Figure 1. Nucleation, growth and breakage phenomena in wet granulation

processes, adapted from Ennis and Litster (1997). ....................................... 7
Figure 2. Diagram of a MP-1 air handling system showing the parts and
locations at which the following process parameters were measured:
(a) ambient temperature, (b) inlet air relative humidity, (c) airflow
rate, (d) inlet air temperature, (e) granule bed temperature, (f)
outlet air relative humidity and (g) outlet air temperature. Arrows
indicate the direction of air flow. ................................................................ 10
Figure 3. Schematic diagrams of (a) top-spray granulator, (b) tangential-spray

granulator: double chamber rotary processor and (c) bottom-spray
granulator. Arrows represent air flow. .......................................................... 12
Figure 4. Photographs of PG features: (a) air distribution plate showing

central orifice, (b) air distribution plate showing graduated open
area, (c) AAIs of various opening diameters and (d) air swirl
accelerator. .................................................................................................. 34
Figure 5. Assembled PG module. ................................................................................ 37
Figure 6. Hydrolytic reaction of ASA.......................................................................... 45
Figure 7. Photographs of (a) PG and (b) TG modules fitted onto the MP-1 air
handling system. ........................................................................................... 51
Figure 8. Schematic diagram showing the air distribution and zones in the PG
process, with arrows representing airflow.................................................... 74
Figure 9. Influence of (a) partition gap (AAI diameter of 30 mm) and (b) AAI
diameter (partition gap of 26 mm) on air velocity within the
partition column at airflow rates of 50 ( ), 60 ( ), 70 ( ), 80 ( ), 90
( ), 100 ( ) and 110 ( ) m3/h. Error bars represent standard
deviation among independent runs. .............................................................. 76
Figure 10. Air velocity within the partition column (averaged across airflow
rates of 50, 60, 70, 80, 90, 100 and 110 m3/h) at defined conditions
of the factorial design. ................................................................................ 78
Figure 11. Response surface graphs of the effect of (a) AAI diameter and
binder spray rate (hold values at partition gap = 26 mm) on fines
and (b) AAI diameter and partition gap (hold values at binder
spray rate = 21 g/min) on lumps. ............................................................... 87
xiv
List of figures
Figure 12. Response surface graphs of the effect of (a) AAI diameter and
partition gap (hold values at binder spray rate = 21 g/min) and (b)
binder spray rate and partition gap (hold values at AAI diameter
= 29.5 mm) on aspect ratio. ...................................................................... 93
Figure 13. Mean drug content of PG and TG granules: PG/small ( ),

PG/medium ( ), PG/large ( ), TG/small ( ), TG/medium ( )
and TG/large ( ) when (a) binder spray rate and (b) lactose
powder blend were varied. Error bars represent inter-batch
standard deviation. .................................................................................... 97
Figure 14. Mean RSD of drug content of PG and TG granules: PG/small ( ),

PG/medium ( ), PG/large ( ), TG/small ( ), TG/medium ( ) and
TG/large ( ) when (a) binder spray rate and (b) lactose powder
blend were varied. Error bars represent inter-batch standard
deviation. Values in parentheses denote mean amounts of small,
medium and large granules within the batches (%, w/w). ....................... 100
Figure 15. Overall weighted RSD of drug content of PG (■) and TG (□)
batches when (a) binder spray rate and (b) lactose powder blend
were varied. .............................................................................................. 101
Figure 16. Mode of wetting and granule growth in PG and TG. ............................... 103
Figure 17. Schematic diagram showing the air flow pattern and zones in the
TG process with arrows representing airflow. .......................................... 105
Figure 18. Scanning electron photomicrographs of PG and TG granules

(taken at 100 x magnification) prepared with various binder spray
rates. ........................................................................................................ 109
Figure 19. Scanning electron photomicrographs showing overview of (a) PG

and (b) TG granules (taken at 35 × magnification) prepared with
binder spray rate of 21 g/min. .................................................................. 111
Figure 20. Influence of feed material on MMD (■,□) and span (●,○) in PG
(closed symbols) and TG (open symbols). Error bars represent
inter-batch standard deviation. ................................................................. 115
Figure 21. Heckel plots of PG (■) and TG (□) granules with ( ) and
( ) representing the regressed lines (PG: y = 0.0071x + 1.0, R2
= 0.995; TG: y = 0.0065x + 1.1, R2 = 0.992) respectively. Error
bars represent inter-batch standard deviation. .......................................... 121
Figure 22. PG and TG granules in powder bed with increasing compaction

pressures. .................................................................................................. 125
Figure 23. Optical photomicrographs of macro-surfaces (taken at 1.2 ×

magnification) of PG and TG tablets. .................................................... 127
xv
List of figures
Figure 24. Micro-surface roughness, (a) Ra and (b) Rq of PG (■) and TG (□)
tablets with ( ) and ( ) representing the regressed lines
(PG/Ra: y = 10651e-0.140x, R2 = 0.947; TG/Ra: y = 12614e-0.151x, R2
= 0.940; PG/Rq: y = 14610e-0.135x, R2 = 0.947; TG/Rq: y = 16983e-
0.143x
, R2 = 0.940) respectively: Error bars represent inter-batch
standard deviation..................................................................................... 130
Figure 25. Three-dimensional plots of micro-surfaces (taken at 20.64 ×

magnification) of PG and TG tablets. .................................................... 131
Figure 26. Porosity of PG (■) and TG (□) tablets with ( ) and ( )

representing the regressed lines (PG/porosity: y = 0.414e-0.008x, R2
= 0.980; TG/porosity: y = 0.403e-0.008x, R2 = 0.976) respectively.
Error bars represent inter-batch standard deviation. ................................ 134
Figure 27. Tensile strength of PG (■) and TG (□) granules with ( ) and
( ) representing the regressed lines (PG/tensile strength: y =
0.022x – 0.29, R2 = 0.997; TG/tensile strength: y = 0.019x – 0.24,
R2 = 0.997) respectively. Error bars represent inter-batch standard
deviation. .................................................................................................. 135
Figure 28. Loadings plot of data related to granule characteristics ( ■ ),

compactibility (●) and tablet properties (▲). ........................................ 137
Figure 29. Moisture content (■,□) and bed temperature (●,○) in PG (closed
symbols) and TG (open symbols): (a) PG at condition LL (b) TG
at condition LL, (c) PG at condition HH and (d) TG at condition
HH. Error bars denote inter-batch standard deviation. ............................. 153
xvi
List of symbols
LIST OF SYMBOLS
A constant of Heckel plot
AAI air accelerator insert
ASA acetylsalicylic acid
AUCheat area under the temperature against time curve
AUCmoisture area under the moisture content against time curve
a cross-sectional area
b breadth
D relative density
D0 initial relative density
Dapp apparent density
Da extrapolated relative density from the intercept of the linear

portion of the Heckel plot
Db increase in relative density due to particle rearrangement
Dp particle true density
Dt true density
Drugx drug content of a specific size fraction x
d tablet diameter
d10 particle diameter at the 10 percentile of the cumulative percent

undersize plot

undersize plot

undersize plot

undersize plot
F tablet hardness
xvii
List of symbols
HCT hydrochlorothiazide
HH condition of high inlet air temperature and high binder spray

rate
HPLC high performance liquid chromatography
h tablet height
hb absolute humidity of the air at the granule bed at 100 %

relative humidity
hi absolute humidity of inlet air
ho absolute humidity of outlet air
k slope of Heckel plot
LL condition of low inlet air temperature and low binder spray

rate
l length
MMD mass median diameter
ma airflow rate
ml liquid flow rate
NASA number of moles of acetylsalicylic acid
NSA number of moles of salicylic acid
NIR near infrared
P applied pressure
PAT process analytical technology
PC1 and PC2 first and second principal components
PG precision granulation
pr perimeter
px proportion of a specific size fraction x
Ra arithmetic average roughness
Rq root mean square of roughness
xviii
List of symbols
RSD relative standard deviation
RSDx relative standard deviation of drug content of a specific size

fraction x
r correlation coefficient
TG top-spray granulation
tdis disintegration time
t50% time at 50 percentile of dissolution plot
t90% time at 90 percentile of dissolution plot
USP United States Pharmacopeia
v volume before tapping
vc constant volume obtained after tapping
W weight
Wg actual batch weight of collected granules after processing
Wt theoretical batch weight of granules after processing
wi initial weight of granules
wf final weight of granules
X1, X2 and X3 first, second and third linear terms in regression equation
XA linear term (air accelerator insert) in response surface equation
XP linear term (partition gap) in response surface equation
XS linear term (binder spray rate) in response surface equation
XAA squared term (air accelerator insert × air accelerator insert) in

response surface equation
XPP squared term (partition gap × partition gap) in response

surface equation
XSS squared term (binder spray rate × binder spray rate) in

XAP interaction term (air accelerator insert × partition gap) in

xix
List of symbols
XAS interaction term (air accelerator insert × binder spray rate) in

XPS interaction term (partition gap × binder spray rate) in response

surface equation
Xaf linear term (airflow rate) in regression equation
XAAI linear term (air accelerator insert) in regression equation
Xheat linear term (inlet air temperature) in regression equation
Xmoisture linear term (binder spray rate) in regression equation
Y response
Yasp response (aspect ratio) in response surface equation
YASA response (amount of acetylsalicylic degradation) in regression

equation
Yfines response (fines) in response surface equation
Ylumps response (lumps) in response surface equation
Yvel response (air velocity within the partition column) in

regression equation
β0 constant
β1, β2 and β3 coefficient of first, second and third linear terms in regression
equation
βA coefficient of linear term (air accelerator insert) in response

surface equation
βP coefficient of linear term (partition gap) in response surface

equation
βS coefficient of linear term (binder spray rate) in response

surface equation
βAA coefficient of squared term (air accelerator insert × air

accelerator insert) in response surface equation
βPP coefficient of squared term (partition gap × partition gap) in

βSS coefficient of squared term (binder spray rate × binder spray

rate) in response surface equation
xx
List of symbols
βAP coefficient of interaction term (air accelerator insert ×

partition gap) in response surface equation
βAS coefficient of interaction term (air accelerator insert × binder

spray rate) in response surface equation
βPS coefficient of interaction term (partition gap × binder spray

rate) in response surface equation
xxi
PART I:
INTRODUCTION
1
Introduction
I. INTRODUCTION
A. BACKGROUND
The production of dosage forms in the pharmaceutical industry is a complex multi-
stage process involving numerous unit operations. Granulation, one of the key
operations, is a size-enlargement process whereby small particles are gathered into
larger masses while maintaining good control of the size and microstructure of the
product. A binder, either in liquid or solid form, is usually incorporated to promote
agglomeration of particles, and the product formed is termed as granules. The
granulation process generally produces granules of a wide size distribution within the
range of 0.1 to 3 mm (Appelgren, 1985). In most cases, granulated powders are for
production of tablets or caplets and these batches of granules with wide size
distributions served as intermediate products. The active ingredient can be granulated
by itself and then the resultant drug granules blended with other excipients prior to
tablet compaction or capsule filling. Alternatively, the active ingredient is co-
granulated with most or all of the excipients. Granules prepared may also be
subsequently coated and filled into capsules (Schwartz, 1988).
A1. Significance of granulation
Granules show more desirable properties than fine powders as granulated powders
resist segregation and are easier to handle. Uniform, non-segregating blends of fine
materials produced after granulation ensure a definite quantity fill of all the
constituents in the correct proportion in the dies. The problem of dust generation is
addressed, reducing handling hazards of toxic materials and material losses. The bulk
volume of voluminous powder is reduced, making it more convenient for storage and
2
Introduction
transport. The flow, compaction characteristics and appearance of granulated powders
are also better compared to fine powders (Stanley-Wood, 1990). The improved flow
properties help to ensure that the granules flow well through chutes and hoppers into
small volume dies without great variation in weight during tabletting. Granules are
more easily compacted compared to fine powders and produce stronger tablets due to
the presence of well-distributed binders within the granule structures. Another
advantage includes reduced caking and lump formation for hygroscopic materials
after granulation (Kristensen and Schaefer, 1993; Summers and Aulton, 2001).
Due to the simpler and lower cost manufacturing operations associated with preparing
granules for tabletting or capsule filling, there is interest in using similar unit
operations for the preparation of modified release granules. Many other researchers
have shown that controlled release of drug from the tablet matrices can be prepared by
granulating the drug with various polymeric excipients to form slow release granules
(Radtke et al., 2002; Sakkinen et al., 2002; Vaithiyalingam et al., 2002;
Mukhodpadhyay et al., 2005). Promising results have similarly been shown in studies
on rapid release granules, with reports on enhancement in drug dissolution after
granulation (Ghorab and Adeyeye, 2001; Gupta et al., 2001, 2002). In addition to the
development of suitable formulations, the development of novel granulation
techniques, such as steam granulation (Rodriguez, 2002), melt granulation (Perissutti
et al., 2003; Seo et al., 2003; Vilhelmsen et al., 2005; Yang et al., 2007) and
ultrasonic spray congealing (Passerini et al., 2006) for the preparation of rapid release
granules have understandably gained more attention.
3
Introduction
A2. Types of granulation
Several manufacturing techniques are used for producing granules, and they can be
broadly divided into dry and wet granulation processes.
A2.1. Dry granulation processes
In dry granulation processes, power particles are brought together by mechanical
force. The binders used exist in solid form. A major advantage of dry granulation is
the absence of water or any organic solvent. They are especially useful for the
granulation of moisture sensitive or heat sensitive drugs as they rely on
interparticulate bond formation between primary particles for growth; therefore,
wetting of particles is not required (Kurihara, 1993). The need for preparation of
binder solution, usage of heavy mixing equipment and more importantly, the costly
time-consuming drying step required for wet processes is also eliminated. Typical dry
granulation processes include slugging and roller compaction, of which the latter is
more widely studied.
In roller compaction, the feed material is passed through two counter-rotating rolls,
exposing it to high stress. This leads to the formation of a briquette that is
subsequently subjected to milling or screening to achieve the desired granule size
(Bindhumadhavan et al., 2005). The mechanism of roller compaction can be seen as a
combination of four sets of rate processes: (i) particle rearrangement, (ii) particle
deformation, (iii) particle fragmentation, and (iv) particle bonding (Miller, 2005).
When a force is applied to the powder bed, particle rearrangement first occurs to fill
up void spaces. As the pressure on the bed increases, particle deformation occurs and
creates more points of contact for bonding to occur. With an additional increase in the
4
Introduction
compaction force, fragmentation of particles takes place and the number of potential
bonding sites is further increased. Lastly, particle-particle bonding results, together
with plastic deformation and fragmentation.
Roller compaction has found application in the granulation of inorganic materials
(Freitag and Kleinebudde, 2003), granulation of dry herbal materials (Eggelkraut-
Gottanka et al., 2002; Soares et al., 2005), compaction of tablet formulations (Mollan
and Celik, 1996; Skinner et al., 1999) and production of controlled release
formulations (Ohmori and Makino, 2000; Juang and Storey, 2003; Mitchell et al.,
2003). However, there are limitations to its practical application, attributed to inherent
problems such as loss in compactibility (Li and Peck, 1990) and poor homogeneity of
the formed compact (Badawy et al., 1999).
A2.2. Wet granulation processes
Some common examples of wet granulation processes include wet massing, high
shear granulation, pan granulation, extrusion-spheronization, spray drying and
fluidized bed granulation. Of particular interest in this project is fluidized bed
granulation, which will be discussed in greater depth in the next section.
Wet granulation processes involve the spraying of a liquid onto powder particles as
they are agitated in a tumbling drum, high shear mixer or similar device to facilitate
agglomeration. Binders may be incorporated in the spray liquid or as solid particles
forming part of the feed material. Compared to dry granulation processes, the wet
granulation processes provides better control of drug content uniformity at low and
high drug concentrations, better control of product bulk density and ultimately,
5
Introduction
compactibility (Bacher et al., 2008). The main deterrent to adopting wet granulation
processes is that they are relatively more complicated and costly. This is because of
higher demands for labour, time, equipment, energy and space. The many additional
processing steps involved for the preparation of liquid binder and drying of granules
add complexity during process control and process validation (Shangraw, 1990).
Moreover, the issue of drug stability is a major concern for moisture sensitive and
heat sensitive materials. Nonetheless, the disadvantages of wet granulation are
outweighed by its well-established advantages and with advances in equipment design,
there will still be widespread use of wet granulation in the pharmaceutical industry.
Wet granulation had been described by distinct mechanisms such as nucleation,
coalescence, abrasion transfer, breakage and snow-balling (Sastry and Fuerstenau,
1973). However, many now view it as a continuum process combining three different
phenomena (Figure 1), namely (i) wetting and nucleation, (ii) coalescence and
consolidation, and (iii) breakage and attrition (Iveson et al., 2001). Upon the initial
addition of a liquid binder, the powder feed is wetted and nucleation of fine powders
is promoted (Figure 1a). It has been shown that the solid-liquid contact angle and
surface free energies of the system directly affect the characteristics of the granulated
product. As the degree of wetting of the powder mixture increases, larger mean
granule size is observed (Jaiyeoba and Spring, 1980; Wells and Walker, 1983; Gluba
et al., 1990). The efficiency of liquid binder distribution, which is reflected in the
product size distribution (Watano et al., 1997), is strongly affected by the method of
binder delivery (Knight et al., 1998) and efficiency of powder mixing (Tsutsumi et al.,
1998; Miyamoto et al., 1998). As shown in Figure 1b, coalescence and consolidation
6
Introduction
(a) Wetting and nucleation
Liquid droplet
Spreading of liquid
Dry powder Wetted powder
droplet onto dry
particles particles
powder particles
(b) Coalescence and consolidation of wetted powder particles
Coalescence Consolidation Granule growth
(c) Breakage and attrition
Granule Particle
size Fines
reduction
Figure 1. Nucleation, growth and breakage phenomena in wet granulation processes,

adapted from Ennis and Litster (1997).
7
Introduction
next occurred when wetted powder particles collide with one another and/or with the
equipment surface. These collisions reduce their porosity, squeeze out trapped air and
may even squeeze liquid binder to the surface of the particles. Factors influencing
coalescence and consolidation include binder content (Iveson et al., 1996), viscosity
(Ritala et al., 1986), surface tension (Iveson and Litster, 1998a), particle size (Iveson
and Litster., 1998b), equipment speed and type (Knight et al., 2000). This stage
commonly accounts for strength, porosity or dissolution properties of granules.
Formed granules that are structurally weak would be more susceptible to attrition
(Figure 1c), defined by Ennis and Litster (1997) as a breakdown in granule structure
due to impact, wear, or compaction in the granulator or during subsequent product
handling. This breakage phenomenon causes particle size reduction and is particularly
seen in higher intensity and hybrid granulators.
8
Introduction
B. FLUIDIZED BED GRANULATION
Fluidized bed technology has its origins from the petroleum industry in the 1940s.
Since its successful implementation for coating in the pharmaceutical industry by
Wurster (1959), this air suspension technique has been used widely in coating,
granulating, pelletizing and drying processes. As shown in Figure 2, a fluidized bed
processing system typically consists of a control system, air handling unit, product
chamber, air expansion chamber, exhaust filters, exhaust blower, air distribution plate,
spray nozzle, and lastly, a delivery system for the liquid binder (Parikh and Mogavero,
2005). In-line monitoring of process conditions is also often possible to facilitate
process control.
In this system, a bed of powder particles, supported over a fluid distribution plate, is
made to behave like a liquid by the passage of the fluid, typically air, at a flow rate
above a certain critical value. The phenomenon of imparting the properties of this
fluid to the bed of particulate solids by passing the fluid through the latter at a velocity
which brings the stationary bed to its loosest possible state just before its
transformation into a fluid-like bed is termed fluidization (Gupta and Sathiyamoorthy,
1998). During granulation, the powder particles circulate within the product chamber
and provide a constant flow of bed particles through a defined spray granulation zone.
At the spray granulation zone, a fine spray of liquid binder is usually atomized and
deposited onto the fluidizing particles. Particle wetting brings about granule formation.
Partial drying of the wetted particles by the fluidizing air occurs continuously during
granulation. When the spraying of liquid binder is completed, the granules are quickly
dried by the hot air stream and complete drying is achieved.
9
f g
Primary
exhaust sock Exhaust
filters Secondary blower
exhaust sock
filters
Air expansion
chamber
Control
system
Product chamber
Top-spray e
nozzle
Delivery system Air distribution

for liquid binder plate
c
d Air handling b a
unit
Figure 2. Diagram of a MP-1 air handling system showing the parts and locations at which the following process parameters were measured: (a)
ambient temperature, (b) inlet air relative humidity, (c) airflow rate, (d) inlet air temperature, (e) granule bed temperature, (f) outlet air relative
humidity and (g) outlet air temperature. Arrows indicate the direction of air flow.
Introduction
10
Introduction
B1. Techniques of spray
Several types of spray nozzle systems including air atomizing (two-fluid), hydraulic
and ultrasonic are available for use in the fluidized bed processor. The two-fluid
nozzle system where the binder solution is atomized by compressed air is the most
popular because this system is able to control droplet size independently of binder
flow rate and is capable of functioning at very slow flow rates (Olsen, 1989). Though
the spray-drying effect is more pronounced with the two-fluid nozzle system, it is not
a severe problem when the liquid binder sprays are aqueous in nature.
The types of fluidized bed granulation processes can be classified according to the
orientation of their spray nozzle. The orientation determines not only the spray pattern
of the liquid binder, but also how the sprayed droplets impinge and spread on the
powder particles. Consequently, this will impact the type of granule structures formed.
Top-spray: As depicted in Figure 3a, top-spray granulation (TG) is conventionally
used and has been the most extensively studied technique since the 1960s (Banks and
Aulton, 1991). One of the most recognized for wet granulation, it is also widely
known as the down-spray technique. The spray nozzle is placed at the top of the
product chamber and the liquid binder is sprayed onto the bed, counter-current to the
air flow. TG granules are characterized by a low bulk density and a porous surface
with significant interstitial voids that results in fast wicking of liquid into the granules
and good disintegration and/or dispersibility (Jones, 1985).
11
Introduction
(a)
Product chamber
Spray nozzle positioned

at top of chamber
Perforated air distribution

Fluidizing air
plate
(b) Outer product chamber
Inner product chamber

Spray nozzle
Perforated metal plate
postioned at
side of chamber Powder particles
Rotating plate
Gap air
Fluidizing air
(c)
Product chamber
Partition column
Powder particles Perforated air distribution plate
Spray nozzle positioned at

Fluidizing air
bottom of chamber
Figure 3. Schematic diagrams of (a) top-spray granulator, (b) tangential-spray

granulator: double chamber rotary processor and (c) bottom-spray granulator. Arrows
represent air flow.
12
Introduction
Tangential-spray: Tangential-spray technique was conceived for producing denser
granules than typically possible in fluidized bed granulations (Jones, 1994). More
often known as rotary processing, this rotating plate granulator combines centrifugal,
high intensity mixing with the efficiency of fluidized bed drying (Gu et al., 2004).
The spray nozzle is introduced at the side of the product chamber and is embedded in
the powder bed during processing (Figure 3b). A rotating plate provides a centrifugal
force, which forces particles towards the wall of the processing chamber at the
periphery of the product chamber. Fluidizing air provides, via a slit, a vertical force
that lifts the particles upwards before gravitational force causes particles to fall down
onto the disc (Goodhart, 1989). Granules formed by this process are typically
structurally more spherical, denser and less porous than TG granules, and this
technique is a better choice for producing granules that are to be coated (Rubino,
1999).
Bottom-spray: The spray nozzle is positioned in the middle of the air distribution
plate, at the base of the product chamber in this technique (Figure 3c). A partition
column is commonly present and its presence better regulates particle fluidization and
flow into the spray granulation zone (Ishida and Shirai, 1975). Binder solution is
sprayed in the same direction as the air flow. Essentially employed for coating
purposes and less so for granulation (Dixit and Puthli, 2009), there were few reports
on its use for pharmaceutical granulation in the 1990s (Flogel and Egermann, 1996;
Ichikawa and Fukumori, 1999). Nonetheless, interest in granulating with the bottom-
spray technique remains among some researchers (Wang et al., 2003; Ho et al., 2005)
and the development of better bottom-spray processors in more recent years (Walter,
2002) provided new impetus for this granulation technique.
13
Introduction
B2. Advantages and challenges
Fluidized bed granulation is efficient and convenient to use, offering many advantages
over the multistage process of conventional wet granulation (Banks and Aulton, 1991).
Powder can be mixed, granulated and dried in a single container, thereby avoiding
cross-contamination. Since fluidized bed granules are formed and dried within the
same piece of equipment, it cuts cost by saving time needed for transfers and greatly
simplifies the process. By virtue of the air or gas required to fluidize the solids, the
fluidized bed typically provides high rates of heat and mass transfer, leading to
uniform temperature distribution within the bed and relatively short processing times
(Turton et al., 1999). High process yields of 97 to 100 %, w/w with typically less than
1 %, w/w fines and 3 %, w/w lumps can be attained (Olsen, 1985). In comparison to
high shear granulation, a popular wet process to employ for granulation in the
industry, the size distribution of fluidized bed granules is often narrower with the
absence of large size compact granules. This indicates a less frequent need for
regranulation and a less problematic drying step. Fluidized bed granules have also
been generally shown to be more porous, less dense, and more compressible than high
shear granules (Tobyn et al., 1996; Horisawa et al., 2000; Gao et al., 2002; Hausman,
2004).
As mixing and fluidization quality in the fluidized bed is highly dependent on the
characteristics and properties of the powder particles, the process is more sensitive to
the filler characteristics and properties. The filler type was reported to have a more
pronounced effect on granule properties in the conventional fluidized bed granulator
than in the rotary processor (Kristensen and Hansen, 2006). It has also been shown
that a wider selection of feed material can be used in rotary processing (Kawaguchi et
14
Introduction
al., 2001) and high shear granulation (Stahl, 2004). The mixing effect in a fluidized
bed is generally good for particle sizes between 50 to 2000 µm. However, for fine
particles less than 50 µm and particles which are difficult to fluidize when wet,
vibratory forces have to be applied to the powder bed, increasing equipment, cleaning
and maintenance costs (Law and Mujumdar, 2007). A lower critical size where the
usual pharmaceutical powders can be discretely processed will be around 20 µm.
Lower than this size, steady fluidization without any retardation is difficult as
indicated by Geldart’s fluidization map (Geldart, 1973). To process powder mixture
containing components of vastly different densities is another difficult task, as the
different fluidization behaviour of the individual components may result in bed
segregation and non-uniform mixing. Without the aid of mechanical forces in
distributing the liquid binder, the spreading of the liquid binder droplets in the powder
bed is more crucial compared to other wet granulation processes that are aided by
mechanical forces. As such, agglomeration in the fluidized bed granulation process is
highly dependent on this spreading phenomenon (Faure et al., 2001).
Coupled with the inter-relation of variables that influence the agglomerative process,
it is challenging to obtain good control of the process. As an illustration, a myriad of
factors such inlet air temperature, inlet air absolute humidity, temperature of liquid
binder, volume of liquid binder and the extent of evaporation (itself a function of
droplet size, binder spray rate and airflow rate) would influence powder bed humidity.
This is due to the fact that mixing, wetting and drying of particles take place
simultaneously in the same apparatus, and therefore these different elementary
processes play influential inter-dependent roles on each other (Hemati et al., 2003).
15
Introduction
B3. Parameters influencing the process and granule quality
The micro-level interactions between the powder particles and liquid binder have
been shown by many researchers to play important roles in granulation phenomena
(Ennis et al., 1991; Iveson and Litster, 1998a; Liu et al., 2000; Simons and Fairbrother,
2000; Iveson et al., 2003). For instance, Schaefer and Worts (1978) reported that
under constant processing conditions, the relationship between droplet size and
granule size was influenced by the binder-induced mechanical strength of the wet
granule liquid bridges. This accounted for why different liquid binders sprayed at the
same mean droplet size resulted in granules with different properties. Passos and
Mujumdar (2000) observed that the extent of wet bed failure depends on the strength
of the liquid binder bridges between particles and particle shape. These complex
interactions provide explanations for observations made from macroscopic studies
investigating the impact of physicochemical variables and operating variables on end
product granule characteristics. However, thorough knowledge of these micro-level
interactions has yet to be acquired and much remains to be studied to fully understand
them.
Fluidized bed granulation is an intricate process and the factors affecting the process
and granule quality are classified into three categories for discussion below. The first
category involves the nature and characteristics of the ingredients in the formulation.
Even though the discussed scope on this category is focused on fluidized bed granules,
the findings for this category are generally applicable to all other wet granulation
processes. Process factors during liquid binder addition phase and process factors
during the drying phase constitute the second and third categories respectively, and
are more specific to the fluidized bed equipment.
16
Introduction
B3.1. Material related factors
The properties of the raw materials involved in granulation, namely the feed powder,
binder and granulating liquid, will affect granule formation and growth.
Ability of powder particles to be wetted: Wetting is an essential phenomenon needed
to form initial liquid bonds between the particles to enable agglomerative growth. The
feed powder must have reasonably good wetting properties if there is to be uniform
granulating liquid distribution. In fluidized bed granulation, the initial spreading of
the binder in the powder bed is very crucial (Faure et al., 2001). This is because of the
rather low shear forces present in the fluidized bed and liquid within agglomerates
would be less likely to be squeezed out for growth by coalescence. The initial wetting
conditions therefore determine the size distribution of the granule batch. The
important role of this interaction has been emphasized by different groups of
researchers in literature. Pont and co-workers (Pont et al., 2001; Hemati et al., 2003)
have illustrated that granule growth was favoured with an increase in interfacial
tension and a decrease in contact angle between the particles and the liquid binder.
Danjo et al. (1992) reported that harder and less porous granules were formed when
the adhesion-tension of the liquid binder was increased. Spreading coefficients of the
liquid binder over the particles were similarly observed by Planinsek et al. (2000) to
be in good correlation with granule friability.
Solubility of powder particles: Surface dissolution of lactose was proposed to behave
as a secondary binder after solidification upon drying, and contributed to the
sphericity of the granules (Wan and Lim, 1989). An increase in granule hardness with
a decrease in pore volume was reported by Danjo et al. (1992) with increased
17
Introduction
solubility of lactose particles in the solvent used to prepare the liquid binder. Rohera
and Zahir (1993) also found that part dissolution of excipients being granulated was
desirable for granule growth and affected granule size distribution.
Type of powder: The different deformation behaviour during coalescence exhibited
by different types of powder was shown to influence the kinetics of the process
(Abberger, 2001).
Powder load: Due to a larger load to binder ratio, whereby a smaller extent of wetting
took place, an increment in feed load resulted in more of the smaller size granules
being produced (Wan and Lim, 1988; Cryer and Scherer, 2003).
Powder particle size: It was implied by Hemati et al. (2003) that an increase in the
initial particle size led to an increment in particle growth rate and affected the
mechanism of growth.
Powder particle shape: Contact surface between the less spherical particles was
reportedly enhanced as compared to the highly spherical particles. This resulted in
different growth kinetics (Hemati et al., 2003).
Powder particle surface roughness: Growth kinetics was also found to have a strong
dependence on the surface roughness of the particles by Stepanek et al. (2009).
Type of binder: Binder is an essential part of the granulating fluid. Yuksel et al. (2003)
reported that granules prepared using polyvinylpyrrolidone were observed to have
18
Introduction
lower mechanical strength than those prepared using pregelatinized starch and gelatin.
In another study by Rohera and Zahir (1993) where polyvinylpyrrolidone, acacia, and
gelatin were investigated, it was found that different binders had different influences
on granule growth.
Binder concentration and viscosity: In general, increasing the concentration and
viscosity of the liquid binder increased mean granule size and increased granule
strength, as reported in several studies. The types of binders investigated in these
reports included gelatin, acacia, polyvinylpyrrolidones and cellulosic binders (Davies
and Gloor, 1972; Alkan and Yuksel, 1986; Lim, 1989; Rohera and Zahir, 1993; Ling,
1995; Wan et al., 1996; Kokubo et al., 1995, 1998; Bouffard et al., 2005). Other
physical properties such as drug release (Haldar et al., 1989), granule morphology and
porosity (Rajniak et al., 2007) were also found to be influenced by binder
concentration.
Mode of binder addition: Binder addition, either suspended in the spray liquid or dry
mixed in the powder was shown to affect the granular characteristics of the end
product. Binder distribution was found to be more uniform when suspended in the
spray liquid with a smaller amount of oversized granules produced (Kokubo et al.,
1995, 1998; Wan and Lim, 1988).
Volume of liquid binder: The volume of granulating liquid needed depends primarily
on the solubility of the drug and/or components of the binder. Larger granules resulted
when bigger volumes of binder solution were used (Rohera and Zahir, 1993; Merkku
19
Introduction
et al., 1994; Wan et al., 1996). This was likely to be due to promoted wetting of
particles during growth.
B3.2. Process related factors during the liquid binder addition phase
The sensitivity of the process to its bed humidity has been identified by many
researchers, and control of this bed condition is primary for process reliability
(Kokubo and Sunada, 1997; Watano et al., 1997; Hu et al., 2007). Bed humidity is an
indication of the availability of liquid binder at the particle surfaces. A more humid
bed indicates wetter conditions, more liquid binder is available to the surfaces of the
particles and this enhances nucleation and growth. However, if the moisture content in
the granule bed is too high, excessive granule growth can result and the bed can even
collapse by wet quenching due to the poor fluidizing capacity of the wetted mass
(Schaafsma et al., 1999). Accordingly, parameters that affect the temperature and
moisture content of the powder bed play important roles in influencing process and
granule quality.
Binder spray rate: An increase in binder spray rate availed more liquid binder to the
particles and resulted in a more humid bed. Thus, granules of larger size and lower
bulk density typically formed as reported by many researchers (Rankell et al., 1964;
Davies and Gloor, 1971; Lipps and Sakr, 1994; Wan et al., 1995; Menon et al., 1996;
Gao et al., 2002; Cryer and Scherer, 2003; Hemati et al., 2003; Bouffard et al., 2005).
Pulsed spraying of the liquid binder had also been tried by Ehlers et al. (2009) as a
method to control granule growth.
20
Introduction
Binder droplet size: A direct relation between droplet size and granule size at the early
stage of the growth process was reported by Schaafsma et al. (2000). Bigger spray
droplets were found to produce more granules in the larger mass size fractions.
Atomizing air pressure: The degree of atomization of the liquid binder depended on
the air to liquid mass ratio at the nozzle head. A decrease in atomizing air pressure
was extensively shown to result in granules of larger size and lower bulk density. This
is because of the resultant decreased air-to-liquid mass ratio that caused the formation
of bigger spray droplets (Davies and Gloor, 1971; Merkku et al., 1994; Gao et al.,
2002; Rambali et al., 2001; Bouffard et al., 2005). An optimum pressure was found to
be necessary for promoting uniform distribution of a low dose drug, when the drug
was incorporated in the granulating liquid (Wan et al., 1992). The degree of
atomization was also observed to affect granule structures and consequently, granule
strength by Wang et al. (2003).
Spray nozzle position from bed: The position of the spray nozzle in TG was reported
to significantly influence granule growth and granule friability (Rankell et al., 1964;
Davies and Gloor, 1971; Rambali et al., 2001). The nearer the nozzle was placed to
the powder bed from the top, the larger were the granules formed.
Spray nozzle tip protrusion from air cap: This determined the angle at which the
binder solution was sprayed onto the powder bed by changing the airflow rate through
the nozzle. Rambali et al. (2001) found that a higher protrusion resulted in more
granules in the smaller mass size fractions and higher process yield.
21
Introduction
Spray nozzle tip diameter: A wider nozzle tip diameter caused larger spray droplets to
be formed, promoted granule growth and resulted in bigger granules (Rambali et al.,
2001).
Product chamber geometry: Particle flow pattern and distribution were shown to be
affected by the shape of the product chamber, and is an important factor to consider
during process design (Yang et al., 1992; Schaafsma et al., 2006).
Airflow rate: Smaller granules were observed when the airflow rate was increased
(Cryer and Scherer, 2003; Bouffard et al., 2005). This was explained by a more rapid
removal of water from the wetted particles by the air that caused slower growth
kinetics with higher airflow rate. It was also found by Wang et al. (2003) that airflow
rate affected granule size and process yields.
Inlet air temperature: As the inlet air temperature increased, there was faster mass
transfer of water from the wetted particles to the air (i.e. evaporation). This reduced
the binder layer surrounding the powder particle, created fewer opportunities for
coalescence and resulted in smaller granules (Lipps and Sakr, 1994; Schinzinger and
Schmidt, 2005).
B3.3. Process related factors during the drying phase
After complete spraying of the liquid binder, the granules formed are dried for a
further period of time. This is to remove remaining moisture contained in them down
to a moisture level best suited for the stability of the constituent actives and
requirements of the ensuing downstream process. Inefficient or poor process control
22
Introduction
of this drying phase will lead to inconsistent end product quality. For instance,
attrition of the formed granules was reported to occur paradoxically, resulting in
unwanted size reduction (Niskanen and Yliruusu, 1994). Formation of fines by
attrition is, in practice, an important parameter because excessive fines generation can
affect granule flow and should be avoided (Nieuwmeyer et al., 2007b).
Inlet air humidity: Zoglio et al. (1975) reported that the humidity of the drying air
strongly impacted the drying rate for aqueous based granulations. This was attributed
to the diffusion of water vapour through the stagnant air film surrounding the granule
and into the neighbouring fluidizing air - the rate-limiting step in the drying phase.
Based on the findings that an increase in inlet air humidity resulted in higher product
temperatures (Lipsanen et al., 2007, 2008), concern in scenarios where a fixed product
temperature was used as a drying end-point criterion was highlighted by the authors.
This is because the residual moisture content in the dried granules could vary between
batches if the inlet air humidity is not controlled and this would affect the quality of
the product attained at the end of processing. Their findings also implied stability
issues when using a fixed product temperature as a drying end-point criterion for
granulating moisture sensitive and heat sensitive materials.
Inlet air temperature: Reductions in drying time was reported to be possible with
employment of higher inlet air temperatures, and the lower temperatures were found
to cause higher equilibrium moisture content in the granules. (Hlinak and Saleki-
Gerhardt, 2000).
23
Introduction
Airflow rate: Increments in airflow rate was observed to lead to the enhancement of
evaporation rates (Hlinak and Saleki-Gerhardt, 2000) and possibly drying. However
in practice, practical use of airflow rate to enhance the evaporation rate might be
limited due to its potential influence on the particle size distribution of granules
(Faure et al., 2001). Too high an airflow rate may result in an unacceptable level of
attrition.
Atomizing air pressure: High atomizing air pressure, especially when maintained
during the drying phase was shown to contribute substantially to granule breakage
(Bouffard et al., 2005). As the atomizing air is counter-current to the fluidizing air, it
is best switched off after completion of liquid addition. The atomizing air may also
disrupt the fountain like flow of the granules in the fluidized bed.
Liquid binder: Niskanen and Yliruusu (1994) observed that attrition was dependent on
both the amount and the wetting tendency of the liquid binder.
Moisture content: The moisture content of granules during fluidized bed drying was
found to affect the hydrodynamic behaviour (Wormsbecker and Pugsley, 2008) and
granule size (Nieuwmeyer et al., 2007b).
Duration of drying phase: The duration of drying was widely shown to affect granule
size properties (Banks and Aulton, 1991). Extended duration of drying may result in
excessive granule attrition. The drying time was recently shown by Tomuta et al.
(2009) to influence the residual moisture content, bulk and tapped density of the
granules.
24
Introduction
C. RECENT ADVANCES IN FLUIDIZED BED GRANULATION
In the last decade, there have been an increasing number of publications proposing
new analytical tools for in-line process monitoring and new genres of granulation
methods. Those pertinent to the field of fluidized bed granulation research are
discussed below.
C1. Process analytical technology (PAT) in fluidized bed granulation
As a result of the PAT initiative by the United States Food and Drug Administration,
an increased interest in process understanding is seen in the pharmaceutical industry.
PAT is defined as “a system for designing, analyzing, and controlling manufacturing
through timely measurements (i.e. during processing) of critical quality and
performance attributes of raw and in-process materials and processes with the goal of
ensuring final product quality”. Gaining a deep and thorough understanding of the
manufacturing process is at the heart of PAT, with the concept of building quality into
products or by design, and not by final product testing as generally practiced currently
(FDA, 2004).
Granules of high quality can be produced by understanding and controlling the critical
process parameters with timely measurements. Many different PAT tools have now
been proposed to enable scientific, risk-managed pharmaceutical development and
manufacture of fluidized bed granules. Traditionally, control of fluidized bed
granulation was based on indirect measurements, by monitoring the temperatures of
the inlet air, outlet air and product (Alden et al., 1988; Wostheinrich et al., 2000;
Lipsanen et al., 2008). Now, vibrational spectroscopic techniques such as near
infrared (NIR) and Raman are able to provide rapid, direct and real-time information
25
Introduction
related to the entire granulation process. Additionally, they are non-destructive and
the sample interface is located in the process stream and as a result, information can
be derived in-line. On-line techniques require automated sampling and sample
transfer to an automated analyzer. Both at-line and off-line techniques involve manual
sampling but in the former, the samples are transported locally to an analyzer located
in the manufacturing area; whereas samples are transported to a remote laboratory in
the latter (Hassel and Bowman, 1998).
C1.1. Moisture content
The in-line NIR tool has been widely applied to quantitatively assess the water
content of the powder bed, with the intended purpose of improving process
understanding and to determine the end-point of drying (Watano et al., 1996; Frake et
al., 1997; Morris et al., 2000; Rantanen et al., 2000; Wildfong et al., 2002; Findlay et
al., 2005). Rantenen et al. (2001) identified different behaviour of formulations during
granulation by combining NIR moisture measurements with temperature and
humidity measurements. Different phases of fluidized bed drying had similarly been
distinguished by Nieuwmeyer et al. (2007a). NIR monitoring had also been shown to
be useful for the prediction of suitable amounts of water to be added to multi-
component formulations during granulation by Miwa et al. (2008). Nonetheless, due
to its inability to penetrate a powder bed, the NIR tool only measures the surface
moisture of a material and has a common problem of particle layers forming on the
sensor window. Hence, microwave resonance technology (Buschmuller et al., 2008)
was newly proposed to be an alternative in-line method. This suggested method
enabled continuous yet density independent moisture monitoring of the powder bed,
26
Introduction
as it took into account both the moisture content and the powder density during a
single and simultaneous measuring procedure.
C1.2. Particle size
Particle size of a granulation is an important attribute to analyze, because particle size
affects physical properties such as flow, drug release, compaction behaviour and
tablet properties. Simultaneous in-line NIR monitoring of moisture content and
particle size had often been developed together for better in-process control of
fluidized bed granulation and end-point determination (Frake et al., 1997; Findlay et
al., 2005). This approach had been suggested to be useful for monitoring attrition
effects during drying (Nieuwmeyer et al., 2007a). However, accurate in-line NIR
particle size analysis is challenging, because of the differing scattering and absorptive
properties of granules of different sizes. In addition, particle size data are typically not
directly obtained using NIR techniques and hence, pretreatment of spectra and
chemometric modelling are needed.
To overcome these difficulties, both on-line and at-line applications have been
developed. They include (i) image analysis systems whereby digital images of
particles are first captured using a camera and then subjected to analysis (Watano et
al., 1995; Watano, 2001; Laitinen et al., 2004; Narvanen et al., 2008a), (ii) acoustic
chemometric technique that measures vibrational characteristics of the system to
provide information about the state of the system (Halstensen and Esbensen, 2000;
Halstensen et al., 2006); and (iii), the focused beam reflectance method (Hu et al.,
2008) and the spatial filtering technique (Narvanen et al., 2008b) that determine the
chord length of particles using special probes.
27
Introduction
C1.3. Composition of bed material
Walker et al. (2007b, 2009) illustrated that Raman spectroscopy could be used to
provide three-dimensional maps of the concentration and chemical structure of the
particles within a fluidized bed, allowing in-situ real-time measurement of the
composition of the material within the fluidized bed in three spatial dimensions and as
a function of time. Li et al. (2007) also demonstrated changes in relative content of
the bed materials at different processing times using off-line NIR spectral analysis.
C1.4. Solid state transformations
Control of process-induced polymorphic transformations is important because they
may change the properties of the active pharmaceutical ingredient in the drug product,
thereby compromising therapeutic efficacy. The presence of different polymorphs of
theophylline (Rasanen et al., 2001), glycine (Davis et al., 2004), erythromycin (Romer
et al., 2008) and piroxicam (Kogermann et al., 2008) during fluidized bed drying had
been successfully quantified using the NIR tool. Raman spectroscopy had also been
employed to characterize hydration states of risedronate during fluidized bed drying
(Hausman et al., 2005) and was shown to be more useful than NIR in the
quantification of different forms of carbamazepine (Kogermann et al., 2008). With in-
process information obtained using an appropriate PAT tool and knowledge on the
basic properties of the drug, processing conditions can be adjusted to anticipate and
prevent potential polymorphic transformations. Researchers may also gain insights
into the molecular level phenomena of dehydration.
28
Introduction
C2. Fluidized bed granulation methods
Many of the more recently proposed methods of granulation addressed the adverse
issues related to the use of aqueous binders for granulation. These concerns entail
stability issues when processing moisture sensitive or heat sensitive materials. The
manner water is added and removed in wet granulation may contribute to unnecessary
stress to induce excessive decomposition during processing or storage. During wet
granulation, process-induced phase transformation of materials where polymorphs,
hydrates or amorphous forms interconvert may also take place (Zhang et al., 2004).
Additionally, the higher cost associated with the drying step in wet granulation is
another concern. Consequently, dry granulation methods such as slugging and roller
compaction (Kristensen and Schaefer, 1993; Schiller et al., 2003) or melt methods
(Thies and Kleinebudde, 1999; Yanze et al., 2000; Kowalski et al., 2009) are
preferentially employed to granulate such materials. Nonetheless, overcoming the
stability problem in wet granulation of moisture sensitive materials would be of
interest to many. This is because in comparison to these dry methods, wet granulation
provides better control of dust-related problems, drug content uniformity, product
bulk density and ultimately, compactibility (Bacher et al., 2008).
C2.1. Fluidized bed melt granulation
Melt granulation has gained some attention by different researchers because the
process offers certain advantages over conventional wet granulation processes. As the
process involve the use of meltable binders instead of water or solvents to
agglomerate fine particles, it is often referred to as a “dry” process and thus finds
application for moisture sensitive bioactives (Thies and Kleinebudde, 1999; Kowalski
et al., 2009). With the elimination of a drying step, it is also an economical process to
29
Introduction
employ resulting from the avoidance of organic solvent and need of flame-proof
facilities and solvent recovery equipment (Wong et al., 2005).
The melt technique is often carried out in a high shear or tumbling mixer and tends to
produce granules that are dense and hard as a result of the high shearing forces
exerted by the impeller on the powder-binder system and material shrinkage on
cooling. Although production of melt granules by a jacketed high shear mixer is
technologically easier by modification of a high shear granulator to undertake melt
granulation, a scaled-up melt granulator suffers considerably by its inability to cool
the melt granules rapidly enough to minimize heat related material degradation.
Excessively long cooling times is generally not acceptable for large volume batches.
In an effort to overcome the shortcomings of high shear melt granulation, melt
granulation by a fluidized bed had been attempted. Efforts to merge the two
technologies successfully produced porous, lower strength granules that were suitable
for tabletting (Kidokoro et al., 2002). Efficiency in heating or cooling by changing the
fluidizing air temperature can be easily implemented. Effervescent granules and
tablets containing citric acid and sodium bicarbonate were successfully prepared by
Yanze et al. (2000) using fluidized bed melt granulation. Systematic characterization
of the kinetics of fluidized bed melt granulation was presented by Tan et al. (2004,
2005a, b, 2006a, b). Abberger et al. (2002) evaluated the effects of molten binder
droplet size and powder particle size on the mechanism of nucleation during growth.
The effects of granulation time and molten binder concentration on granule growth
kinetics and mechanical properties of the resultant tablets were studied by Walker et
al. (2005, 2006). Atomizing air pressure and the rate of molten binder addition, but
30
Introduction
not the position of the top-spray nozzle, were found to influence granule properties
(Borini et al., 2009). Ansari and Stepanek (2006) reported that in an in situ fluidized
bed melt granulation process, the binder particle size was directly proportional to
granule size, whereas the binder to solids ratio significantly influenced the fraction of
un-granulated fines and average shell thickness of hollow core granules. In another
study by Walker et al. (2007a), an improvement in drug bioavailability of ibuprofen
was reported after co-melt fluidized bed granulation with lactose, polyethylene glycol
10000 and polyvinylpyrrolidone.
C2.2. Fluidized bed binderless granulation
Fluidized bed binderless granulation is another “dry” method developed to avoid
problems created by the use of liquid binders and is carried out using the pressure
swing technology. This method utilizes the spontaneously agglomerating nature of
powders to form granules and was first reported by Nishii et al. (1993). It had been
suggested by Horio (2003) to be suitable for the granulation of water soluble drugs,
encapsulation of drug particles (without carrier particles), and particle design of dry
powder inhalers. Takano et al. (2002, 2003) showed that fine lactose powders
averaging 8.8 µm in diameter could be agglomerated and fluidized smoothly by cyclic
fluidization and downward airflow compaction to obtain spherical granules ranging
from 500 to 710 µm. The weak strength of the granules produced was extremely
applicable to dry powder inhalation technology as weak granules could readily be
dispersed to form an aerosol but yet remained sufficiently strong to withstand the
mechanical stresses during handling and transportation (Cheong et al., 2005). To date,
there have not been any reports on the potential of this method to produce granules for
tabletting.
31
Introduction
C2.3. Bottom-spray granulation
The current gold standard for fluidized bed granulation in the industry is top-spray
granulation (TG). The bottom-spray technique, also commonly known as Wurster
processing, has been primarily used for pellet coating and comparatively less explored
for granulation. The basic concept in Wurster processing consists simply of
supporting particles in a vertical chamber with an upwardly moving air stream during
which the spray liquid is atomized onto the suspending particles in the air stream
(Wurster, 1959).
Using Wurster processing, Ichikawa and Fukumori (1999) proposed the concept of
microagglomeration, a technique where pulverized powders are converted into
agglomerates (that ranged from 20 to 50 µm) for subsequent microencapsulation by
film coating. Attention on its use to prepare larger granules has been growing and
granulation using the Wurster process had been recently studied by Wang et al. (2003).
They found that granules of good physical properties could be obtained under
optimized operation conditions (which were determined using artificial neural
network analysis) and that the stability of a moisture sensitive drug was poorer at
conditions of high binder spray rate. Ho et al. (2005) considered the Wurster system
to be capable of offering promising advantages such as good process control,
facilitation of on-line control of granule size and one step processing of taste masking
and controlled release preparations (since the steps of granulation and coating can be
carried out consecutively in the same equipment). More recently, Rajniak et al. (2007,
2009) examined the impact of binder properties on granule morphology and
developed a methodology that combined theoretical and experimental techniques for
analyzing granule growth in the Wurster process.
32
Introduction
Since its introduction in the pharmaceutical industry, several significant modifications
have been added to the design of the conventional Wurster process. These
modifications include draft tubes or partition columns (Ishida and Shirai, 1975; Song
et al., 1997), vibration (Noda et al., 1998; Levy and Celeste, 2006; Moris and Rocha,
2006) and conical-based and/or conically shaped chambers (Hsiaotao, 2004;
Wormsbecker et al., 2009). One of the latest modifications of the Wurster process is
precision granulation (PG), which uses a modified mode of air distribution to improve
the fluid dynamics in the system (Walter, 2002). There are three distinct features of
the PG process that contribute to its unique fluid dynamics and differentiate it from
other Wurster-based processes.
The first feature is a flat air distribution plate (diameter of 170 mm) with a central
orifice diameter of 65 mm (Figure 4a) and a graduated open area, from 2 % at the
peripheral edge to 1.5 %, 1 % and 0 % at the centre (Figure 4b). The open area is
defined as the total area of perforations of the air distribution plate. The perforations
are tapered with a diameter of 0.8 to 1.0 mm on the side facing the upward flowing air
and 0.7 mm on the product side. The second feature, air accelerator insert (AAI), is a
detachable and bicylindrically shaped solid cylinder (70 mm in diameter) with an
opening in the middle (Figure 4c). The design of the AAI was based on a similar
concept employed by Danelly and Leonard (1978) for air acceleration and a wide
selection of AAIs with different opening diameters is available for employment
during granulation. This AAI made up the central part of the air distribution plate
when placed on a swirl accelerator (Figure 4d), the third feature of the PG process.
This last feature acts to compress, accelerate and impart swirl to the upward flowing
33
Introduction
(a)
Central orifice
(b)
Figure 4. Photographs of PG features: (a) air distribution plate showing central orifice,
(b) air distribution plate showing graduated open area, (c) AAIs of various opening
diameters and (d) air swirl accelerator.
34
Introduction
(c)
(d)
Side view Bottom view
Swirl
vanes
Figure 4 (continued). Photographs of PG features: (a) air distribution plate showing

central orifice, (b) air distribution plate showing graduated open area, (c) AAIs of
various opening diameters and (d) air swirl accelerator.
35
Introduction
central air stream (Mehta, 1997). Swirling improves the travelling velocity of air as it
enters the AAI with much reduced turbulence.
The assembled PG module (Figure 5), consisting of the air distribution plate, AAI,
swirl accelerator and a partition column is placed at the centre of the product chamber
during granulation. The partition column (75 mm in diameter and 250 mm in height)
is adjustably mounted above the air distribution plate and the partition gap is defined
by the vertical distance between the base of the partition column and the horizontal air
distribution plate. Different partition gaps are obtained by mounting the partition
column at different heights. The AAI sits on the swirl accelerator and is secured when
the air distribution plate is fitted onto the swirl accelerator.
This bottom-spray process was suggested by Walter (2002) to be able to carry out
rapid drying after wetting. Earlier studies on PG carried out by Liew et al. (2002)
showed that PG may be a suitable process to use for investigating granulation of
“difficult to granulate” materials that are soluble, sticky or hygroscopic in nature.
They compared PG, TG and high shear granulation on an industrial scale for
tabletting and reported that the porosity, strength and density of PG granules were
intermediate to those of TG and high shear granules. For equivalent tablet weight and
hardness, PG tablet batches showed faster disintegration times. This group of
researchers also comparatively studied PG and TG for the granulation of
acetaminophen, and observed that PG granules were generally less friable, had
smaller mean size and relatively lower proportion of oversize particles than the TG
granules. Real-time determination of operating conditions such as inlet air
36
Introduction
Stand to mount
partition column
above air distribution
plate
Partition column
AAI
Air distribution
plate
Partition gap
Air swirl
accelerator
Opening for
insertion of spray
nozzle body
Figure 5. Assembled PG module.
37
Introduction
temperature, inlet air relative humidity, inlet airflow rate, granule bed temperature,
liquid binder spray rate, outlet air temperature and outlet air relative humidity can also
be carried out during the PG process, hence facilitating process control and
understanding (Walter et al., 2003). PG challenges what has been the standard mode
of operation and the above findings suggested the potential of this bottom-spray
technique as an alternative to the conventional top-spray technique.
38
PART II:
HYPOTHESIS AND
OBJECTIVES
39
Hypothesis and objectives
II. HYPOTHESIS AND OBJECTIVES
Despite the great potential that could possibly be offered by the bottom-spray
technique, it has not been widely explored by pharmaceutical scientists for
granulation. There is a current need for more scientific knowledge in this area and yet
to date, there have been no comprehensive evaluative studies on the merits and
potential of bottom-spray granulation despite the proposed advantages. This led to the
main motivation behind this work and it was aimed at bridging the gap in the
fundamental knowledge as well as building up the understanding on bottom-spray
granulation. The modified Wurster process, PG, was the subject of exploration in this
study. The first part of this work was designed to gain a good understanding of PG
and to identify the critical process parameters for granule formation using the PG
process. Identification of the critical process parameters and their optimized ranges
would provide the basis for the selection of the range of process parameters to be used.
For the subsequent parts of this study, comparative studies of PG with the better
understood and widely accepted TG process were undertaken for a clearer illustration
of the potential of the relatively less explored PG process.
A. HYPOTHESIS
It was hypothesized that the highly ordered particle circulation pattern and unique
fluid dynamics in the PG process would be suitable for the following applications: (i)
spray deposition of a low dose, poorly soluble drug and (ii) wet granulation of a
moisture sensitive drug.
Achieving good drug content uniformity in dosage forms containing a low dose drug
is always a challenge. It would be valuable if a uniform mix of low dose drug with the
40
rest of the excipients could be attained together with the convenience and benefits
brought about by particle size enlargement during the granulation process. The
granules containing the uniformly distributed drug could then be made into tablets. In
a bottom-spray process with the presence of a partition column, there is cyclic particle
circulation path and would in theory ensure a high degree of product uniformity
(Cunha et al., 2009). Therefore, it was of interest to determine if the PG process can
be employed for the precise spray deposition of a low dose drug (dispersed in the
liquid binder) onto feed particles during granulation.
As previously mentioned, the wet granulation of moisture sensitive materials has
always provided many challenges to the pharmaceutical industry due to the inherent
requirement for contact with water during processing, often also accompanied by heat
during drying. There had been few reported investigative studies on the influence of
processing on the chemical stability of such materials. Hence, the potential of PG for
the wet granulation of moisture sensitive drugs was also investigated.
B. OBJECTIVES
To test the abovementioned hypothesis, the work for this thesis was carried out in four
main parts with the following objectives:
(1) to investigate the role of fluid dynamics and wetting on granule formation in PG,
(2) to illustrate the suitability of PG in comparison to TG for the spray deposition of a
low dose, poorly soluble drug onto feed particles during granulation and to investigate
the applicability of both processes to different wetting conditions and feed materials
for this purpose,
(3) to investigate the compaction behaviour of PG and TG granules, and
41
(4) to assess and to compare the capabilities of PG and TG to wet granulate moisture
sensitive drugs
The investigations carried out for objectives (1), (2), (3) and (4) can be found in Parts
A, B, C and D of the section on results and discussion respectively.
42
PART III:
EXPERIMENTAL
43
Experimental
III. EXPERIMENTAL
A. MATERIALS
A1. Feed material
Lactose monohydrate (Pharmatose 200M; Pharmatose 450M, DMV, The Netherlands)
was used.
A2. Liquid binder
The liquid binder was prepared using a dispersion of two grades of
polyvinylpyrrolidone (Povidone K25; Povidone K90, ISP Technologies, USA) in
deionized water.
A3. Model drugs
The low dose, poorly soluble micronized drug used for deposition onto the lactose
particles to test the first hypothesized application was hydrochlorothiazide (HCT; B.P.
grade, Sinochem, China). HCT has limited solubility in water and its reported
aqueous solubility at room temperature was approximately 0.6 mg/mL (Bergstrom et
al., 2002).
For testing of the second hypothesized application, a moisture sensitive drug,
acetylsalicylic acid (ASA; B.P. grade, Sintor, Romania) was used. Commonly known
as aspirin, ASA is easily hydrolyzed to salicylic acid and acetic acid in the presence of
moisture due to its substituted phenyl ester group (Yang and Brooke, 1982;
Carstensen et al., 1988). This hydrolytic reaction is shown in Figure 6.
44
Experimental
COOH COOH
OCOCH3 OH
+ CH3COOH
ASA Salicylic acid Acetic acid
Figure 6. Hydrolytic reaction of ASA.
Aspirin is also a good model for use to study granulation as it is a difficult candidate
for direct compression. This is because the crystalline powder has poor flow and
compressibility properties.
A4. Tablet excipients
The disintegrants investigated were croscarmellose (Ac-Di-Sol, FMC BioPolymer,
USA), sodium starch glycolate (Explotab, Penwest Pharmaceuticals Co., UK), sodium
starch glycolate (Starch 1500, Colorcon Asia Pacific, Singapore) and crospovidone
XL, crospovidone XL-10 (Polyplasdone, ISP Technologies, USA). Magnesium
stearate (Riedel-de-Haën, Sigma-Aldrich Laborchemilien GmbH, Germany) was
added in powder form to act as a lubricant or used as a suspension in isopropyl
alcohol (Technical grade, Schedelco, Singapore) to pre-lubricate the punch and die set
during compaction studies.
45
Experimental
A5. Chemicals for dissolution media preparation and high performance liquid
chromatography (HPLC) analyses
Hydrochloric acid (37 %, Merck, Germany) was diluted to 0.1 N with deionized water
and used as the media in dissolution studies. For the HPLC analyses, acetonitrile
(HPLC grade, Merck, Germany) and phosphate buffer were used as the mobile phase.
The phosphate buffer was prepared using a mixture of acid and salt solution. The acid
solution prepared using ortho-phosphoric acid (85 %, Merck, Germany) was diluted
to 0.1 M with deionized water, and potassium dihydrogen phosphate (Merck,
Germany) was dissolved in deionized water to prepare a 0.1 M salt solution.
46
Experimental
B. METHODS
B1. Feed material
Coded as powder blend 1 in Table 1, 1 kg of lactose 200M was used as the feed
material for all granulation runs in this study unless otherwise stated.
In Part B of the study, various lactose powder blends were investigated as feed
material. Lactose 200M was blended with various percentages of lactose 450M to
give a range of lactose powder blends, coded as 2 to 7 for investigation (Table 1).
In Part D of the study, powder blend 8, consisting of lactose 200M and ASA, was
used. Lactose powder and ASA were pre-sieved through a 710 µm aperture size sieve
and a 355 µm aperture size sieve respectively to remove any aggregates.
Table 1. Compositions of powder blends used as feed material.

Powder blend Lactose 200M (kg) Lactose 450M (kg) ASA (kg)
*
1 1 0 0
2 0.9 0.1 0
3 0.8 0.2 0
4 0.7 0.3 0
5 0.6 0.4 0
6 0.5 0.5 0
7 0 1 0
8 1 0 0.05
*
indicates composition used unless otherwise stated.
47
Experimental
B1.1. Blending of powder
All materials were accurately weighed out and blended according to the compositions
required in a double-cone mixer (AR 400E, Erweka, Germany) at 40 turns/min for 50
min prior to characterization and processing.
B1.2. Determination of powder particle size
The mass median diameter (MMD) and span of powder blends 1 to 7 were determined
using a laser diffraction particle sizer with the dry powder module attachment (LS 230,
Coulter Corporation, USA). Using the system software (Coulter® LS version 2.11a), a
cumulative percent undersize plot was derived by comparing the light scattering
pattern of the particles in the blends with an optical model. The optical model used for
comparison in this study was Fraunhofer approximation.
For each blend, three representative samples were randomly obtained and sized.
MMD and span were defined as follows:
MMD = d 50 (1)
d 90  d10
Span  (2)
d 50
where d10, d50 and d90 are the particle diameters at the 10, 50, and 90 percentiles of the
cumulative percent undersize plot respectively.
B1.3. Determination of powder flow with angle of repose
The flow properties of powder blends 1 to 7 were evaluated using a powder tester
(PT-N, Hosokawa Micron, Japan). The flow parameter, angle of repose, was
determined by manually feeding powder through a funnel onto a fixed base to form a
48
Experimental
cone, and an angle pointer was then used to determine the angle of the formed cone.
Five measurements were obtained for each powder blend.
B2. Liquid binder
The formulations of liquid binder used for granulation are shown in Table 2. For Parts
A, B and C of the study, formulation I was used to prepare each batch of granules.
Formulation II was used for Part D.
Table 2. Formulations of liquid binder used for granulation.

Formulation I Formulation II
Povidone K25 (g) 45 45
Povidone K90 (g) 15 15
Micronized HCT (g) 25 0
Deionized water (g) 415 440
Total weight (g) 500 500
B2.1. Micronization of HCT
HCT was micronized using a fluidized bed hammer mill (50 ZPS, Hosokawa Alpine,
Germany) with long grinding zones at an inlet airflow rate of 90 m3/h, beater
rotational speed of 20000 rpm and classifier speed of 10000 rpm. The batch size used
for milling was 1 kg.
49
Experimental
B2.2. Determination of particle size of micronized HCT
The milled drug particles were examined at 1000 × magnification, using a light
microscope (BH2, Olympus, Japan). The microscope was connected to a monitor via
a video camera (YS-W130P, Sony, Japan). Representative samples of the drug were
randomly obtained and mounted onto slides. The slides were moved in a systematic
manner to view different areas of the mounted samples, and 15 particles were
measured in each defined area of the slide. The size of each batch of milled drug
particles was determined from at least 625 projected images of different particles,
across the longest diameter of the projected plane. The diameter at the 99 percentile
(d99) of the cumulative percent undersize plot was employed to characterize the
particle size of the drug to indicate the upper limit of the particle size distribution and
was reported as the mean of four batches.
B2.3. Preparation of HCT-incorporated liquid binder
Just prior to granulation, the micronized drug was added to an aqueous dispersion of
polyvinylpyrrolidone and stirred using a high shear homogenizer (L4RT, Silverson
Machines, USA) for 10 min at 3500 rpm.
B3. Granulation process
As shown in Figure 7, either the PG or TG module was fitted onto the air handling
system (MP-1 Multi-processor, GEA Aeromatic-Fielder, UK) where appropriate.
Details on the PG module can be found from Figures 4 and 5. The air distribution
plate used in TG has a diameter of 170 mm with circular orifices (3 mm in diameter
and uniformly spaced at a distance of 10 mm apart) throughout the plate (Figure 7b).
50
Experimental
(a)
PG module assembly
Bottom-spray nozzle
body with atomizing
air tube and feed tube
attached
(b)
Top-spray nozzle
body with atomizing
air tube and feed tube
attached
Magnified view of air

distribution plate
Figure 7. Photographs of (a) PG and (b) TG modules fitted onto the MP-1 air handling
system.
51
Experimental
The air handling system was warmed up under standardized conditions prior to
addition of powder into the conical acrylic product chamber for granulation (Table 3).
At the start of each run, the system was activated with the appropriate airflow and
atomizing pressure while the liquid binder was fed to the spray nozzle using a
peristaltic pump (504U, Watson-Marlow, UK).
During the liquid binder addition phase, the fluidizing airflow rate was slowly
increased under standardized conditions to maintain adequate fluidization. The
process variables and their operating conditions used are shown in Table 3.
Throughout the run, the beaker of binder dispersion was stirred continuously with a
magnetic hot plate stirrer (Cb162, Bibby Sterlin, UK) while the weight of the liquid
binder sprayed was monitored using a weighing balance (Libror EB3200H, Shimadzu,
Japan). The point of completion of liquid binder addition marked the start of the
drying phase.
At the end of drying, the granules were carefully collected from the product chamber
and left to cool to room temperature. After cooling, the prepared granules were stored
in sealed plastic bags and used for further tests (in Parts A, B and C of the study). For
Part D of the study, the prepared granules containing ASA were sealed in plastic bags
and then stored in desiccators unless otherwise specified.
B3.1. Real-time measurement of process conditions
During processing, inlet air relative humidity, inlet air temperature, outlet air relative
humidity, outlet air temperature and granule bed temperature were continuously
recorded. The positions whereby the process parameters were measured are shown in
52
Experimental
Table 3. Process variables and their operating conditions in PG and TG.

Process variables Operating conditions
PG TG
Nozzle tip diameter (mm) 1 1
Nozzle tip protrusion from air cap (mm) 1.2 1.2

†
Partition gap (mm) 20, *26, 32 N.A.
†
AAI diameter (mm) 24, 30, *35 N.A.
Nozzle height from base plate (mm) N.A. 235
Warm-up
Duration (min) 20 20
Airflow rate (m3/h) 80 80
Inlet air temperature (°C) 60 60
Liquid binder addition

†
Binder spray rate (g/min) 18-37 18-37
Atomizing air pressure (bar) 0.8 0.8
Airflow rate (m3/h) 50-110 70-110

† * *
Inlet air temperature (°C) 60, 65, 70, 75, 80 60, 80
Drying
Duration (min) 10 10
Airflow rate (m3/h) 80 80
Inlet air temperature (°C) 60 60

† *
indicates variable is specified by experimental design, indicates value used unless otherwise stated
and N.A. abbreviates not applicable.
53
Experimental
Figure 2. The relative humidity of air was measured using a humidity transmitter (I-
1000, Rotronic Instruments, UK) and temperature was measured using a dry bulb
temperature element (PT-100, Testtemp, UK). Measurements were taken every 10 s
with a data acquisition system (Orchestrator Version 2.5.0.0, Measuresoft
Development, Ireland) linked to the air handling system. Baseline calibration of inlet
and outlet conditions was carried out before the start of granulation. Inlet ambient air
was maintained at a relative humidity of 50 % and temperature of 25 °C.
B3.2. Determination of process drying efficiency
The process drying efficiency during granulation was defined as the ability of the
incoming air to remove the moisture introduced into the system (Tang et al., 2008). A
process drying efficiency of 100 % suggested optimal condition when all the moisture
introduced was removed by the drying process. It was calculated using the following
equation.
ma ho
Process drying efficiency (%) = × 100 (3)
ma hi  ml
where ma is the airflow rate (kg/h), ml is the liquid flow rate (kg/h), hi is the inlet air
absolute humidity (kg/kg dry air), ho is the outlet air absolute humidity (kg/kg dry air).
Absolute humidity was determined from the psychrometric chart of water-air system
at 1 atmospheric pressure using dry bulb temperature and relative humidity
(Shallcross, 1997).
B3.3. Determination of granule bed temperature profiles
From the bed temperature measurements recorded every 10 s by the data acquisition
system linked to the air handling system, the temperature profiles of the triplicate runs
54
Experimental
were obtained. The area under the temperature against time curve, referred to as
AUCheat (°Cmin), was calculated with statistical software (Matlab® R2009a) to
determine the extent of exposure of the granule bed to heat for the entire duration of
the process.
B3.4. Determination of capacity for moisture removal
The capacity for moisture removal during granulation was defined as the maximum
amount of moisture that can be removed from the system by the incoming air. It was
calculated as the difference between the maximum amount of moisture the air at the
granule bed can hold and the amount of moisture introduced into the system by the
inlet air.
Capacity for moisture removal (g/min) = ma × (hb – hi) (4)
where ma is the airflow rate (kg/min), hb is the absolute humidity of the air at the
granule bed at 100 % relative humidity (g/kg dry air) and hi is the inlet air absolute
humidity (g/kg dry air).
B3.5. Determination of granule bed moisture content profiles
The moisture content profiles of PG and TG granule beds were charted by
determining the moisture contents of granules sampled at 2 min intervals throughout
processing via a sampling port at the side of the product chamber. A moisture balance
(EB-330 MOC, Shimadzu, Japan) was used to dry 1 g samples at 105 °C for 30 min.
Triplicate determinations were carried out and averaged for each batch of granules.
The moisture content profile of each batch was obtained by plotting the mean
moisture content of granules against time. The area under the curve, AUCmoisture
55
Experimental
(%min) was calculated with statistical software (Matlab® R2009a) to determine the
amount of moisture in the granule bed for the entire duration of the process.
B3.6. Determination of air velocity within partition column
A digital micromanometer (8705 DP-CALC, TSI, USA) was used to measure the air
velocity within the partition column of the PG module. The L-shaped probe was
inserted into the product chamber through an opening whereby a rubber stopper held
the probe in place and sealed the opening. The probe was placed with the tip
positioned in the centre of the partition column, 125 mm above the air distribution
plate during the measurements.
The reading on the digital display was zeroed before the start of each run and the run
conditions were allowed to stabilize for at least 1 min before taking the air velocity
reading. The readings were taken at different conditions of AAI diameter and partition
gap used in the study. Airflow rate was increased from 50 to 110 m3/h, in intervals of
10 m3/h, while the atomizing air pressure and inlet air temperature were set at the
levels used for granulation. The air velocity at each different condition was
investigated from three independent runs, with triplicate readings for each run.
B3.7. Determination of process yield
The process yield of each batch, calculated according to Equation (5), was the actual
batch weight of collected granules after processing (Wg) as a percentage of the
theoretical batch weight (Wt). Wt was the sum of the weight of the feed material and
solids content of the liquid binder sprayed.
56
Experimental
Wg
Process yield (%, w/w) = × 100 (5)
Wt
B4. Characterization of granules
B4.1. Granule size
The granules prepared were divided into random samples of approximately 120 g
using a riffler (PT, Retsch, Germany), and subjected to size analysis using a nest of
sieves (Endecotts, UK). The series of sieves with aperture sizes 90, 125, 180, 250, 355,
500, 710, 1000 and 1400 μm was vibrated at an amplitude of 1 mm for 15 min
(VS1000, Retsch, Germany).
A cumulative percent undersize plot was derived based on weight measurements of
the granules in the various size fractions. MMD and span were defined as above in
Equations (1) and (2). The fractions of granules smaller than 90 μm and larger than
1400 μm were defined as fines and lumps, respectively in Part A of the study.
B4.2. Granule shape
The granules from the 355 to 500 μm size fractions were first gently sieved through a
500 μm aperture size sieve manually. Granules trapped at the sieve apertures were
then carefully removed and subjected to analysis. Particle shape of 60 randomly
chosen granules was assessed using a stereomicroscope (SZH, Olympus, Japan),
linked to an image analysis program (Micro Image, Media Cybernetics LP, USA).
The captured images were digitalized and analyzed by the software.
57
Experimental
Sphericity was determined from the cross-sectional area (a) and perimeter (pr), and
aspect ratio was determined from the length (l) and breadth (b) of the granule images
using the equations below.
4a
Sphericity  2
(6)
pr
l
Aspect ratio = (7)
b
Sphericity values range from 0 to 1, whereby a value of 1 indicates a perfect sphere
and greater deviations from a sphere will give rise to lower sphericity values.
B4.3. Granule surface morphology
The morphology of the granules was also assessed qualitatively using a scanning
electron microscope (JSM-5200, Jeol, Japan) after pretreatment of samples by gold
sputtering (JFC-1100, Jeol, Japan).
B4.4. Granule flow
Using a procedure similar to that discussed in section B1.3, granule flowability was
evaluated by the determination of angles of repose.
Bulk and tapped densities were determined according to the United States
Pharmacopeia (USP) method, using a USP tap density tester (TD2, Sotax,
Switzerland). Granules were filled up to 100 mL (v) in a graduated cylinder and the
weight (W) determined. The granules were subjected to tapping until a constant
volume (vc) was obtained. Duplicate analyses were carried out for each batch. Bulk
density, tapped density and Carr index were defined as shown below.
58
Experimental
W
Bulk density (g/mL)  (8)
v
W
Tapped density (g/mL)  (9)
vc
 bulk density 
Carr index (%) = 1   × 100 (10)
 tapped density 
B4.5. Granule porosity
The porosity of the granules was derived from tapped density and particle true density
(Dp) estimations, as shown in Equation (11). A helium pentapycnometer (PPY-14,
Quantachrome, USA) was used for particle true density estimations. The granules
were oven-dried at 105 °C for 2 h and cooled to room temperature in a desiccator
prior to use. Triplicate tests were performed on each granule batch.
 tapped density 
Porosity (%) = 1   × 100 (11)
 D 
 p 
B4.6. Granule friability
A friabilator (TA 20, Erweka GmbH, Germany) was used to tumble accurately
weighed 7 g samples of granules (wi) with 20 steel balls, each measuring 6 mm in
diameter and weighing 0.88 g. The steel balls acted as attrition agents during the test
and the granules were subjected to 250 revolutions. After tumbling, the granules were
sieved through a 180 μm aperture size sieve and the weight of granules retained on the
180 μm aperture size sieve (wf) was recorded. Each experiment was repeated thrice
and the results averaged. The friability index was evaluated in the following manner.
 wf 
Friability index (%)  1   × 100 (12)
 wi 
59
Experimental
B4.7. Content determination of HCT in granules
Drug contents in the granules of various size fractions, ranging from the 1400 µm
oversize fraction in a decreasing √2 progression to the 90 µm undersize fraction for
each granule batch were determined. Approximately 60 mg of granules was randomly
sampled from each size fraction and dissolved in 100 mL of deionized water. UV
spectrometry (UV-1201, Shimadzu, Japan) at 273 nm was used to detect the amount
of drug present. Triplicate analyses were carried out for each size fraction in each of
the granule batches. The readings of the three granule batches were totalled up and
averaged to obtain Drugx, the inter-batch drug content in a weighed amount of
granules of the specific size fraction x. As a measure of drug content uniformity
within the specific size fraction x, the relative standard deviation (RSD) of Drugx was
calculated to give RSDx. A lower RSD value signified better drug content uniformity.
The granules were subsequently classified as small, medium and large for those
belonging to the size fractions ≤ 250 µm, 250 to 710 µm, and ≥710 µm respectively.
The mean drug content and mean RSD of drug content for the classified small,
medium and large granules were then calculated according to Equations (13) and (14).
1 n
Mean drug content (%, w/w) =  ( Drug x )
n i 1
(13)
1 n
Mean RSD of drug content (%) =  ( RSDx )
n i 1
(14)
where n is the number of size fractions within the granule size classifications.
Taking into consideration the different proportions of the various size fractions within
a granule batch and thus their relative contributions to the overall batch drug content
60
Experimental
uniformity, the overall weighted RSD of drug content was calculated as shown in
Equation (15).
n
Overall weighted RSD of drug content (%) =  ( p x )(RSD x ) (15)
i=1
where px is the proportion of a specific size fraction x calculated from triplicate
batches.
B4.8. Dissolution of HCT from granules
Accurately weighed 600 mg samples of granules were analyzed. Dissolution was
carried out in 900 mL of deionized water, using a diode array spectrophotometer
(8452A, Hewlett Packard, USA) at wavelength 273 nm, according to USP paddle
method II (DT1, Optimal Control Inc., USA). The temperature of the dissolution
medium was controlled at 37 °C and stirred constantly at 100 rpm. The time required
for 50 % (t50%) and 90 % (t90%) of the drug to be released were obtained graphically
from the dissolution profile. The final drug content of the granule samples was
determined after 30 min. Eight random samples were analyzed for each batch of
granules.
B4.9. Amount of ASA degradation
The number of moles of salicylic acid (NSA), a product of hydrolysis of ASA, and the
number of moles of remaining ASA (NASA) were assayed using HPLC analyses (LC
2010A, Shimadzu, Japan). NSA and NASA were determined in collected samples of
powder mixtures after blending, wet granules sampled during the granulation process
and final dried granules. The samples were kept in glass containers and stored in a
freezer at -20 °C prior to analyses. Analyses were carried out in accordance to a
method previously established (Chee et al., 2005).
61
Experimental
A reversed phase C-18 column (Hypersil® BDS-C18, Thermo Electron Corporation,
UK) was employed as the stationary phase whereas the mobile phase consisted of
phosphate buffer (pH 2.6) and acetonitrile in a ratio of 4:1, at a flow rate of 1 mL/min.
The powders and granules were pulverized before analyses. An accurately weighed
amount of the pulverized material (approximately 200 mg) was dissolved and made
up to a final volume of 20 mL with the mobile phase. The suspension was then
ultrasonicated (LC60H, Fisher Scientific, Germany) for 10 min before being filtered
through a 0.45 µm membrane filter (RC, Sartorius, Germany). Ten µL of the filtrate
was used for the assay. The column was maintained at 40 °C throughout the analyses,
and the detection wavelength employed was 254 nm. Triplicate assays were carried
out and results averaged.
The areas under the curves of salicylic acid and remaining ASA were determined and
their corresponding amounts present were calculated according to standard calibration
curves. The % ASA degradation was calculated in the following manner.
N SA
Amount of ASA degradation (%) = × 100 (16)
N SA  N ASA
The % ASA degradation obtained for the control powder blends of lactose and ASA
was taken as the baseline for the amount of ASA degradation. This was largely the
degradation that occurred during storage and was already present prior to use in this
study. This baseline amount was used to correct the % ASA degradation values
obtained for granule samples and the reported values had been corrected.
From the amount of ASA degradation determined from wet samples collected at 2
min intervals, the amount of ASA degradation versus time for the entire process was
62
Experimental
charted. The slope of this graph was calculated and defined as the rate of ASA
degradation (%min-1).
The ratio below was derived from the amounts of ASA degradation found in final
dried granules and was defined as the ASA degradation index in this study.
Amount of ASA degradation in PG

ASA degradation index (%) = × 100 (17)
Amount of ASA degradation in TG
B5. Compaction process
Tablets were made by compressing accurately weighed 350 mg granules from the 355
to 500 µm size fractions using a microprocessor controlled universal testing machine
(Autograph AG-100KNE, Shimadzu, Japan). A set of 10 mm diameter flat faced
punches and die was employed for compression at a speed of 5 mm/min. The punch
and die set were pre-lubricated with 1 %, w/w magnesium stearate suspended in
isopropyl alcohol. For each batch of granules, tablets were compacted at a fixed
applied pressure (13, 25, 38, 51, 76, 102, 127 and 153 MPa) and then stored in a
desiccator for at least 24 h before they were subjected to testing.
For the disintegration and dissolution studies, randomly sampled granules were taken
from a selected batch prepared using a particular set of parameters and compacted
with various disintegrants. The 350 mg tablet formulation contained 96 %, w/w
granules, 3 %, w/w disintegrant and 1 %, w/w magnesium stearate.
63
Experimental
B5.1. Heckel plot analysis
The “out-of-die” Heckel analysis method was shown by Sun and Grant (2001) to
describe powder consolidation and compaction more accurately, and therefore was
used in this study to derive the Heckel plots (Heckel, 1961a, b) as shown below.
 1 
ln   kP + A (18)
1 D 
where k and A are constants obtained from the slope and intercept of the plot ln [1/ (1-
D)] versus P, respectively. D referred to the relative density of the granule column at
the applied pressure P and (1-D) denotes the pore fraction or porosity.
D was derived by dividing apparent density (Dapp) by true density (Dt) of the granule
column. Dapp was calculated from the mean density (after recovery) of ten tablets and
Dt was calculated from Dp estimations of the granules and extragranular components
in the tablet, based on their proportion in the tablet formulation. Dp estimations of the
granules and extragranular components in the tablet were carried out using helium
pycnometry as discussed in section B4.5.
The initial curvature of the Heckel plot was evaluated as the deviation from a straight
line and expressed as the correlation coefficient, r (Cai, 2002). This deviation
indicated the extent of particle rearrangement and slippage in the die during early
stages of compaction. A larger deviation from linearity i.e. a smaller r value would
suggest a larger extent of particle rearrangement and slippage.
Constant A obtained from the plot relates to volume reduction before deformation and
bonding of the discrete particles. Hence, the extent of particle rearrangement and
slippage was also quantified using the following relationship.

64
Experimental
Db = Da – D0 (19)
where Db is the increase in relative density due to particle rearrangement. Da is the
extrapolated relative density from the intercept of the linear portion of the Heckel plot
and was calculated from constant A using Equation (20). D0 is the initial relative
density and was derived by dividing bulk density by Dt of the granule column. Bulk
density of the granule column was determined by filling the granules up to 10 mL in a
graduated cylinder and determining their weight.
Da  1  e  A (20)
The slope, k, of the Heckel plot gives a measure of the plasticity of a compressed
material and a greater slope indicates a greater degree of plasticity. Yield pressure was
defined as the reciprocal of k. The yield pressure gives a general impression of the
deformation tendency of a powder column and a smaller yield pressure indicates a
greater ease of deformation (Paronen and Iikka, 1996).
B6. Characterization of tablets
B6.1. Tablet surface morphology and roughness
The macro-surface morphology of tablets was examined on a stereomicroscope (SZ61,
Olympus, Japan). The images were captured using a camera (DP71, Olympus, Japan)
and digitalized by a software (DP Controller, Olympus, Japan) linked to the
stereomicroscope.
An optical profiler (Wyko, NT1100, Veeco, USA) was also used to examine tablet
micro-surface roughness. The optical profiler splits a beam of light into two and
directs it onto the sample surface. The light is reflected back to create an interference
65
Experimental
pattern which is used to derive the topographical image of the sample. The tablet was
placed onto a slide and imaged using a 20 × objective with 1 × field-of-view lens. The
effective magnification was 20.64 × and the effective field of view was 300 by 228
μm. For each tablet, the surface was assessed at five different spots, and the values
averaged to obtain the intra-tablet surface roughness. The inter-tablet mean surface
roughness of ten tablets was then calculated for each compaction pressure.
The roughness parameters Ra and Rq used to quantify the surface roughness of the
tablets in this study were calculated and derived by the software. Ra represents the
roughness average, the arithmetic mean of the absolute values of the surface
departures from the mean plane; whereas Rq represents the root mean square
roughness, obtained by squaring each height value in the dataset, then taking the
square root of the mean. As height values are squared in the calculation, the root mean
square roughness statistics are more sensitive to peaks and valleys than average
roughness statistics, making Rq a better parameter for discriminating between
different types of surfaces. If a surface contains no large deviations from the mean
surface, Rq and Ra values will be similar. However, if there are appreciable numbers
of large bumps or holes, Rq values will be larger than Ra.
B6.2. Tablet porosity
The tablet porosity was calculated according to Equation (21), where Dapp and Dt were
defined as above in section B5.1. The mean of ten determinations was calculated.
 Dapp 
Tablet porosity (%)  1   × 100 (21)
 Dt 
66
Experimental
B6.3. Tablet tensile strength
The hardness (F) of recovered tablets formed at applied pressures of 25, 38, 51, 76,
102, 127 and 153 MPa were determined using a diametral tablet hardness tester (HT1,
Sotax, Switzerland). Tablets formed at 13 MPa were too weak for readings to be
registered by the tester and hence could not be reported. A micrometer screw gauge
(Model 293-761-30, Mitutoyo Corporation, Japan) was used to determine the tablet
heights (h) and diameters (d). Average tensile strength of ten tablets was calculated
according to the equation below (Fell and Newton, 1970).
2F
Tensile strength (N/mm2)  (22)
dh
B6.4. Disintegration of tablets
Disintegration times (tdis) were measured in 900 mL deionized water at 37 ± 2 °C
according to USP method without disc in a disintegration tester (DT2, Sotax,
Switzerland). The average disintegration time was determined from six tablets.
B6.5. Dissolution of HCT from tablets
Dissolution was performed using a USP dissolution apparatus (DT1, Optimal Control
Inc, USA) in both deionized water and 0.1 N hydrochloric acid solution, according to
USP paddle method II. Temperature was controlled at 37 °C and stirred constantly at
100 rpm. At predetermined time intervals, 5 mL samples were withdrawn and
analyzed using a UV spectrophotometer (UV-1201, Shimadzu, Japan) at a wavelength
of 273 nm. At 60 min, paddle speed was increased to 300 rpm for 15 min, and the last
reading taken at 75 min. The time required for 50 % (t50%) of the drug to be released
was obtained graphically from the dissolution profile. Dissolution analyses were done
in triplicate.
67
Experimental
B7. Statistical analyses
B7.1. Design-of-Experiment and response surface modelling
For Part A of the study, Design-of-Experiment was carried out to show, in an
objective manner, the relationship between variables and to improve product and
process success (Harwood and Molnar, 1998). A randomized full-factorial design (33)
was carried out. All experimental batches were performed in triplicates to increase the
level of confidence in the resultant empirical relationships derived. Before the
application of the experimental design, several preliminary trials were conducted to
determine the range of conditions at which the process was capable of forming usable
granules of reasonable quality, defined as a granule batch with MMD larger than 200
µm. The size analysis was determined by sieving. The low, intermediate and high
levels of the variables used in the factorial design as defined in Table 4 were also
derived by this procedure. Regression analyses were carried out using coded units and
the statistical analyses were carried out using MINITAB® Release 14 (Minitab Inc.,
USA).
Table 4. Factorial design: variables and their defined levels.

Variables Levels
Low Intermediate High
XA: AAI diameter (mm) 24 30 35
XP: Partition gap (mm) 20 26 32
XS: Binder spray rate (g/min) 18 21 24
68
Experimental
Attempts were made to fit the responses (Y) to a quadratic model using response
surface methodology. The quadratic equation used for response surface modelling of
the three above independent variables is as follows.
Y = β0 + βAXA + βPXP + βSXS + βAAXA2 + βPPXP2 + βSSXS2 + βAPXAXP + βASXAXS + βPSXPXS (23)
where β0 is the constant, βA, βP and βS are the coefficients of the linear terms XA, XP
and XS, βAA, βPP and βSS are the coefficients of the squared terms XA2, XP2 and XS2, and
βAP, βAS and βPS are the coefficients of the interaction terms XAXP, XAXS and XPXS.
B7.2. Multivariate data analysis
For Part C of the study, Unscrambler® 9.7 (Camo Software AS, Norway) was used to
perform multivariate data analysis using the principal component analytical modelling
technique. A principal component model is an approximation to a given data matrix
and it consists of a set of orthogonal axes determined as maximum variance directions,
and having the same common origin (Esbensen, 2002). A multi-dimensional data
matrix is rendered and allows for geometrical insight into the hidden data structure.
Typical loadings plots derived from principal component analyses thus provide a
projection view of the inter-variable relationships.
B7.3. Regression analyses
Simple linear regression was used to quantify the relationship between a single
response and a single variable according to Equation (24). The relationship between a
single response and three variables was quantified by fitting the data to Equation (25)
in Part D of the study.
Y = β0 + β1X1 (24)
Y = β0 +β1X1 + β2X2 + β3X3 (25)
69
Experimental
where β0 is the constant, β1, β2 and β3 are the coefficients of the linear terms X1, X2 and
X3 respectively.
B7.4. Other data analyses
Other data analyses including Pearson’s correlation, t-test and one-way ANOVA were
carried out using MINITAB® Release 14 (Minitab Inc, USA). Independent sample t-
test was used to compare two sample sets. One-way ANOVA was used to compare
more than two sample sets with Tukey’s test as the post hoc analyses.
B7.5. Level of significance
The level of significance in this study was defined as p < 0.05 unless otherwise stated.
70
PART IV:
RESULTS AND DISCUSSION
71
Results and discussion – Part A
IV. RESULTS AND DISCUSSION
A. ROLE OF FLUID DYNAMICS AND WETTING ON GRANULE
FORMATION IN PG
Air accelerator insert diameter, partition gap and binder spray rate were postulated to
affect granule growth in PG. The postulation of their significance stems from the
important roles they have played in other related studies. Thus, it was of interest to
study the influences of AAI diameter and partition gap because of their potential
influences on the system’s fluid dynamics. For instance, the important role of the
partition gap in regulating particle entry into the coating zone of the bottom-spray
systems had been identified (Deasy, 1984; Christensen and Bertelsen, 1997) and it
was observed that agglomeration of coated pellets can be minimized with the use of
an optimal AAI diameter and partition gap (Chan et al., 2006; Tang et al., 2008).
Liquid binder spray rate was chosen as the third parameter for investigation due to the
commonly reported sensitivity of fluidized bed granulation processes to changes in
wetting and resultant moisture content in the powder bed (Kokubo and Sunada, 1997;
Faure et al., 2001; Hemati et al., 2003). A 33 factorial design was thus carried out to
determine the main effects of these three variables on properties of the granule
batches and their interdependencies, if any, over the wide range of wetting and/or
drying conditions selected.
In the conventional Wurster process, a large proportion of the air flowed up the
annular bed which was then fully fluidized. Without a partition column to regulate
movement, these fluidized powder particles flood into the central spray granulation
zone. In contrast, much more of the upward flowing air was directed into the central
partition column where the spray granulation zone is located via the graduated air
72
distribution plate and the swirl accelerator in PG (Figure 8). This resulted in a
comparatively smaller proportion of the air being distributed to the annular down flow
bed. The swirl accelerator promoted air flow through the partition column by reducing
the turbulence of air as it entered a narrowed orifice, the AAI. By swirling the air,
improved air flow rates can be achieved, thus conferring fluid dynamics to the PG
system. As the central upward flowing air stream passed through the swirl accelerator
at the plenum, it was compressed and directed through a narrowed passage by the
AAI, before expanding in the partition column. By the law of conservation of mass
(Batchelor, 2000), the same volume of air flowing by in the same time through a
narrower opening moved faster, giving rise to an air stream of higher velocity and
lower pressure as the air entered the base of the partition column.
This design based on the law of conservation of mass created unique fluid dynamics
in the PG process by causing the formation of a spray granulation zone of very high
air velocity and low local pressure as the compressed air through the AAI was
released into the partition column. The zone of low local pressure within the partition
column drew particles from the annular down flow bed (region between the partition
column and the wall of the product chamber) into the partition column. This strong
suction effect experienced at the annular down flow bed is known as the Venturi
effect (Dixit and Puthli, 2009) and is influenced by the high velocity airflow rate
passing through the column.
A1. Factors influencing air velocity within the partition column
At a fixed partition gap height, a faster flowing air stream would create a zone of
lower pressure immediately above the spray nozzle. This resulted in a stronger suction
73
Partition
column Drying zone
Annular down
flow bed
Graduated air Spray

distribution plate granulation
zone
Small volume of
fluidizing air at Partition gap
low velocity
AAI
Large volume of
heated drying air Air swirl
at high velocity accelerator
Heated air
Figure 8. Schematic diagram showing the air distribution and zones in the PG process,
with arrows representing airflow.
74
effect being experienced in the annular down flow bed. The air velocity within the
partition column not only influence the strength of this suction effect but also impact
wetting and drying by altering the product residence time in the partition column. For
a comprehensive understanding on the overall drying ability of the PG process,
information on air velocity within the partition column would be extremely useful.
The air velocity within the partition column was measured at conditions of different
airflow rate, AAI diameter and partition gap. From Figure 9, it could be observed that
for all the investigated conditions, an increase in airflow rate led to an increase in air
velocity within the partition column. Simple linear regression was performed on
airflow rate (Xaf) and air velocity within the partition column (Yvel), at an AAI
diameter of 30 mm and partition gap of 26 mm. Equation (26) shown below indicated
a proportional relationship between the two variables. The obtained estimate of
goodness-of-fit of the line, R2, was 0.998. This value represented that 99.8 % of the
variation in the data was explained by the fitted line.
Yvel = 0.249Xaf + 7.95 (26)
The extent of increments in air velocity with airflow rate appeared to be consistent for
the investigated partition gaps (Figure 9a). On the other hand, the same increments in
airflow rate led to steeper increases in air velocity for AAIs of smaller diameters
(Figure 9b). It was observed that when the 35 mm AAI was used, the air velocity
within the partition column was less influenced by different airflow rates as compared
to when smaller AAIs of 30 mm or 24 mm were used.
75
(a)
50
40
Air velocity (m/s)
30
20
10
0
20 26 32
Partition gap (mm)
(b)
50
40
Air velocity (m/s)
30
20
10
0
24 30 35
AAI diameter (mm)
Figure 9. Influence of (a) partition gap (AAI diameter of 30 mm) and (b) AAI
diameter (partition gap of 26 mm) on air velocity within the partition column at
airflow rates of 50 ( ), 60 ( ), 70 ( ), 80 ( ), 90 ( ), 100 ( ) and 110 ( ) m3/h. Error
bars represent standard deviation among independent runs.
76
The air velocity within the partition column, averaged across the various airflow rates,
at the nine defined conditions of the factorial design is shown in Figure 10. It can be
seen that AAI diameter had a greater impact than partition gap on the air velocity
within the partition column. Using simple linear regression, the relationship between
air velocity (Yvel; averaged across the various airflow rates and partition gaps) and
AAI diameter was also found. Equation (27) was obtained with a R2 value of 0.974. It
was established that AAIs of larger diameters generated a lower air velocity within
the partition column.
Yvel = -1.93XA + 91.2 (27)
A2. Factors influencing characteristics of granule batches
The various response parameters (process yield, size, shape and flow) of the granule
batches were obtained and first analyzed by factorial analyses to determine the main
effects of the variables and interactions, if any. Subsequently, response surface
modelling was carried out on the parameters and the responses were checked for
model significance in addition to lack-of-fit to the model. The significance values
obtained are shown in Table 5. Equations were derived only for responses that were
of both model significance and lack-of-fit insignificance, namely fines, lumps and
aspect ratio.
A2.1. Influence of variables on process yield
The granule batches prepared had good process yields ranging from 79.55 to 94.70 %,
w/w (Table 6). Among the three investigated variables, it was found that partition gap
and binder spray rate had significant influences on the process yield of the granule
batches (Table 7). The results shown in Table 6 advocated the usage of an optimal
77
50
40
Air velocity (m/s)
30
20
10
32
Partition gap
26
(mm)
20
0
24 30 35
AAI diameter (mm)
Figure 10. Air velocity within the partition column (averaged across airflow rates of
50, 60, 70, 80, 90, 100 and 110 m3/h) at defined conditions of the factorial design.
78
Table 5. Response surface modelling: regression coefficients of effect of variables on characteristics of the granule batches.
Process Modal size Aspect Angle of
Coefficient Fines Lumps MMD Span Sphericity
yield fraction ratio repose
β0 92.4*** 3.65*** 0.439 27.6*** 342*** 1.36*** 1.29*** 0.785*** 39.4***
βA -0.281 -0.802* 0.199 1.55*** 25.5*** -0.0820*** 0.0169** -0.0160*** -0.814***
βP 1.18* 0.208 -0.209 0.421 -6.00 -0.00704 -0.00423 0.000824 -0.134
βS 3.22*** -3.08*** -0.131 0.112 6.91 -0.0638*** -0.0250*** 0.0540*** -0.869***
βAA -1.34 -1.11 0.473* -1.77*** 32.5** 0.0305 0.00222 -0.0229*** -1.04***
βPP -3.27** 0.0985 -0.380* 1.68** 8.52 -0.0886** -0.0319*** -0.0433*** 1.66***
βSS -1.46 1.83** 0.221 -1.10* 3.52 0.118*** 0.0115 -0.00302 0.0337
βAP 0.512 -0.107 0.0160 0.419 -3.63 -0.0171 0.00634 -0.00521 -0.105
βAS -0.790 0.676 -0.195 -0.505 -1.87 0.0276 0.00245 0.00900* 0.100
βPS -0.638 -0.397 -0.101 0.427 6.67 -0.0213 0.000360 -0.00328 0.159
R2 0.422 0.631 0.244 0.493 0.290 0.538 0.459 0.830 0.706
Model
0.000 0.000 0.014 0.000 0.002 0.000 0.000 0.000 0.000
significance
F value 5.82 13.50 2.54 7.68 3.22 9.17 6.71 38.59 18.99
Lack of fit
0.010 0.089 0.456 0.027 0.000 0.000 0.120 0.006 0.000
significance
* ** ***
denotes statistical significance at 0.005 level, at 0.01 level and at 0.001 level.
79
Table 6. Effect of variables on characteristics of granule batches.
AAI Binder Process Modal size
Partition Fines Lumps MMD Aspect Angle of
diameter spray rate yield fraction Span Sphericity
gap (mm) (%, w/w) (%, w/w) (μm) ratio repose (°)
(mm) (g/min) (%, w/w) (%, w/w)
7.46 0.72 1.55 1.28
24 20 18 79.55 (2.70) 24.62 (0.72) 373 (25) 0.67 (0.03) 40.9 (0.2)
(0.53) (0.55) (0.04) (0.02)
2.78 0.78 1.40 1.26
24 20 21 83.01 (0.44) 25.53 (0.95) 418 (40) 0.72 (0.02) 40.0 (0.4)
(1.47) (0.47) (0.06) (0.01)
1.82 1.68 1.44 1.24
24 20 24 90.89 (5.25) 25.55 (1.23) 383 (15) 0.80 (0.01) 39.1 (0.3)
(0.79) (1.11) (0.06) (0.01)
8.83 0.32 1.78 1.33
24 26 18 90.08 (2.01) 22.70 (0.86) 308 (10) 0.75 (0.03) 41.6 (0.7)
(4.50) (0.29) (0.14) (0.04)
4.75 0.07 1.29 1.27
24 26 21 93.68 (3.59) 25.24 (1.90) 272 (26) 0.78 (0.01) 40.1 (0.2)
(1.58) (0.10) (0.08) (0.03)
1.76 0.67 1.51 1.27
24 26 24 93.59 (1.92) 23.84 (1.61) 335 (44) 0.81 (0.01) 39.3 (0.2)
(0.49) (0.61) (0.07) (0.08)
8.76 0.27 1.56 1.24
24 32 18 81.81 (2.28) 24.81 (1.21) 367 (43) 0.69 (0.03) 41.8 (0.2)
(5.26) (0.17) (0.15) (0.03)
3.70 0.42 1.51 1.23
24 32 21 92.32 (3.48) 23.72 (0.42) 367 (15) 0.73 (0.00) 40.4 (0.2)
(1.00) (0.12) (0.03) (0.00)
1.80 0.53 1.41 1.20
24 32 24 88.50 (4.17) 25.67 (1.06) 387 (21) 0.79 (0.04) 39.3 (0.6)
(0.82) (0.07) (0.11) (0.02)
7.21 0.11 1.38 1.28
30 20 18 83.98 (1.58) 27.09 (5.55) 323 (50) 0.69 (0.01) 42.6 (0.3)
(6.04) (0.09) (0.19) (0.01)
4.60 0.08 1.31 1.25
30 20 21 89.81 (2.88) 29.43 (0.65) 315 (5) 0.74 (0.02) 42.6 (0.4)
(0.19) (0.03) (0.03) (0.03)
1.45 0.23 1.28 1.24
30 20 24 94.70 (1.19) 27.22 (1.01) 332 (3) 0.80 (0.01) 40.8 (0.8)
(0.47) (0.04) (0.10) (0.01)
12.00 0.13 1.67 1.38
30 26 18 84.79 (2.22) 27.58 (1.26) 388 (13) 0.71 (0.03) 39.1 (1.5)
(0.94) (0.02) (0.03) (0.03)
3.53 0.71 1.42 1.27
30 26 21 94.48 (5.80) 25.57 (1.01) 375 (26) 0.77 (0.02) 39.0 (0.5)
(1.68) (0.31) (0.05) (0.03)
Values in parentheses denote standard deviations.
80
Table 6 (continued). Effect of variables on characteristics of granule batches.
AAI Binder Process Modal size
Partition Fines Lumps MMD Aspect Angle of
diameter spray rate yield fraction Span Sphericity
gap (mm) (%, w/w) (%, w/w) (μm) ratio repose (°)
(mm) (g/min) (%, w/w) (%, w/w)
1.22 1.43 1.48 1.25
30 26 24 90.00 (5.38) 25.96 (1.43) 415 (48) 0.80 (0.01) 38.4 (0.6)
(0.29) (1.17) (0.01) (0.02)
9.94 0.09 1.44 1.31
30 32 18 85.06 (0.79) 26.47 (3.88) 335 (46) 0.71 (0.01) 41.0 (0.2)
(3.88) (0.05) (0.07) (0.01)
1.77 0.19 1.18 1.27
30 32 21 86.65 (5.52) 33.31 (0.86) 355 (5) 0.76 (0.01) 40.4 (0.4)
(0.66) (0.08) (0.02) (0.03)
2.06 0.22 1.28 1.24
30 32 24 93.47 (2.48) 30.05 (1.12) 332 (26) 0.79 (0.02) 40.0 (0.2)
(0.99) (0.31) (0.04) (0.02)
6.47 0.95 1.39 1.31
35 20 18 79.78 (1.82) 28.10 (1.97) 455 (44) 0.63 (0.02) 40.7 (0.2)
(0.86) (0.55) (0.04) (0.03)
2.13 0.97 1.34 1.31
35 20 21 85.93 (2.37) 27.51 (1.45) 425 (25) 0.70 (0.02) 39.0 (0.1)
(0.43) (0.61) (0.09) (0.07)
2.07 1.12 1.31 1.26
35 20 24 86.87 (4.75) 27.38 (0.62) 405 (18) 0.77 (0.01) 38.6 (0.3)
(0.59) (0.79) (0.05) (0.02)
2.51 2.24 1.30 1.33
35 26 18 89.77 (6.25) 28.47 (2.30) 365 (13) 0.71 (0.01) 38.3 (0.0)
(1.21) (2.78) (0.12) (0.02)
0.76 1.05 1.29 1.28
35 26 21 89.80 (4.30) 27.02 (2.49) 422 (16) 0.77 (0.03) 37.1 (0.3)
(0.13) (1.21) (0.13) (0.06)
1.64 1.56 1.42 1.30
35 26 24 91.66 (2.48) 24.89 (1.79) 418 (73) 0.81 (0.00) 35.3 (0.2)
(0.43) (1.51) (0.02) (0.01)
7.43 0.60 1.49 1.29
35 32 18 86.74 (3.94) 27.32 (0.09) 383 (64) 0.60 (0.03) 40.0 (0.5)
(2.90) (0.31) (0.09) (0.05)
2.52 0.30 1.17 1.28
35 32 21 88.01 (0.57) 30.56 (2.23) 380 (33) 0.69 (0.04) 39.2 (0.1)
(0.75) (0.08) (0.14) (0.03)
1.71 0.25 1.26 1.27
35 32 24 93.15 (0.71) 28.35 (1.25) 415 (13) 0.76 (0.03) 39.7 (0.1)
(0.60) (0.17) (0.09) (0.03)
Values in parentheses denote standard deviations.
81
Table 7. Analysis of variance of effect of variables on characteristics of the granule batches.
Process Modal size Aspect Angle of
Source Fines Lumps MMD Span Sphericity
yield fraction ratio repose
XA - ** * *** *** *** ** *** ***
XP *** - * ** - *** *** *** ***
XS *** *** - - - *** *** *** ***
XAXP * - * - *** ** - *** ***
XAXS - * - - - - - * **
XPXS * - - - - * - - -
XAXPXS - - - * - ** - - ***
Statistical significance is denoted by * at 0.05 level, ** at 0.01 level, *** at 0.001 level and statistical insignificance is denoted by (-).
82
partition gap (at the intermediate setting) and a high binder spray rate to improve
process yields. Significant interactions were found between AAI diameter and
partition gap, as well as between partition gap and binder spray rate.
The presence of the partition column in a bottom-spray system (Figure 8) improved
particle fluidization, enhanced system stability and encouraged cyclical particle flow
(Cheng and Turton, 2000; Cunha et al., 2009). Essentially, powder particles at the
annular down flow bed find their way into the spray granulation zone within the
partition column via the partition gap. The gap setting determined the physical
clearance, i.e. cylindrical lateral surface area formed by the gap, and served as a
“doorway” for powder to enter the partition column. The cylindrically-shaped lateral
physical clearances formed between the column itself and the air distribution plate in
the PG system were calculated to be 5027, 6535 and 8044 mm2 at partition gaps of 20,
26 and 32 mm respectively.
As the physical clearance increased with increasing gap settings, it created a larger
“doorway” for more particles to enter the column. However, this increment in gap
setting might weaken and undermine the suction effect on the annular down flow bed.
Therefore, when the physical clearance was low (20 mm), it limited the amount of
powder entering the column. At 32 mm, the high physical clearance might have
allowed much greater amount of powder to enter the column, but it also weakened the
suction effect. Hence at 26 mm, a maximal amount of powder was drawn into the
column and was found to be an optimal gap setting. The influence of partition gap on
the flow of materials into the partition column and the need for an optimal gap setting
83
to maximize flow in Wurster type processors has also been observed by Dixit and
Puthli (2009).
The process yields observed in this study were highest at the optimal gap setting of 26
mm. At the start of the granulation process, fine powder that was sucked into the
partition column through the partition gap travelled upwards all the way to become
trapped at the sock filters. This was due to the dry state that caused the built up of
some static charges. When this optimal gap setting was used, a maximal amount of
powder was drawn into the partition column and it was comparatively more difficult
for the upward flowing air stream to transport the particles upwards with the presence
of more powder in the column. Hence, the particles were lifted to a comparatively
lower height before falling freely outwards onto the annular down flow bed. This
resulted in a reduced amount of the static charged powder trapped onto the sock filters
after the initial phase of the process and improved the process yields as observed at
this optimal gap setting.
The diameter of the AAI was found to have a significant interaction with partition gap
and played a less direct role in influencing process yield. As the AAI diameter
determined the air velocity passing through the partition column, it affected the
suction effect on the annular down flow bed and hence material movement into the
partition column together with the partition gap.
A higher binder spray rate increased the wetting rate of the lactose powder, bringing
about reduced powder loss to the sock filters and availed more powder for granulation.
The more humid environment in the product chamber brought about by high binder
84
spray rates also promoted agglomeration. Also as fines were dislodged from the sock
filters, they could be trapped by adhering to the wetted agglomerates. This led to the
observation of better process yields with increasing binder spray rates. Higher process
yields were seen in batches under processing conditions with intermediate partition
gap and high binder spray rates due to a synergistic interaction between the two
variables (Tables 6 and 7). Lewis et al. (1999) explained that an interaction is the
failure of a factor to produce the same effect at the same response for the different
levels of the other factor. Hence it implied that with intermediate partition gap and
high binder spray rate, the increase in process yield would be more than with
intermediate partition gap and intermediate level of binder spray rate.
A2.2. Influence of variables on granule size and size distribution
The influence of AAI, partition gap and binder spray rate on fines, lumps, modal size
fraction, MMD and span are discussed below.
A2.2.1. Influence of variables on fines
The amount of fines seen in the granule batches ranged from 0.76 to 12.00 %, w/w.
The analysis of variance indicated that significantly higher amounts of fines were seen
in batches under processing conditions with AAI of small diameters and low binder
spray rates, with synergistic interaction between the two variables (Tables 6 and 7).
The regression equation after fitting to the quadratic model, Equation (23), for fines
(Yfines) is shown below.
Yfines = 3.65 – 0.802XA – 3.08XS + 1.83XS2 (28)
where XA and XS are the variables AAI diameter and binder spray rate respectively.
85
In Equation (28), the coefficients of the binder spray rate terms (linear and squared)
were higher than that of the AAI linear term. This indicated that binder spray rate had
a greater influence on the amount of fines generated compared to AAI diameter
(Figure 11a). When high binder spray rates were employed, wetter conditions in the
powder bed that resulted promoted the agglomeration of powders. This decreased the
amount of fines. More wetting also occurred when AAIs with medium and large
diameters were used, due to the relatively longer residence time of the powder
particles at the spray granulation zone resulting from the lower air velocity within.
The slower transition through the spray granulation zone allowed greater
opportunities for agglomeration in the spray granulation zone. The change in the
extent of wetting caused by dissimilar fluid dynamics with different AAIs influenced
the amount of fines generated.
Additionally, the dissimilar fluid dynamics with different AAIs also affected the
amount of fines by affecting the amount of fine powder trapped on the sock filters.
When an AAI with a small diameter was used, powder mass was rapidly transported
out of the partition column onto the staging annular down flow bed and the strong air
velocity could have caused a lot of the fine powder to be trapped on the sock filters at
the early phase of the process. As the process progressed, fines from the sock filters
were gradually blown down into the product chamber to be granulated and thus did
not affect the eventual process yield. However this would have contributed in part to
the higher amount of fines observed at conditions when AAI of small diameter was
used (Table 6). Hence, to reduce the amount of fines, the use of an AAI of large
diameter with a high binder spray rate would be recommended.
86
(a)
8
Fines 6
(%, w/w) 4
2
24
21
25 30 18 Binder spray
35
rate (g/min)
AAI diameter (mm)
(b)
1.2
0.8
Lumps
(%, w/w) 0.4
0.0 32
26
25 30 20
35 Partition gap
(mm)
AAI diameter (mm)
Figure 11. Response surface graphs of the effect of (a) AAI diameter and binder spray
rate (hold values at partition gap = 26 mm) on fines and (b) AAI diameter and
partition gap (hold values at binder spray rate = 21 g/min) on lumps.
87
A2.2.2. Influence of variables on lumps
Within the conditions investigated, relatively small amounts of lumps, ranging from
0.07 to 2.24 %, w/w, were seen in the batches prepared (Table 6). Significantly more
lumps were observed when AAIs with small or large diameters were used and there
was also a higher amount of lumps produced at the intermediate level of partition gap
as compared to other gap settings. An interaction between AAI diameter and partition
gap for lumps was also observed (Table 7). As explained above in section A2.1, these
two factors together affected the fluid dynamics and suction effect on the annular
down flow bed and hence material movement into the partition column. Equation (29)
was obtained for lumps (Ylumps) after fitting to the quadratic model.
Ylumps = 0.473XA2 – 0.380XP2 (29)
where XA and XP are the variables AAI diameter and partition gap respectively.
At conditions when AAI of small diameter was employed, there was an initial lower
load of actively granulating powder in the product chamber as a lot of the fine powder
was trapped at the sock filters. Consequently, larger granules were produced as the
cyclic flow of powder into the spray granulation zone was more frequent as compared
to a process with a higher load of actively granulating powder. The amount of lumps
was also elevated as reduced granulating powder load caused some episodes of
overwetting. Hence more lumps formed with small AAI diameter (Figure 11b). The
higher amount of lumps seen with large AAI diameter was due to the relatively longer
residence time of the powder particles at the spray granulation zone that promoted the
extent of wetting and granule growth.
88
The highest amount of lumps formed was observed at the condition when AAI of
large diameter and intermediate level of partition gap were used (Figure 11b). At the
intermediate level of partition gap, a higher amount of powder was drawn into the
column because this gap setting was the most favourable for powder entry as
compared to the other two gap settings. This resulted in even more opportunities for
agglomeration at the spray granulation zone in addition to the longer residence time
caused by the relatively lower air velocity within the partition column when AAI of
large diameter was used.
A2.2.3. Influence of variables on modal size fraction
The amounts of resultant fines and lumps under the different conditions
correspondingly determined the proportion of the granule modal size fraction. The
high amounts of fines and lumps in batches when AAI of small diameter were used
significantly decreased the proportion of the modal size fraction (Table 6). Slightly
lower amounts of modal size fraction were obtained at the intermediate level of
partition gap, where comparatively higher amount of lumps were formed. An
interaction between the three variables was also observed (Table 7).
A2.2.4. Influence of variables on MMD
From Table 7, AAI diameter was the only significant variable found to influence
MMD. An increase from small to medium AAI diameter led to a very small decrease
whereas a marked increase was observed with an increase from medium to large AAI
diameter (Table 6). This could be explained by the initial lower effective powder
loads for granulation as discussed previously in section A2.2.2 when AAI of small
diameter was used, which led to the formation of a comparatively greater amount of
89
large granules within the size distribution. This resulted in larger than expected
MMDs at this setting.
The correlation between the air velocity within the partition column and MMDs of
granule batches when AAI diameter was increased from medium to large at the
defined conditions of the factorial design was significant (Pearson correlation of –
0.553, p < 0.001). A decrease in air velocity within the partition column corresponded
to larger granule size within the batch. This meant that the air velocity within the
partition column indeed led to wetter conditions at the spray granulation zone and
helped to promote granule growth.
Even though a slight increase in MMD values was observed as binder spray rate
increased, this variable was insignificant. This finding was in contrast to earlier
reports, in which binder spray rate was found to result in significant increase in
granule size (Lipps and Sakr, 1994; Gao et al., 2002; Bouffard et al., 2005). This
interestingly pointed out that in this process, control of the AAI diameter was more
important than binder spray rate in affecting granule growth. The relative insensitivity
of the process to binder spray rate due to its good drying efficiency suggested that it
may be possible to granulate moisture sensitive drugs using the PG process and this
would be investigated in Part D of this study. It is postulated that a shortening in
processing and thus exposure time of the moisture sensitive drugs to water may also
be achieved by employing high binder spray rates, with further usage of high inlet air
temperature to enhance process drying efficiency. The use of a working spray rate
range of 18 to 24 g/min in this part of the study may be within well-controlled
granulating conditions, thus effects of spray rate might have been masked.
90
A significant interaction was observed between AAI diameter and partition gap
(Table 7). This suggested that even though granule growth was shown to be dictated
by the air velocity at the spray granulation zone, usage of a partition gap at an optimal
setting could generally promote growth. Therefore it is important to take into
consideration the influence of partition gap in the granulation process.
A2.2.5. Influence of variables on span
The results indicated that all variables studied affected the span with significant
interactions (Table 7). Wider size distributions with maximum mean span of 1.78,
were obtained for batches using small AAI diameter, low binder spray rate, and
intermediate partition gap (Table 6). This was due to the large amounts of fines and
lumps formed under these conditions. AAI diameter accounted for the production of
lower amounts of fines when AAIs of medium and large diameters were used,
resulting in narrow size distributions. The larger amount of lumps produced at the
intermediate level of partition gap also consistently led to wider size distributions
across all conditions investigated. There appeared to be an optimal decrease in span
with increasing binder spray rates. This was attributed to the high amount of fines
produced at the dry conditions created at low binder spray rate and the formation of
more lumps during wetter conditions at high binder spray rate. Therefore a minimal in
span values was generally observed when intermediate binder spray rate was
employed.
A2.3. Influence of variables on granule shape
The main effects of the three variables on aspect ratio and sphericity were found to be
statistically significant (Table 7). Significant interactions among the investigated
91
variables were also observed. The data obtained was fitted to the quadratic model and
the equation obtained for aspect ratio (Yasp) is as follows.
Yasp = 1.29 + 0.0169XA – 0.0250XS – 0.0319XP2 (30)
where XA, XS and XP are the variables AAI diameter, binder spray rate and partition
gap respectively.
An increase in AAI diameter led to granules that were less spherical with higher
aspect ratios (Figure 12a). The model suggested that to obtain granules that were more
spherical, the air velocity at the spray granulation zone should be fast and the smallest
AAI diameter of 24 mm should be used. At this setting, batches with comparatively
higher amount of small particles, fines and lumps resulted. The small particles and
fines subsequently coalesced onto the larger particles and the coalescence of these
fines onto the larger particles helped to produce a more spherical structure. Attributed
to the fluid dynamics at this setting, the fast air through the spray granulation zone
would give rise to a stronger shear action on the coalesced particles and help to shape
them. In addition, protuberances on granules would also be broken down due to
stronger impact forces as granules slip past each other.
When slower air velocities were generated from usage of larger AAI diameters,
particles moved up the partition column at a slower rate, allowing them longer
residence times at the spray granulation zone and generated batches with large
particles and less fines. Thus coalescence of these large particles with one another
predominated. On top of the weaker shear action of the slower air flowing through the
spray granulation zone, granules that were less spherical were thus observed.
92
(a)
1.30
Aspect 1.28
ratio
1.26
1.24 32
26
25
30 20 Partition gap
35
(mm)
AAI diameter (mm)
(b)
1.33
1.30
Aspect
ratio 1.27
1.24 32
26
18
21 20
24
Partition gap
Binder spray rate (g/min) (mm)
Figure 12. Response surface graphs of the effect of (a) AAI diameter and partition gap
(hold values at binder spray rate = 21 g/min) and (b) binder spray rate and partition
gap (hold values at AAI diameter = 29.5 mm) on aspect ratio.
93
Less spherical granules were also observed at the intermediate level of partition gap
of 26 mm (Figure 12). The gap setting of 26 mm was earlier found to result in a
maximal amount of powder to enter the partition column. Hence, the presence of
more powder within the partition column and more lumps (as discussed in section
A2.2.2) at this gap setting gave rise to the higher tendency of the powder particles and
lumps to coalesce with one another in a more crowded condition. This attributed to
the formation of granules that were less spherical.
The findings emphasized the important role of fluid dynamics at the spray granulation
zone in influencing mode of granule growth and thus granule morphology in PG. This
highlighted the difference between this bottom-spray process and the conventional TG
process. This difference led to the investigations carried out in Part B of this study
where the differences would be illustrated.
The influence of wetting on granule morphology too cannot be neglected. A general
decrease in aspect ratio and increase in sphericity values were observed as binder
spray rate increased and granules with the highest degree of sphericity were obtained
at high binder spray rate level (Table 6). When the binder spray rate increased,
surfaces of these particles were wetted more thoroughly, thus the particles deformed
and coalesced evenly in all directions, resulting in structures that were more spherical.
In comparison, agglomeration was observed to take place in a less uniform manner
under drier conditions when lower binder spray rates were used. As suggested by
Figure 12b, low binder spray rate along with high AAI diameter and intermediate
partition gap should be avoided if granules with higher degree of sphericity are
desired.
94
A2.4. Influence of variables on granule flow
The batches produced had good general bulk flow with angle of repose values ranging
from 35.3 ° to 42.6 ° (Table 6). The results indicated that batches with larger granules
flowed better with lower angles of repose. The lowest mean angle of repose was
observed when large AAI diameter, intermediate partition gap and high binder spray
rate were employed. The resultant bulk flow of the batches was dependent on granule
size and shape. The improvement in bulk granule flow with usage of large AAI
diameter was largely due to the larger granules that were formed; being less cohesive,
large granules flowed better than smaller granules. The lesser amount of fines that
resulted at this gap setting also contributed to improving flow and the high binder
spray rate resulted in structures that were comparatively more spherical and thus
flowed better.
95
Results and discussion – Part B
B. APPLICABILITY OF PG AND TG FOR SPRAY DEPOSITION OF DRUG
DURING GRANULATION
It was hypothesized that the PG technique can be applied for precise deposition of a
low dose, poorly soluble drug (dispersed in the liquid binder) onto feed particles
during granulation due to its highly ordered particle circulation pattern and unique
fluid dynamics. The widely-accepted TG process was used as the standard for
comparison to PG to illustrate this. The model drug used in this part of the study,
HCT, was micronized (d99: 12.51 ± 0.59 μm) and dispersed in the liquid binder.
Various binder spray rates and particle size of starting feed material were employed to
study the applicability of the processes to different processing conditions for this
application.
B1. Drug content and drug content uniformity of PG and TG granules
All granule batches prepared at the various investigated conditions had process yields
ranging from 80 to 95 %, w/w. The theoretical loading of 25 g of micronized HCT
onto each granule batch (with total solid content of 1085 g) was calculated to be
2.3 %, w/w. Granules were classified into small, medium and large granules.
From Figure 13, it could be observed that for both PG and TG, small granules had
drug content lower than the expected drug content of 2.3 %, w/w whereas medium
and large granules had higher drug content than small granules, with actual drug
content close to the expected. Between medium and large granules, there was
generally no difference in drug content, indicating that the drug content of granules
within each batch did not vary much for granules larger than 250 µm. This
observation was consistent for granules from both processes.
96
(a)
w/w)
(%w/w)
content(%, 3
2.3
drugcontent
2
Meandrug
1
Mean
0
18 21 24
Spray rate (g/min)
(b)
3
(%,(%w/w)
w/w)
2.3
content
2
content
drug
drug
1
Mean
Mean
0
1 2 3 4
Lactose powder blend
Figure 13. Mean drug content of PG and TG granules: PG/small ( ), PG/medium ( ),

PG/large ( ), TG/small ( ), TG/medium ( ) and TG/large ( ) when (a) binder spray
rate and (b) lactose powder blend were varied. Error bars represent inter-batch
standard deviation.
97
At the start of both granulation processes before the powder feed material was
sufficiently moistened by the liquid binder spray, the relatively dry powder particles
trapped onto the sock filters gave rise to a lower than expected remaining load of feed
particles at the product chamber. A lower feed load would result in the particles being
circulated through the spray granulation zone at a faster rate than it would be if the
expected load was present. Meanwhile, at the sock filters, trapped fines were
gradually dislodged by the blow-back air into the product chamber after every 10 s
throughout processing. Over time, these fines rejoined the granulating load at the
product chamber, increasing the total amount of feed material available for
granulation. Nonetheless, their shortened duration at the product chamber meant that
these fines had lesser opportunities to undergo circulation through the spray
granulation zone and were less likely to have drug particles deposited on them and to
grow. Consequently, they formed the bulk of the small granules, and with less drug
deposition, had lower drug content than expected.
Likewise, this observation accounted for the higher drug content values obtained for
medium and large granules, which primarily grew from feed particles that remained at
the product chamber throughout the entire duration of granulation. As the feed
material that made up the medium and large granules were mainly present at the
product chamber throughout the entire process, they underwent comparatively more
circulation cycles through the spray granulation zone. This accounted for the greater
amount of drug deposited on them and hence higher than expected drug content
values.
98
In PG, the mean RSD of drug content for the different classes of granules were found
to be less than 10 % (Figure 14) at the various investigated conditions. On the
contrary, higher RSDs of drug content were observed for small TG granules. This
could be due to the nearly unavoidable higher extent of spray drying with the use of
the top-spray technique (Jones, 1989). The poor drug content uniformity of small TG
granules would be less of a concern at wetter bed conditions (21 and 24 g/min) and
with uni-component feed material that flowed well (lactose powder blend 1), as they
made up only less than 5 %, w/w of a granule batch. For batches prepared at the other
investigated conditions, though small granules were not the representative class of
granule size, they still made up 10 to 20 %, w/w of the batch and their poor drug
content uniformity had a bigger impact on the overall batch drug content uniformity.
As such, graphs of the overall weighted RSD of drug content of these TG batches
(Figures 15) had higher values. Conversely, the overall weighted RSDs of drug
content of PG batches were found to be less influenced by the changes in processing
conditions. The observed differences between the two processes could be explained
by their difference in the dominant mode of granule growth that resulted from
dissimilar particle circulation patterns in the fluidized bed.
B2. Impact of particle circulation pattern and fluid dynamics in PG and TG on
granule growth
The impact of particle circulation pattern and fluid dynamics on the resultant modes
of growth and process sensitivities in the two processes are discussed below.
99
(a)
(10.0 %)
60
Mean RSD of drug content (%)
50
40
(3.6 %)
(4.6 %)
30
(15.2 %)
(60.9 %)
(23.9 %)
(14.6 %)
(59.3 %)
(26.1 %)
(69.3 %)
(20.7 %)
(10.6 %)
(64.9 %)
(24.5 %)
(61.1 %)
(35.3 %)
(48.1 %)
(47.3 %)
20
10
0
18 21 24
-10
Spray rate (g/min)
(b) (13.7 %)
50
(20.1 %)
40
(41.1 %)
Mean RSD of drug content (%)
(3.6 %)
(13.6 %)
30
(39.5 %)
(16.1 %)
(45.3 %)
(10.6 %)
(35.8 %)
(33.6 %)
(46.5 %)
(21.9 %)
(69.3 %)
(51.3 %)
(28.6 %)
(68.9 %)
(15.0 %)
(64.9 %)
(24.5 %)
(10.6 %)
(61.1 %)
20
(35.3 %)
(8.8 %)
10
0
1 2 3 4
-10
Figure 14. Mean RSD of drug content of PG and TG granules: PG/small ( ),

PG/medium ( ), PG/large ( ), TG/small ( ), TG/medium ( ) and TG/large ( ) when
(a) binder spray rate and (b) lactose powder blend were varied. Error bars represent
inter-batch standard deviation. Values in parentheses denote mean amounts of small,
medium and large granules within the batches (%, w/w).
100
(a)
15
Overall weighted RSD of drug content
10
(%)
0
18 21 24
Spray rate (g/min)
(b)
15
Overall weighted RSD of drug content
10
(%)
0
1 2 3 4
Figure 15. Overall weighted RSD of drug content of PG (■) and TG (□) batches
when (a) binder spray rate and (b) lactose powder blend were varied.
101
B2.1. Resultant mode of granule growth in PG and TG
Growth by surface layering occurs when evaporation of the solvent from a binder
suspension or solution leaves behind the deposited solid materials on particles as
layers (Link and Schlunder, 1997). This layered mode of growth was dominant in PG.
At the spray granulation zone, the atomized binder droplets were dispersed onto
surfaces of the feed particles. This induced surface wetting and rapidly formed a layer
of liquid binder on the feed particles. Growth occurred via the layering of liquid
binder onto the particles during each cyclic pass through the spray granulation zone.
In addition, growth via agglomeration of binder-layered feed particles onto larger
particles may have occurred when the wet particles successfully coalesced and
consolidated with each other after collision (Figure 16).
Consolidation of these coalesced particles was timely aided by the shear force of the
high velocity air stream passing through the partition column (Figure 8). This stream
of hot drying air not only imparted shear onto the particles, but also caused rapid
solidification of the binder layer and lifted the particles into the drying zone almost
instantaneously after wetting. The presence of a distinct drying zone above a spouting
bed had been earlier shown to promote spherical granule growth by surface layering
(Becher and Schlunder, 1998), as the binder-layered particles could be dried before
the next cyclic pass through the spray granulation zone.
During each cycle, particles at the bottom of the product chamber were drawn into the
partition column where they were first wetted then dried. The almost dried particles
began to decelerate in the expansion chamber after exiting the partition column and
then fell outwards freely in an inverted U-shaped trajectory down to the staging
102
Feed powder particles

PG TG
Layering of binder Wetting and spreading

dispersion onto of binder dispersion
particle surfaces onto particle surfaces
Coalescence and Agglomerate formation

consolidation of by solidification of
layered particles liquid bridges
Figure 16. Mode of wetting and granule growth in PG and TG.
103
annular down flow bed to await re-entry into the partition column. At the annular
down flow bed, the particles remained loosely packed with the low volume of air
passing through and continued moving towards the bottom of the product chamber.
This fountain-like cyclic flow was repeated for the powder/granules until the process
run was terminated. This circulation pattern was repeated throughout processing as
the feed particles underwent distinct steps of wetting, growth, drying and awaiting re-
entry. Because of the distinguishable zones in the fluidized bed and highly ordered
circulation pattern present in PG, layered growth of granules was dominant and made
the bottom-spray process a suitable technique to be employed for the spray deposition
of drug onto feed particles during granulation.
The fluid dynamics and circulation pattern in the TG bed was comparatively much
less conducive for layered growth. At the same time, the nearly unavoidable spray
drying in TG presented serious challenges to development personnel attempting to use
this technique for layering (Iyer et al., 1993). Due to the evenly distributed and
relatively large air orifices (Figure 7b) present in the TG air distribution plate, an
almost even distribution of upward flowing air across the plate caused the air to flow
upwards through the powder bed at a relatively much lower velocity. Therefore, there
was a comparative lack of shear force from the air to aid coalescence and
consolidation in the top-spray process, resulting in the dominant growth of TG
granules by the formation of liquid bridges between particles as they were brought
together.
The TG process is shown in Figure 17. As with the PG process, particles in TG were
recycled through the spray granulation zone in a matter of seconds. However in
104
Indistinct spray
granulation and
drying zones
Even distribution
of air through
Air distribution
entire plate
plate with orifices
evenly spaced
from one other
Fluidizing air
Figure 17. Schematic diagram showing the air flow pattern and zones in the TG
process with arrows representing airflow.
105
contrast to PG, the circulation pattern was much less ordered in TG and the process is
without clear distinguishable spray granulation and drying zones. Wetting, growth and
drying occurred within the same region in the fluidized bed. Though the circulation
pattern was repeated throughout the process, there were no distinct steps for wetting,
growth and drying during the cycle. However, an advantage of TG is that the process
favoured the granulation of smaller particles under the influence of gravity.
In statistical terms, the liquid binder was sprayed counter-currently into the randomly
fluidizing bed and there was scattered and unpredictable spread of liquid binder onto
the particle surfaces (Figure 16). The smaller, lighter particles were favoured as they
were lighter and rose higher. Wetting of particles may occur again before they were
completely dried. Agglomeration of particles may occur immediately after wetting, or
after partial drying. As wetting and spreading of the liquid binder was more random in
the TG process, some particles might have been wetted to a greater extent, resulting in
a higher amount of deposited drug. Similarly, particles that were wetted to a lesser
extent would have a lower amount of deposited drug. This in turn led to the generally
poorer intra-batch drug content uniformity observed in the TG granules.
B2.2. Process sensitivity to binder spray rate and the resultant influences on
granule growth
With the exception of a markedly high mean RSD of drug content (≥ 40 %) at the
lowest binder spray rate employed for small TG granules, drug content and drug
content uniformity of both PG and TG granules were relatively unaffected by changes
in binder spray rate (Figure 14a and 15a). This observation was due to more
106
significant and evident spray drying effect on the liquid binder, which was related to
the dry bed conditions at low binder spray rate.
Generally in a spray granulation process, an increase in wetness of the powder bed
would result when the liquid binder was sprayed at a faster rate while the drying
conditions remained unchanged. This was found to promote coalescence of particles,
giving rise to granules that were more spherical and less porous in both processes
(Table 8 and Figure 18). Increasing binder spray rates would also lead to an increase
in the moisture content of the powder bed and granule growth, as typically observed
in conventional TG in this study and in others (Menon et al., 1996; Watano et al.,
1997; Cryer and Scherer, 2003). However, interestingly, no significant differences in
MMD, span and lump values were observed for the PG process (Table 8). The size
characteristics of PG granule batches formed at the three investigated binder spray
rates were similar, indicating that granule growth in PG was relatively unaffected by
changes in binder spray rate.
Litster et al. (2001) suggested that an increase in binder spray rate would create an
increase in dimensionless spray flux, defined as “the ratio of wetted area covered by
the nozzle to the spray granulation area in the nucleation zone”. This would lead to
more rampant overlapping of spray droplet footprints on the powder particles. As the
spray granulation area in PG was much smaller as compared to TG, the bottom-spray
process already possessed a higher dimensionless spray flux. In addition to the further
increase in dimensionless spray flux with increased binder spray rate within the same
spray granulation area, the resultant very rampant overlapping of spray droplets
promoted layered growth by forming a thicker binder layer around the particles during
107
Table 8. Influence of binder spray rate on PG and TG granule properties.
Binder Bulk Tapped
MMD Lumps Porosity Angle of Carr index
Granules spray rate Span Sphericity density density
(µm) (%, w/w) (%) repose (°) (%)
(g/min) (g/mL) (g/mL)
365 1.30 2.24 0.71 61.8 38.3 0.500 0.568 12.2

18
(13) (0.12) (2.78) (0.03) (2.1) (0.0) (0.027) (0.032) (0.8)
422 1.29 1.05 0.77 59.9 37.1 0.523 0.604 13.5

PG 21
(16) (0.13) (1.21) (0.03) (1.9) (0.3) (0.032) (0.028) (1.3)
418 1.42 1.56 0.81 57.3 35.3 0.567 0.646 12.2

24
(73) (0.02) (1.51) (0.02) (1.2) (0.2) (0.009) (0.017) (1.0)
440 0.96 0.27 0.57 68.8 45.1 0.393 0.465 15.5

18
(20) (0.07) (0.30) (0.01) (2.0) (0.5) (0.019) (0.028) (1.3)
525 1.33 4.07 0.66 67.4 40.1 0.429 0.489 12.3

TG 21
(55) (0.18) (4.08) (0.03) (1.1) (0.1) (0.018) (0.016) (1.0)
585 1.52 9.55 0.70 64.8 39.8 0.473 0.531 11.0

24
(54) (0.08) (2.00) (0.08) (1.6) (0.1) (0.028) (0.027) (1.0)
Values in parentheses denote inter-batch standard deviations.

108
PG granules TG granules
(a) (d) 21 g/min
18 g/min 18 g/min
(b) (e)
21 g/min 21 g/min
(c) (f)
24 g/min 24 g/min
Figure 18. Scanning electron photomicrographs of PG and TG granules (taken at 100

x magnification) prepared with various binder spray rates.
109
each cycle. Though there was thicker and a more thorough surface spread of liquid
binder on the powder particles at wetter conditions, the number of particles that were
wetted and hence nuclei for growth in each cycle remained unchanged since there was
a limitation on the number of particles entering the spray granulation zone. Hence
similar size characteristics resulted even though binder spray rate was varied. The
comparable size characteristics of granule batches formed also indicated the ability of
the process to efficiently dry binder-layered particles under different wetting
conditions without causing uncontrolled growth, and its strong potential to prepare
batches with short processing times.
Attributing to the layered mode of growth in PG, it was also observed that the formed
granules were generally less porous but more spherical in structure (Table 8 and
Figure 18). The overview of PG and TG granules formed at a binder spray rate of 21
g/min is shown in Figure 19. The rounder PG structures observed were attributed to a
slow and steady build-up of layers around the aggregated powder particles. These
findings suggested a strong impact of fluid dynamics on agglomerate growth in the
bottom-spray process. At the spray granulation zone, the high velocity air stream
through the zone imparted shear force on the coalesced particles and encouraged
consolidation of the agglomerates. Increased consolidation prior to drying reduced
structure porosity. As most of the agglomerates’ surfaces were already wetted and
softened by the liquid binder, they were easier to be remodelled and consolidated.
On the contrary, with the same binder spray rate, a comparatively lower
dimensionless spray flux was present in the larger TG spray granulation zone. Hence,
under the same increments of binder spray rate, the dynamics of coalescence in the
110
(a)
(b)
Figure 19. Scanning electron photomicrographs showing overview of (a) PG and (b)
TG granules (taken at 35 × magnification) prepared with binder spray rate of 21 g/min.
111
spray granulation zone of TG varied from PG. The overlapping of spray droplets took
place more frequently when they were sprayed at an increasing rate and this created
the presence of droplets of wider size distributions at the spray zone (Wan et al.,
1995). Since spray droplets of a wider size distribution were deposited onto the
particles, it correspondingly created broader nuclei distributions at the TG powder bed.
Additionally, the higher dimensionless spray flux with increased binder spray rate
also promoted the wetting of more particles and hence contributed to an increase in
nuclei available for growth (Litster et al., 2001). As the wetter conditions employed
were yet insufficient to cause layer deposition on the particles, only a higher extent of
surface wetting by the spray droplets resulted. The mode of growth by agglomeration
of these wetted particles by solidification of liquid bridges (that bonded them after
drying) therefore remained dominant. This was supported by the observation that even
at high binder spray rates, the characteristic highly irregular shaped and porous
structures of TG granules could still be seen (Figure 18), with lower sphericity and
higher porosity values than PG granules. The broader nuclei size distribution that
resulted also led to granule batches with wider size distribution and larger granules.
Increase in lump formation was also significant at higher spray rates (Table 8).
B2.3. Process sensitivity to particle size of feed material and the resultant influences
on granule growth
Increasing the quantity of lactose 450M mixed with lactose 200M theoretically should
produce more cohesive powder blends with smaller MMD and poorer flow properties.
This was observed from Table 9. For PG, it was found that granulation of blends 5, 6
and 7 could not be successfully carried out and there was a reduction in the ease to
loosen the powder bed during the start of granulation for blends 1 to 4.
112
Table 9. MMD, span and angle of repose of the various lactose blends.
Powder Amount of lactose 450 M in MMD Angle of

Span
blend lactose powder blend (%, w/w) (µm) repose (°)
1 0 36.0 (1.7) 1.66 (0.07) 49.5 (1.2)
2 10 34.8 (0.2) 1.66 (0.05) 52.4 (0.4)
3 20 34.5 (0.6) 1.33 (0.01) 54.2 (0.5)
4 30 30.9 (0.1) 1.63 (0.05) 55.1 (0.2)
5 40 30.2 (2.1) 1.58 (0.16) 56.2 (0.4)
6 50 28.9 (1.3) 1.48 (0.11) 56.9 (0.5)
7 100 22.7 (0.4) 1.88 (0.08) 60.2 (0.4)

The type and geometry of the air distribution plate situated at the base of the
processing unit plays an important role in influencing the fluid dynamics of particles.
The pattern of open areas on the plate will also affect the air distribution in the
product chamber (Dixit and Puthli, 2009). The air volume at the annular down flow
bed depends on the size and number of holes in the peripheral area outside the
partition tube in a bottom-spray process as well as the size of the central orifice. This
air volume should be enough only to loosen the down bed and enhance downward
motion by keeping the down flow bed suspended (Jones, 1994). For PG, the incoming
heated air was distributed between the partition column and the annular down flow
bed, with most of the air directed through the column due to the graduated plate
design. Peripheral fluidization at the annular down flow bed was comparatively
weaker in this process and the drawing in of particles into the low pressure spray
113
granulation zone depended on its strong inward suction. This made the process less
suitable for use with cohesive powders as getting the peripheral staging bed in a fluid-
like low friction state was challenging for such powders.
Though PG faced a decreasing ease in loosening the powder bed of blends 1 to 4 at
the start of processing, the suction force was still sufficient to draw the more cohesive
mass with smaller lactose 450M particles into the spray granulation zone for growth
to take place. Hence, physical characteristics such as particle size, shape and porosity
of PG batches obtained did not vary significantly as the particle size and flow of feed
material decreased from blends 1 to 4 (Figure 20 and Table 10). Drug content and
drug content uniformity of PG granules were also found not to be influenced (Figures
13b and 14b). This clearly suggested that with sufficient suction force to draw
particles into the partition column, the reasonably good flowing powders used had
limited influence on granule growth in the PG process.
In TG, all the investigated powder blends could be granulated. This was largely due to
the differences in fluid dynamics between the two processes. The incoming fluidizing
air in TG was distributed almost evenly across the powder bed as air passed upwards
from the plenum (Figure 17) since the orifices on the distribution plate were evenly
spaced from one another (Figure 7b). Transport of particles into the spray granulation
zone depended greatly on the success of bed fluidization and gravity. Unlike in PG,
no suction force was required and thus the process was able to granulate a wider range
of cohesive powders.
114
1 2 3 4 5 6 7

1000 2.0
800 1.5
MMD (μm)
600 1.0
Span
400 0.5
200 0.0
0 10 20 30 40 50 60 70 80 90 100
Amount of lactose 450M in lactose powder blend (%, w/w)
Figure 20. Influence of feed material on MMD (■,□) and span (●,○) in PG (closed
symbols) and TG (open symbols). Error bars represent inter-batch standard deviation.
115
Table 10. Influence of lactose powder blend on PG and TG granule properties.
Powder Porosity Angle of Bulk density Tapped density Carr index
Granules Sphericity
blend (%) repose (°) (g/mL) (g/mL) (%)
1 0.77 (0.03) 59.9 (1.9) 37.1 (0.3) 0.523 (0.032) 0.604 (0.028) 13.5 (1.3)
2 0.77 (0.03) 59.5 (1.1) 40.6 (0.7) 0.528 (0.004) 0.609 (0.018) 13.3 (2.7)
PG
3 0.73 (0.03) 61.0 (2.4) 40.5 (0.3) 0.505 (0.047) 0.586 (0.032) 13.8 (3.5)
4 0.75 (0.03) 60.3 (1.2) 41.0 (0.7) 0.528 (0.026) 0.599 (0.015) 11.8 (2.0)
1 0.66 (0.02) 67.4 (1.1) 40.1 (0.1) 0.429 (0.018) 0.489 (0.016) 12.3 (1.0)
2 0.59 (0.03) 63.2 (1.9) 44.3 (1.0) 0.465 (0.014) 0.554 (0.030) 16.0 (3.0)
TG
3 0.64 (0.02) 65.6 (3.0) 44.2 (0.9) 0.447 (0.036) 0.518 (0.048) 13.6 (1.0)
4 0.59 (0.01) 65.7 (2.2) 45.5 (1.7) 0.436 (0.035) 0.516 (0.035) 15.5 (1.7)

116
Across blends 1 to 4, MMD, span, sphericity and porosity of TG granules formed
were found not to differ significantly (Figure 20 and Table 10). However, higher
proportions of small granules were observed to be formed when powder blends 2, 3
and 4 were granulated, as compared to powder blend 1 (Figure 14b). This was
because the smaller lactose 450M particles present in these blends required a lower
fluidization velocity and these particles were easily lifted by the incoming air to the
expansion chamber above the spray nozzle. Being physically smaller, they were
lighter and it was more difficult for them to fall back onto the powder bed by
gravitational force. In comparison to the larger lactose 200M particles, they spent less
time at the powder bed and were largely suspended in the air or trapped at the sock
filters. A periodic blow-back purging air may dislodge the adhered particles at the
filter socks. However this operation left a proportion of particles still adhering to the
filters. Upon end of granulation, these particles that were still adhering to the filters
fell back onto the powder bed when the product chamber seal was deflated and made
up a higher proportion of small granules within the batch. This resulted in low drug
content and poor drug content uniformity among the small granules in powder blends
2, 3 and 4.
B3. Drug release properties of PG and TG granules
Due to the strong influence of binder spray rate on the resultant granule structures,
especially in TG, it was of interest to investigate if this variable affected drug release
from the structurally different PG and TG granules. Table 11 shows the results
obtained from dissolution studies in which deionized water was used as the media.
117
Table 11. Influence of binder spray rate on drug release (in deionized water) from PG
and TG granules.
Granules Binder spray rate (g/min) t50% (s) t90% (s)
18 34.9 (1.4) 49.2 (1.8)
PG 21 34.0 (2.3) 53.5 (4.4)
24 35.3 (1.3) 52.7 (4.5)
18 35.3 (2.6) 49.0 (3.2)
TG 21 35.1 (1.8) 48.5 (3.5)
24 35.2 (1.8) 48.9 (5.2)

Generally, drug release from the granules was very rapid as the lactose feed particles
were hydrophilic and soluble in water. This helped to draw water into the core of
granules, facilitating the break up of their structures. Binder spray rate was observed
to have no significance influence on the t50% and t90% of both PG and TG granules.
However, generally higher t90% values were observed for PG granules compared to
TG granules. This could be attributed to the more prominent layering effect during
granule formation at higher binder spray rates that resulted in denser granules,
especially at the core. Hence, there was a longer lifetime during dissolution runs for
PG granules. As the mode of growth in TG granules was primarily by agglomeration
of particles, the comparatively more porous agglomerates broke up rapidly in water
and caused an increase in particle surface area available for wetting.
118
B4. Flow properties of PG and TG granules
From Tables 8 and 10, the granule batches prepared by both processes had good flow
properties (angles of repose ≤ 45 ° and Carr indices ≤ 20%). As granule flow can be
influenced by an array of factors that could influence granule flow such as bulk
density, size, shape, surface area roughness, moisture content and cohesiveness of
materials, the methods of flow assessment employed did not show the same
indications when binder spray rate and feed material were varied. This discrepancy
was not unexpected as all current techniques for determining powder flow are based
on different principles and have their own advantages and limitations, as shown in
other studies (Antequera et al., 1994; Amidon, 1995; Lee et al., 2000). Nonetheless,
the assessment methods showed some apparent trends.
A decrease in flow of TG batches was observed for powder blends 2, 3 and 4 as
compared to powder blend 1 (Table 10). This was attributed to the higher proportions
of small TG granules in these batches as discussed. The presence of higher amount of
small granules increased cohesion between granules in these batches. Between the
two processes, lower angles of repose, higher bulk densities and lower Carr indices
were observed for PG batches. This was because of the rounder PG granules as they
were less likely to interlock with one another, leading to lower inter-granular
frictional force when compared to TG granules. Being rounder, PG granules were also
able to pack more closely in a powder column and this resulted in the higher bulk
densities observed.
119
Results and discussion – Part C
C. COMPACTIBILITY STUDY ON PG AND TG GRANULES
It was of importance to study the compactibility of PG and TG granules, as well as
their resultant tablet properties as granules are often prepared with the eventual aim
for use in tabletting. The purpose of Part C of this study was to investigate the effect
of structurally different PG and TG granules in terms of shape and porosity, on the
compaction behaviour and tablet forming ability. The compactibility of the granules,
with and without the addition of tablet excipients was studied.
C1. Compaction behaviour of PG and TG granules
Granules in the 355 to 500 µm size fractions from representative batches of PG and
TG were used to derive the respective Heckel plots, proposed by Heckel (1961a, b) to
describe the change in relative density as a function of pressure. The properties of the
granules used are shown in Table 12, and Figure 21 illustrates the Heckel plot
obtained for each process, derived from their respective representative batches.
Table 12. Characteristics of PG and TG granules in size fraction 355 to 500 µm.
Granule characteristics
Granule batch
Friability Angle of
Sphericity Porosity (%)
index (%) repose (°)
PG-1 0.81 (0.04) 58.6 (4.0) 10.6 (0.9) 35.8 (0.4)
*
PG-2 0.79 (0.06) 58.8 (1.1) 12.8 (0.2) 37.6 (0.3)
PG-3 0.69 (0.08) 64.2 (0.7) 14.0 (0.7) 37.8 (0.6)
TG-1 0.70 (0.07) 63.0 (0.4) 15.0 (0.1) 39.2 (0.7)

*
TG-2 0.63 (0.09) 66.5 (1.1) 17.9 (0.6) 39.7 (0.7)
TG-3 0.56 (0.09) 68.6 (0.4) 18.2 (0.2) 40.8 (0.9)

*
indicates batches selected for disintegration and dissolution studies; values in parentheses denote
intra-batch standard deviation.
120
2.4
1.6
ln 1/(1-D)
1.2
0.8
0.4
0
0 50 100 150
Compaction pressure (MPa)
Figure 21. Heckel plots of PG (■) and TG (□) granules with ( ) and ( )
representing the regressed lines (PG: y = 0.0071x + 1.0, R2 = 0.995; TG: y = 0.0065x
+ 1.1, R2 = 0.992) respectively. Error bars represent inter-batch standard deviation.
121
During the compaction process, force on the upper punch puts pressure on the granule
bed and caused volume reduction. Van der Zwan and Siskens (1982) suggested a
series of volume reduction mechanisms for granules. They included (i) filling of
spaces between the granules (i.e. granule rearrangement and slippage), (ii)
fragmentation and plastic deformation of granules, (iii) filling of spaces between the
primary particles (i.e. granule densification), and (iv) fragmentation and plastic
deformation of primary particles. These mechanisms would not necessarily happen
sequentially and can occur simultaneously. Nonetheless when pressure is gradually
increased on the granule bed, volume reduction due to granule rearrangement and
slippage would generally first be experienced. Then, volume reduction due to
fragmentation and plastic deformation of the discrete granules would occur. With
increased pressure, a compromise on granule integrity would take place due to
granule densification, primary particle fragmentation and plastic deformation of
primary particles.
At relatively low applied pressures during the early stages of compaction, volume
reduction was strongly enhanced by particle rearrangement and slippage. Hence, the
magnitude of r values, obtained from linear regression analysis of the initial curvature
of the Heckel plot, can be related to the ability of the particles to rearrange in the die
as volume reduced during compaction. From Table 13, it can be observed that the r
values derived for TG granules in the early compaction stages at low pressures (0 to
38 MPa) were of smaller magnitudes than those derived for PG granules. The smaller
r values reflected larger deviations from a straight line and a stronger occurrence of
granule rearrangement and slippage for TG granules. The degree of particle slippage
122
Table 13. Heckel plot parameters and properties of tablets formed from PG and TG granules.
Heckel plot parameters Properties of tablets formed at 153 MPa
Low pressures
Granule High pressures (51 to 153 MPa)
(0 to 38 MPa)
batch
Yield Tensile
Porosity
r D0 Da Db pressure R2 strength Ra (nm) Rq (nm)
(%)
(MPa) (N/mm2)
PG-1 0.963 0.382 0.649 0.267 147.05 0.997 12.5 (0.4) 2.82 (0.08) 1730 (261) 2560 (350)
*
PG-2 0.972 0.354 0.628 0.274 136.99 0.997 12.5 (0.5) 2.97 (0.09) 2030 (156) 2950 (168)
PG-3 0.953 0.301 0.636 0.335 140.85 0.989 12.7 (0.5) 2.97 (0.08) 2700 (162) 3790 (194)
TG-1 0.952 0.327 0.659 0.331 161.30 0.980 13.7 (0.7) 2.51 (0.12) 2610 (359) 3700 (440)
TG-2 0.947 0.287 0.653 0.366 154.85 0.986 13.2 (0.5) 2.68 (0.13) 2420 (509) 3540 (645)
*
TG-3 0.943 0.276 0.644 0.368 147.06 0.999 12.5 (0.4) 2.79 (0.11) 2150 (486) 3200 (576)
*
indicates batches selected for disintegration and dissolution studies; values in parentheses denote intra-batch standard deviation.
123
and rearrangement taking place during compaction had also been earlier shown by
York (1978) to be less extensive for more spherical particles (as they packed more
densely in the die) and supported the observations made in this study.
The difference in packing of PG and TG granules in the die prior to compaction is
illustrated in Figure 22 and quantified by the D0 values obtained. Generally, higher D0
values were observed for PG granules (Table 13) and this indicated a higher initial
relative density of the PG granule bed in the die prior to the start of compaction. This
was a result of the structural difference between PG and TG granules. As PG granules
were of a higher degree of sphericity, they packed better in the die. On the other hand,
the more irregular TG granules packed with higher porosity as they had more surface
protrusions preventing close packing. Therefore lower D0 values were observed for
TG granules.
Linear regression analyses were also carried out on the linear portions of the Heckel
plots at high pressures (51 to 153 MPa) and the parameters derived for each batch are
given in Table 13. Da values, derived from the sum of the D0 and Db values were
found to be comparable for both PG and TG granules. Db, the difference between Da
and D0, were larger for TG granules since their D0 values were lower. The extent of
granule rearrangement and slippage could also be indicated by the Db value. In this
study, the generally lower Db values obtained for PG granules aptly provided further
supporting evidence for a smaller extent of granule rearrangement and slippage at low
compaction pressures in addition to the larger r values observed. As there was less
inter-granular space available among the tightly packed PG granules, rearrangement
and slippage was slightly less favoured when the granule bed was under pressure. On
124
PG granules TG granules
Packing of
granules in die
before
compaction
Fragmentation
and
deformation
of granules
After
compaction
Figure 22. PG and TG granules in powder bed with increasing compaction pressures.
125
the contrary, when applied pressure on the TG granule bed was similarly increased,
the granules rearranged and slipped past one another easily due to the availability of
inter-granular space within the loosely packed bed. This difference in packing
accounted for the lower resistance to granule movement and higher Db values
obtained for TG granules.
The yield pressure is a measure of the softness of the granules and ease for plastic
deformation. From Figure 21, the steeper slope of the regressed line from the linear
portion of the PG Heckel plot indicated a smaller yield pressure for the PG granules.
This meant that PG granules were more plastic and susceptible to plastic deformation
at low compaction pressures. At low compaction pressures, the forces applied on the
PG granule bed caused granule deformation into spaces between granules and
appeared to “flattened” the spherical structures of the granules. This was because they
were integrally stronger and comparatively more resistant to granule fragmentation
than TG granules. On the other hand, the gentler slope of the regressed line from the
linear portion of the Heckel plot for TG granules indicated larger yield pressures and a
weaker tendency to display plastic deformation. Instead, TG granules had
comparatively higher fragmentation propensity and were more prone to granule
densification. This could be attributed to the structurally more porous and weaker
granule structures formed using the TG process. Yield pressure values of the
individual granule batches can be found in Table 13.
C1.1. Influence of compactibility of granules on tablet properties
The macro-surface morphological photomicrographs (Figure 23) provided supporting
evidence to results obtained from Heckel plots. Plastic deformation and “flattening”
126
PG tablets TG tablets
(a) (b)
13 MPa
(c) (d)
25 MPa
(e) (f)
38 MPa
(g) (h)
51 MPa
Figure 23. Optical photomicrographs of macro-surfaces (taken at 1.2 × magnification)

of PG and TG tablets.
127
(i) (j)
76 MPa
(k) (l)
102 MPa
(m) (n)
127 MPa
(o) (p)
153 MPa
Figure 23 (continued). Optical photomicrographs of macro-surfaces (taken at 1.2 ×

magnification) of PG and TG tablets.
128
of PG granules was apparent at low pressures as ridges around granules were clearly
seen, demarcating the granules, from one another, which seemed to remain as
coherent units after compaction. A pavement structure on the tablet surfaces resulted
and demonstrated the low propensity of PG granules to fragment and lose their
integrity. This demarcation around TG granules was less obvious and instead, a more
mosaic fused surface with a pitted appearance was seen on TG tablet surfaces for
tablets prepared at similar pressures. This could have been the combined effect of the
irregularity of TG granules in the die before compaction and a higher degree of
granule fragmentation during compaction. During compaction of the more porous TG
granules even at low pressures, fragmentation appeared to be occurring alongside
deformation.
From Figure 24, micro-surface roughness measurements of the tablets revealed that
TG tablets were rougher at pressures 13 to 51 MPa. As TG granules were more
porous, the tablets formed during these initial stages of compaction had a higher
frequency of peaks and valleys on their micro-surfaces, as shown by the three-
dimensional plots (Figure 25). It was evident that the less tightly bonded constituent
particles in TG granules contributed to the distinctness of each constituent
components, hence, higher micro-surface roughness. This gave rise to the larger
measured values of Ra and Rq values for compacted TG granules. Being better fused,
PG granules had comparatively smoother micro-surfaces and formed tablets with
smaller Ra and Rq values at pressures 13 to 51 MPa. At higher pressures (76 to 153
MPa), the integrity of component constituents for both PG and TG granules were lost
due to fragmentation and granule densification with both primary particle deformation
and primary particle fragmentation. Hence, comparable surface roughness for both
129
(a)
16000
12000
Ra (nm)
8000
4000
0
0 20 40 60 80 100 120 140 160
(b)
20000
16000
12000
Rq (nm)
8000
4000
0
0 20 40 60 80 100 120 140 160
Figure 24. Micro-surface roughness, (a) Ra and (b) Rq of PG (■) and TG (□) tablets
with ( ) and ( ) representing the regressed lines (PG/Ra: y = 10651e-0.140x, R2
= 0.947; TG/Ra: y = 12614e-0.151x, R2 = 0.940; PG/Rq: y = 14610e-0.135x, R2 = 0.947;
TG/Rq: y = 16983e-0.143x, R2 = 0.940) respectively: Error bars represent inter-batch
standard deviation.
130
(a) (b)
Ra: 12320 nm, Rq: 16890 nm Ra: 14780 nm, Rq: 18560 nm
13 MPa
(c) (d)
25 MPa
(e) (f)
Ra: 6120 nm, Rq: 8330 µm Ra: 7060 nm, Rq: 9800 nm
38 MPa
(g) (h)
51 MPa
Figure 25. Three-dimensional plots of micro-surfaces (taken at 20.64 × magnification)

of PG and TG tablets.
131
(i) (j)
76 MPa
(k) (l)
102 MPa
(m) (n)
127 MPa
(o) (p)
153 MPa
Figure 25 (continued). Three-dimensional plots of micro-surfaces (taken at 20.64 ×

magnification) of PG and TG tablets.
132
types of tablets was seen, although the PG granules generally produced marginally
smoother tablets at similar compaction pressures.
When the applied pressure was increased during the compaction process, it resulted in
larger volume reductions of the granule bed and therefore caused tablets of decreasing
porosity and increasing tensile strength to be formed (Figures 26 and 27). The
decrease in porosity was found to be exponential for both processes and regressed
equations showed comparable extents of change in tablet porosity with pressure. The
regression results demonstrated that the total degree of bulk volume reduction was
similar between PG and TG granules (Figure 26). This was in agreement with earlier
reports (Johansson et al., 1995; Johansson and Alderborn, 2001; Nicklasson et al.,
1999), in which tablet porosity was found to be primarily dependent on the pressure
applied during compaction and the physical properties of the granules were of minor
importance.
From Figure 27, PG tablets showed a slightly steeper increase in tensile strength with
pressure, with significant differences found at the higher compaction forces of 102,
127 and 153 MPa. Since the porosity of TG and PG tablets were comparable at
similar compaction pressures, the difference in tablet tensile strength observed was
likely to be attributed to the quality of pore structure in the tablet. As PG granules had
lower yield pressures, capable of more plastic deformation and subsequent lower
elastic recovery, they were able to remain in close contact after volume reduction.
This not only helped to maintain small inter-granular pores, but also increased the
area of contact between granules (and therefore increased bonding force and the
number of bonding zones). As a consequence, stronger tablets formed when PG
133
45
40
35
Tablet porosity (%)
30
25
20
15
10
0 20 40 60 80 100 120 140 160
Figure 26. Porosity of PG (■) and TG (□) tablets with ( ) and ( )

representing the regressed lines (PG/porosity: y = 0.414e-0.008x, R2 = 0.980;
TG/porosity: y = 0.403e-0.008x, R2 = 0.976) respectively. Error bars represent inter-
batch standard deviation.
134
3.5
2.5
Tensile strength (N/mm2 )
1.5
0.5
0
0 20 40 60 80 100 120 140 160
Figure 27. Tensile strength of PG (■) and TG (□) granules with ( ) and ( )
representing the regressed lines (PG/tensile strength: y = 0.022x – 0.29, R2 = 0.997;
TG/tensile strength: y = 0.019x – 0.24, R2 = 0.997) respectively. Error bars represent
inter-batch standard deviation.
135
granules were compacted. The influence of yield pressure on mechanical strength
found in this study is supported by a similar observation by Nordstrom et al. (2008).
Comparatively, the higher yield pressure, lower deformation and higher fragmentation
propensities of TG granules gave rise to a marginally weaker tablet pore structure.
C1.2. General relation between granule characteristics, granule compactibility and
tablet properties
Multivariate analyses were performed on obtained data to give a better insight into the
inter-relation and inter-dependence between the granule characteristics, granule
compactibility and the properties of tablets formed since they are widely known to be
related as shown in literature. For instance, the compactibility of granules have been
demonstrated to be dependent on bulk density (Zuurman et al., 1994; Murakami et al.,
2001) while the fragmentation propensity during compaction was reported by
Wikberg and Alderborn (1991) to be related to the granule porosity. Tablet strength
was also found to be influenced by granule strength (Horisawa et al., 2000). The
multivariate approach has been similarly employed by Haware et al. (2009) to
describe and predict compaction and tablet properties of various direct compression
excipients.
Data from Tables 12 and 13 was evaluated by means of principal component analysis
to create a new coordinate system, in which the data cloud was scattered in three
dimensional space by the principal components to derive a loadings plot (Figure 28).
The origin of this coordinate system, 0, is the grand mean and is where the mean of
each variable becomes the 0 in the system. The first principal component (PC1)
extends through the longest extent of the data cloud, and describes the direction
136
Yield pressure Da
Tablet porosity blue
red D0
Sphericity
r
Ra
Db Angle of repose
Friability index
Granule porosity
green
Tensile strength
Figure 28. Loadings plot of data related to granule characteristics (■), compactibility (●) and tablet properties (▲).
137
through the data cloud which expresses the largest variation in the data (Lindberg and
Lundstedt, 1995). The second principal component (PC2) is orthogonal to PC1,
intercepts it at the origin and extends through the second longest side of the data cloud
and shows the second largest variation. Eighty-six percent of the data variance in this
study could be accounted for by the principal components model, in which 64 % was
explained by PC1 and 22 % explained by PC2.
On the loadings plot, variables that displayed similar loadings would be situated close
together geometrically on the same side of the same principal component axis. For
instance, the geometric positions of tablet porosity, yield pressure and Da were close
together in the region defined by the negative side of PC1 and positive side of PC2
since they displayed similar loadings in this data set (Figure 28). By the same manner,
the similar loadings displayed by D0, sphericity and r resulted in their close proximity
to one another in the region defined by the positive side of PC1 and positive side of
PC2. When variables are geometrically clustered as such, possible positive
correlations within the cluster are suggested. Three groups of clustered variables
identified in the derived loadings plot were labelled as red, blue and green (Figure 28).
The loadings plot suggested that the variables in the red group may be positively
correlated with one another (e.g. higher yield pressure of granules results in higher
tablet porosity) since they were clustered together, and akin for variables found within
the other two groups.
In contrast, variables that co-vary negatively would be situated geometrically on
opposite sides of the same principal component axis. Hence it can be inferred that
tensile strength may be negatively correlated to the variables in the green group since
138
tensile strength was positioned on the positive side of PC1 whereas the variables in
the green group were positioned on the negative side of this principal component axis
(Figure 28). Likewise, the plot suggested that variables in the red group may have
negative correlations to those in the green group because they were found on opposite
sides of PC2.
Correlation analyses between the variables were carried out and the Pearson’s
coefficients are shown in Table 14. The results identified variables that correlated
significantly with one another and their level of significance. As shown by their close
proximity in the loadings plot, significant correlations found between variables that
fell within the same group were positive, i.e. positive Pearson’s coefficients were
observed. The results also confirmed that significant correlations between variables
situated on opposite sides of the same principal component axis were negative. For
instance, sphericity (blue group) and granule porosity (green group) were on opposite
sides of PC2 (Figure 28) and their Pearson’s coefficient was found to be -0.993 (Table
14).
From Table 14, it was seen that granule characteristics (sphericity, granule porosity,
friability index and angle of repose) correlated significantly with one another,
indicating the inter-dependence of these characteristics. Sphericity and granule
porosity were observed to have the most significant correlation (p < 0.001) and a very
high Pearson’s coefficient value of -0.993. This indicated that granules of high
sphericity resulted when powder particles within these granule structures consolidated
with little intra-granular space (as indicated by the low porosity values). The other
significant correlation suggested that more porous granule structures with
139
Table 14. Pearson’s coefficients of correlated variables.
Granule characteristics (■) Compactibility (●) Tablet properties (▲)
Granule Friability Angle of Yield Tablet Tensile
Sphericity r D0 Da Db Ra
porosity index repose pressure porosity strength
Sphericity
Granule
-0.993***
porosity
Friability
-0.952** 0.939**
index
Angle of
-0.924** 0.889* 0.968**
Granule
characteristics (■)
repose
r 0.922** -0.944** -0.837* -0.785
D0 0.956** -0.968** -0.931** -0.878* 0.856*
Da -0.265 0.286 0.290 0.276 -0.547 -0.120
Db -0.964** 0.980** 0.946** 0.892* -0.942** -0.968** 0.366

Yield
-0.325 0.336 0.399 0.414 -0.552 -0.212 0.965** 0.442
Compactibility (●)
pressure
Ra -0.450 0.501 0.463 0.460 -0.506 -0.620 0.196 0.627 0.347
Tablet
-0.187 0.209 0.321 0.356 -0.361 -0.205 0.741 0.377 0.870* 0.643
porosity
Tensile
0.304 -0.296 -0.394 -0.444 0.492 0.172 -0.931** -0.395 -0.986*** -0.286 -0.858*
Tablet
properties (▲)
strength
Variable grouping in Figure 28 is indicated by respective colour fill. Statistical significance is denoted by * at 0.05 level, ** at 0.01 level and *** at 0.001 level.
140
more intra-granular space would cause weaker (i.e. higher friability index) granules to
form. Better flow (i.e. smaller angle of repose) was also observed to correlate to
granules that were more spherical, less porous and stronger.
These granule characteristics were found to have significant correlations with Heckel
plot parameters such as r, D0 and Db (Table 14). The extent of rearrangement and
slippage at the early stages of compaction, as indicated by r and Db, were found to be
negatively correlated to sphericity but positively correlated to granule porosity and
friability. Hence it can be inferred that a smaller extent of rearrangement and slippage
(i.e. larger r and lower Db) resulted from granules that were more spherical, less
porous with lower friability index. Likewise, a closer packing in the die (i.e. higher D0)
correlated to granules of structures that were more spherical, less porous and stronger
(i.e. lower friability index). Good granule flow (i.e. small angles of repose) also
indicated high D0 and small Db. r, D0 and Db were also found to correlate significantly
with one another. Granule characteristics were not found to significantly influence
other Heckel plot parameters such as yield pressure and Da as well as the properties of
the tablets formed (Table 14).
The yield pressure of granules was found to have a positive correlation to Da and this
indicated that granules that deformed easily (i.e. smaller yield pressures) undergone a
smaller extent of densification before deformation (i.e. smaller Da). Tablet properties
such as tablet porosity and tensile strength were found to depend on the yield
pressures of the granules comprising the tablets. From Table 14, yield pressure was
found to correlate positively to tablet porosity and negatively to tensile strength.
Granules with higher yield pressures formed tablets that were of a higher porosity and
141
lower tensile strength. Da and tensile strength were also shown to have a significant
negative correlation (p < 0.01) but this was less significant than the relationship
between yield pressure and tensile strength (p < 0.001). Tensile strength was found to
have a stronger correlation to the yield pressure as compared to Da. Tablet porosity
and tensile strength correlated negatively to each other. Tablets with more inter-
granular space (i.e. higher tablet porosity) were found to be structurally weaker (i.e.
lower tensile strength). Tablet roughness parameters Ra was found to have no
significant relationship with other variables.
To summarize the multivariate analytical findings, granule characteristics correlated
to Heckel plot parameters such as r, D0 and Db and hence suggested that granule
characteristics largely affected volume reduction mechanisms such as granule
rearrangement and slippage at the early stages of the compaction process. Other
volume reduction mechanisms during compaction such as granule densification prior
to deformation and ease of deformation (indicated by Da and yield pressure
respectively) were not affected by the granule characteristics. Da and yield pressure
instead correlated to properties of the resultant tablets, namely tablet porosity and
tensile strength. Generally, these properties of the resultant tablets were found to have
a direct strong dependence on granule compactibility, and less directly on the granule
characteristics.
C2. Compaction behaviour of PG and TG granules with tablet excipients
It was also of interest to find out how the compaction behaviour of TG and PG
granules would differ when compacted with common tablet excipients. The granules
used in this section were randomly sampled from one representative batch of each of
142
the two processes. These two batches were selected based on their similarities in
granule mean size, size distribution and drug release properties (Table 15) to allow
easier comparison. The other physical characteristics of these two granule batches
were earlier shown in Table 12.
Table 15. Size and dissolution properties of PG and TG granules used to prepare
tablets for disintegration and dissolution studies.
Size and drug release properties PG TG
MMD (µm) 440 470
Span 1.26 1.38
Fines ≤ 90 µm (%, w/w) 0.65 0.18
Amount in modal size fraction 355 to 500 µm (%, w/w) 27.22 32.76
t90% of granules in water (s) 49.7 (1.2) 48.2 (3.3)

Values in parentheses denote intra-batch standard deviation.
Tablets comprising granules, magnesium stearate and a disintegrant were prepared
and Heckel plots were obtained for the respective tablet formulations. The parameters
derived are presented in Table 16. It can also be observed that generally, higher r,
higher D0 and lower Db values were derived from Heckel plots for PG granules. This
suggested that the extent of granule rearrangement and slippage at low pressures was
also small in the presence of other excipients. The yield pressures derived from the
Heckel plots of PG and TG formulations were however rather similar, in contrast to
the values derived from the Heckel plots of granules without additives. This indicated
that the TG granules with excipients exhibited an increased plasticity. A possible
explanation could be that the disintegrant and magnesium stearate particles filled up
143
Table 16. Heckel plot parameters of PG and TG tablets with different disintegrants incorporated.
Heckel plot parameters
Low pressures
Granules Disintegrant High pressures (51 to 153 MPa)
(0 to 38 MPa)
Yield pressure
r D0 Da Db R2
(MPa)
Starch 0.991 0.425 0.674 0.249 135.14 0.992
Sodium starch glycolate 0.991 0.419 0.691 0.272 142.86 0.963
PG Croscarmellose sodium 0.989 0.409 0.676 0.267 136.99 0.998
Crospovidone XL 0.989 0.412 0.691 0.279 140.85 0.964
Crospovidone XL-10 0.986 0.416 0.679 0.263 125.63 0.980
Starch 0.981 0.355 0.670 0.315 135.14 0.999
Sodium starch glycolate 0.976 0.337 0.673 0.336 140.85 0.988
TG Croscarmellose sodium 0.961 0.330 0.665 0.335 142.85 0.994
Crospovidone XL 0.977 0.341 0.667 0.326 136.99 0.975
Crospovidone XL-10 0.977 0.346 0.670 0.324 129.87 0.968
144
the surface cavities of the rougher TG granules, and effectively decreased the effects
of the existing intrinsic granule porosity. This enhanced the deformability of the TG
granules. As the PG granules were more spherical, they were comparatively less
influenced by the advantageous attributes conferred by the presence of the excipients.
C2.1. Influence of compactibility of granules on disintegrant efficacy
For all the tablet formulations studied, longer tablet disintegration and dissolution
times were observed for tablets produced using increased compaction pressure (Table
17). Tablets produced with increased compaction pressures were less porous and
stronger. It was therefore harder for water to penetrate the tablets and break up the
matrices upon introduction into the aqueous media. Among the different tablet
formulations, starch, the traditional disintegrant, exhibited the longest disintegration
and dissolution times. Using equivalent amounts, starch had been shown to be less
efficient than the newer classes of superdisintegrants in promoting tablet break up and
drug release as the newer classes of superdisintegrants are chemically modified and
were able to undergo tremendous swelling and/or wicking.
An interesting observation was made when the crospovidones were used and this
observation highlighted the important role of granule characteristics on the choice of
the disintegrating agent. Efficacy of crospovidone XL-10 appeared to be superior
when compacted with TG granules as the resultant tablets were found to have
markedly shorter disintegration and dissolution times as compared to the similarly
produced PG tablets. This phenomenon was not observed when crospovidone XL
(100 to 130 µm), the larger particle size grade was used as the disintegrant.
145
Table 17. Disintegration and drug release properties of PG and TG tablets with different disintegrants incorporated.
Low pressure (51 MPa) Intermediate pressure (102 MPa) High pressure (153 MPa)
t50% t50% t50%
Porosity tdis t50% acid Porosity tdis t50% acid Porosity tdis t50% acid
Granules Disintegrant water water water
(%) (min) (min) (%) (min) (min) (%) (min) (min)
(min) (min) (min)
#* #* # # #
22.9 8.3 7.0 4.5 15.0 18.1 18.7 14.0 10.5 21.0 18.3 23.7
Starch
(0.2) (2.0) (1.0) (0.9) (0.2) (1.8) (6.7) (1.7) (0.2) (1.5) (4.0) (4.0)
# * #* # * * # * #*
Sodium starch 22.7 4.9 3.8 7.7 14.6 17.1 11.3 14.4 10.8 18.1 15.2 22.2
glycolate (0.3) (0.5) (0.8) (0.6) (0.4) (1.9) (0.8) (1.3) (0.3) (1.0) (1.8) (2.6)
# # * *
PG Croscarmellose 22.1 4.1 5.0 4.4 15.9 8.6 8.5 12.0 10.9 13.0 10.0 13.3
sodium (0.5) (0.6) (1.3) (1.4) (0.4) (0.8) (0.5) (2.8) (0.4) (0.8) (1.0) (0.6)
# #
Crospovidone 22.7 2.3 2.8 1.7 14.6 10.2 5.8 4.5 10.8 16.3 10.7 10.5
XL (0.3) (0.6) (1.6) (2.0) (0.4) (1.9) (1.61) (2.6) (0.3) (1.6) (1.5) (1.3)
#* * # # # # # #
Crospovidone 22.5 4.8 8.7 4.5 14.1 12.2 14.6 12.3 9.9 15.3 18.0 16.0
XL-10 (0.4) (0.9) (0.6) (0.5) (0.4) (0.6) (1.2) (2.3) (0.4) (1.1) (1.3) (4.0)
# # # # #
22.7 10.6 11.5 9.3 15.4 15.6 13.0 11.3 10.6 18.9 16.5 15.0
Starch
(0.3) (1.8) (1.3) (0.3) (0.3) (1.9) (1.0) (3.1) (0.5) (0.4) (0.5) (2.5)
# * #* # # #
Sodium starch 23.7 4.3 3.8 5.6 15.5 13.6 9.3 12.1 11.5 16.9 13.0 14.8
glycolate (0.2) (0.2) (0.3) (0.2) (0.2) (0.7) (1.4) (1.7) (0.3) (0.6) (1.7) (1.4)
# #
Croscarmellose 23.9 5.4 5.8 4.5 15.3 8.8 7.8 8.2 22.6 13.9 10.2 11.7
TG
sodium (0.4) (0.4) (0.3) (1.3) (0.4) (0.8) (0.8) (1.0) (0.3) (0.4) (0.8) (2.1)
#* #*
Crospovidone 23.8 2.7 2.2 3.5 15.7 11.5 8.8 10.7 11.3 17.1 11.2 8.7
XL (0.5) (0.6) (1.3) (0.9) (0.1) (1.4) (0.8) (0.6) (0.3) (0.3) (1.0) (1.3)
#* * # # # # # #
Crospovidone 23.8 4.4 5.7 4.2 15.1 5.8 6.3 5.8 10.8 8.8 8.7 8.2
XL-10 (0.4) (0.1) (0.3) (0.5) (0.6) (0.7) (0.6) (0.9) (0.1) (0.5) (0.3) (1.0)
# *
indicates significant difference between PG and TG; indicates significant difference between deionized water and acid media; values in parentheses denote inter-tablet
standard deviation.
146
Due to the small particle size of crospovidone XL-10 (30 to 50 µm), it could be more
efficiently distributed with the crevices of the irregular TG granules in contrast to the
highly spherical PG granules. These small crospovidone XL-10 particles were better
retained onto the surface cavities of the rougher TG granules, in a manner similar to
powder coating. As crospovidones swelled very little and worked primarily by the
mechanism of wicking (Kornblum and Stoopak, 1973), a uniform distribution of the
disintegrant facilitated water penetration into the tablet matrix system, thus promoting
matrix breakdown and followed by faster drug release.
Unlike for the crospovidones, swelling played a larger role in the disintegratability
action by the disintegrants, sodium starch glycolate and croscarmellose sodium. Upon
water uptake, these two classes of superdisintegrants swelled to a much larger extent
in comparison to the crospovidones. The rapid and extensive swelling of these
superdisintegrants against the matrix superstructures led to the development of a
swelling force which caused matrix breakdown. Often, this swelling action is the
result of collective contributions of a cluster of disintegrant particles within the tablet
matrix, acting synergistically. It was shown in this study that formulations containing
sodium starch glycolate and croscarmellose sodium generally had appreciably slower
drug release in acid media compared to in deionized water. This above finding was
not uncommon (Chen et al., 1997; Zhao and Augsburger, 2005) and was attributed to
the presence of carboxymethyl sodium moieties in these disintegrants. These
carboxymethyl sodium moieties converted to their free acid forms in acid media,
bringing about a reduction in the water holding capacity of the individual disintegrant
particles. The reduced water holding capacity eventually led to a smaller extent of
swelling for individual sodium starch glycolate and croscarmellose sodium particles.
147
The influence of acid media on the extent of swelling was observed to be more
consequential for sodium starch glycolate as compared to croscarmellose sodium.
Upon absorption of water, sodium starch glycolate particles had a high tendency to
hold on to the water and a low tendency to transfer it to its neighbouring particles.
This caused sodium starch glycolate to rely primarily on the mechanism of swelling
and the development of a swelling force for matrix breakdown. Although
croscarmellose sodium particles also worked by the mechanism of swelling, they were
comparatively less affected by changes in the extent of swelling. This is because the
fiber-shaped croscarmellose sodium particles swelled preferentially in longitudinal
axes, in contrast to the generally spherical-shaped sodium starch glycolate particles
that swelled in three dimensions (Shangraw et al., 1981; Zhao and Augsburger, 2005).
Assuming that the change in length was reduced by the same amount in acid media,
particles that swelled in two dimensions would experience a smaller volume decrease
as compared to those that swelled in three dimensions. Therefore, the smaller decrease
in the volume of croscarmellose sodium particles could have weakened the swelling
force by a lesser extent, causing a shorter delay in drug release in acid media. In
addition, the fiber-shaped croscarmellose sodium particles were able to act
individually as hydrophilic channels to pull water into the system. This assisted
matrix breakdown.
Another observation was that the discrepancy between drug release rates in water and
acid media was more profound for PG tablets than TG tablets. Augsburger et al. (2007)
reported that a matrix that yielded readily through plastic deformation might partly
accommodate any disintegrant swelling provided that swelling does not occur rapidly
enough. The results in this study suggested that this might have been the case with the
148
more deformable PG matrices since swelling was less rapid in acid media.
Compaction behaviour of the granule bed could possibly play an important role for
disintegrants that relied strongly on the mechanism of swelling.
149
Results and discussion – Part D
D. INVESTIGATIVE STUDY ON THE ABILITY OF PG TO GRANULATE
MOISTURE SENSITIVE DRUGS
Modification of the fluidized bed wet granulation technique for moisture sensitive
materials is attractive since the process enables efficient mass and heat transfers
between the moistened agglomerates and drying air. The efficient mass and heat
transfer occurs by three-dimensional vaporization of water from wetted solids into the
constantly renewed air stream (Hlinak and Saleki-Gerhardt, 2000; Romer et al., 2008).
The efficient mass and heat transfer also prevents excessive build-up of granule bed
temperature. Concurrent wetting and drying during the granulation process lessens the
moisture stress induced after wetting by moisture removal, and potentially reduces
processing times (Turton et al., 1999; Wildfong et al., 2002; Law and Mujumdar,
2007).
In this part of the study, it was hypothesized that the modified Wurster process, PG,
may be applied for the wet granulation of moisture sensitive drugs due to its highly
ordered particle circulation pattern and advantageous fluid dynamics. The secondary
aim was to examine the influence of air velocity at the granulation zone, inlet air
temperature and binder spray rate on ASA stability. For better illustration of PG’s
potential to wet granulate moisture sensitive materials, the top-spray process was
again employed as the standard granulation process for comparison.
D1. ASA stability in PG and TG during processing
PG and TG granules were prepared under two sets of test conditions: (i) low inlet air
temperature (60 °C) and low binder spray rate (22 g/min) or (ii) high inlet air
temperature (80 °C) and high binder spray rate (31 g/min). They were defined as
150
condition LL and condition HH respectively. As shown in Table 18, the similar and
high process drying efficiencies obtained for the processes at the investigated
conditions indicated that both sets of conditions were tuned at the optimal level and
would provide a fair basis for comparison. The granule batches produced also had
comparable size characteristics, with MMDs and spans ranging from 517 to 627 µm
and 1.30 to 1.78 respectively. At the end of the drying phase, low residual moisture
contents remained, ranging from 0.08 to 0.22 %, w/w (Table 18).
For both sets of conditions, it was observed that during granulation, moisture content
in the granule bed rose and granule bed temperature dropped when the liquid binder
was introduced into the system at the initiation of granulation (Figure 29). After all
the liquid binder was sprayed, a 10 min drying phase commenced. In comparison,
shorter processing times were needed for runs at condition HH as the same amount of
liquid binder was sprayed at a faster rate. During drying, moisture content in the
granule bed decreased rapidly with a sharp increase in granule bed temperature.
Throughout the granulation runs, the amount of ASA degradation in granules sampled
at 2 min intervals was found to increase steadily with time. The results showed higher
rates of ASA degradation and higher amounts of ASA degradation in the final
granules at the investigated conditions for TG as compared to PG (Table 18).
It has been extensively reported in literature that the hydrolytic reaction during ASA
degradation is dependent on not only moisture content, but also the temperature
(Alibrandi et al., 1995), pH (Choudhury and Mitra, 1993; Some et al., 2000) and type
of excipients (Landin et al., 1994; Du and Hoag, 2001; Heidarian et al., 2006;
151
Table 18. Processing conditions and granule properties in PG and TG.
Process Residual Amount of
Rate of ASA ASA
drying AUCheat AUCmoisture MMD moisture ASA
Condition Process Span degradation degradation
efficiency (°Cmin) (%min) (µm) content degradation
(%min-1) index (%)
(%) (%, w/w) (%)
PG 96.8 (2.9) 957 (15) 92.8 (10.1) 627 (6) 1.78 (0.05) 0.08 (0.08) 0.110 (0.002) 3.04 (0.04)
LL 52.7
TG 96.9 (1.1) 1000 (12) 48.0 (9.1) 517 (24) 1.43 (0.05) 0.22 (0.05) 0.183 (0.003) 5.77 (0.04)
PG 92.3 (3.4) 782 (14) 67.5 (0.4) 620 (79) 1.70 (0.09) 0.19 (0.12) 0.098 (0.001) 2.30 (0.16)
HH 31.5
TG 93.1 (2.4) 811 (32) 59.3 (3.1) 565 (18) 1.30 (0.04) 0.22 (0.06) 0.239 (0.002) 7.30 (0.15)
Values in parentheses denote inter-batch standard deviation.

152
(a)
8 55
Residual moisture content (%, w/w) 50

6
45
Temperature (°C)
4 40
35
2
30
0 25
0 4 8 12 16 20 24 28 32
Time (min)
(b)
8 55
Residual moisture content (%, w/w)
50
6
45 Temperature (°C)
4 40
35
2
30
0 25
0 4 8 12 16 20 24 28 32
Time (min)
Figure 29. Moisture content (■,□) and bed temperature (●,○) in PG (closed symbols)
and TG (open symbols): (a) PG at condition LL (b) TG at condition LL, (c) PG at
condition HH and (d) TG at condition HH. Error bars denote inter-batch standard
deviation.
153
(c)
8 55
Residual moisture content (%, w/w) 50

6
45
Temperature (°C)
4 40
35
2
30
0 25
0 4 8 12 16 20 24
Time (min)
(d)
8 55
Residual moisture content (%, w/w)
6
45
Temperature (°C)
4
35
2
0 25
0 4 8 12 16 20 24
Time (min)
Figure 29 (continued). Moisture content (■,□) and bed temperature (●,○) in PG

(closed symbols) and TG (open symbols): (a) PG at condition LL (b) TG at condition
LL, (c) PG at condition HH and (d) TG at condition HH. Error bars denote inter-batch
standard deviation.
154
Mihranyan et al., 2006). As pH of the liquid binder and the type of excipients were
kept constant in this study, moisture and heat factors influenced ASA stability and
these factors were likely to be due to the differences in particle circulation pattern and
fluid dynamics in the PG and TG processes. The hydrolysis of ASA was attributed to
both moisture and heat stresses in the processes, brought about by the introduction of
the liquid binder and heated drying air into the system respectively.
D1.1. Impact of particle circulation pattern and fluid dynamics in PG and TG on
ASA stability
Particle movement in the bottom spray PG system preceded a highly ordered
circulation pattern due to the central partition column mounted above the air
distribution plate. This helped to contribute to the existence of distinct zones, (i) spray
granulation zone, (ii) drying zone and (iii) annular down flow bed in the bottom-spray
system (Figure 8). In addition, the presence of the partition column in the bottom-
spray system increased air-solid contact and facilitated high mass and heat transfer
between the particles and heated drying air (Cunha et al., 2009).
During the liquid binder addition phase in PG, at any point in time, a comparatively
small fraction of the total material for granulation was drawn from the annular down
flow bed into the spray granulation zone within the partition column. At the spray
granulation zone, moisture was introduced to the powder particles by the liquid binder
spray, thereby enabling them to aggregate but also subjecting them to moisture stress.
The powder particles were next lifted into the drying zone by the heated air stream
after wetting. Within hundredths of a second, the wetted particles conveyed through
the drying zone and were almost dried before they rejoined the staging annular down
155
flow bed to queue to await re-entry into the spray granulation zone in an orderly
manner.
Moisture stress on the granules in PG was limited to the short duration during which
the powder particles were harshly wetted while cycling through the zones in the
bottom-spray system. As the wetted particles were swiftly pneumatically conveyed up
the partition column through the spray granulation zone to the drying zone almost
immediately after wetting, drying occurred very rapidly and efficiently. The efficient
removal of moisture from the wetted particles was a consequence of the unique design
of the graduated air distribution plate and swirl accelerator in the PG process. These
two features directed a large volume of the incoming heated air in the system through
the centre of its air distribution plate at a high velocity (Figure 8). This central air
stream at high velocity in the partition column was continuous and the constantly
renewing air stream prevented saturation of the air with moisture. Also, minimal heat
stress was induced by the heated drying air on the granules at the drying zone due to
the short duration spent there. Vaporization of moisture kept the wetted particles cool
by heat loss through conversion to latent heat. Heat from the drying air was desirably
utilized to promote moisture removal during the passage through the drying zone and
undue heating of the granules was localized and limited.
The unique mode of air distribution in the PG system also desirably caused fluidizing
air of a small volume at a low velocity to escape through the annular down flow bed.
This low velocity fluidizing air passing through annular down flow bed was just
sufficient to keep the particles loosely packed while they wait for re-entry into the
partition column. As the volume and velocity of the annular fluidizing air was low
156
compared to that distributed to the central partition column, it limited the heat
exposure of the granules at the annular down flow bed. This configuration was
advantageous to ensure limited ASA instability or degradation. Tolerance of ASA to a
low amount of heat while the granules were reasonably dry was relatively good.
There was a rather different scenario in the TG process. Without a partition column to
regulate particle movement, there was comparatively turbulent and disorderly
circulation pattern for the particles. As a result, there were no distinct zones present in
the system for wetting and drying. Liquid binder was sprayed rain-like onto the
fluidizing particles while heated air was passed through the granule bed consistently
during the process. The top-spray process also produced a rather different fluid
dynamics as the air openings in the air distribution plate were evenly spaced from one
another (Figure 17), unlike in the graduated PG air distribution plate. The incoming
air was therefore distributed almost evenly across the entire granule bed and served
both purposes of drying and fluidization. Whereas for PG, air was predominantly
conveyed through the central partition column for drying and a comparatively small
volume was passed through the annular down flow bed for fluidization.
The differences in fluid dynamics in the TG processor subjected the entire TG granule
bed to continuous contact with the drying air and thereby causing higher heat stress to
the granules at the conditions investigated. This can be seen from the generally higher
AUCheat and lower AUCmoisture values in TG (Table 18), calculated from temperature
and moisture content profiles (Figure 29) of the granule beds respectively. In PG, at
any time, only a comparatively small fraction of granules enter the partition column
where the heated drying air is concentrated. The majority of the granules remained at
157
the annular down flow bed where there was comparatively a small volume of heated
air. Therefore, heating of the PG granules was limited mainly to the period of
conveyance through the drying zone. The comparatively greater exposure of the
wetted particles to heat from the drying air in TG increased the kinetics of the
hydrolytic reaction of ASA. Saturation of the air surrounding the granules in the upper
region of the spray granulation and/or drying zone in TG was also more likely to
occur, impeding the transfer of moisture from the granules to the air. The
comparatively less ideal fluid dynamics and less focused drying contributed to a
greater degradation rate of ASA with the TG process as compared to PG (Table 18).
D1.2. Influence of inlet air temperature and binder spray rate
Prior to the start of drying, the moisture content of the PG annular down flow bed
peaked approximately at a level of 6 %, w/w (Figure 29a) in contrast to the lower
approximate maximum level of 3 %, w/w in TG (Figure 29b) at condition LL.
AUCmoisture values were corresponding higher in PG compared to TG at this condition
(Table 18). Even though a higher amount of moisture was observed in the annular
down flow bed throughout the PG process, the rate and amount of ASA degradation
was significantly lower for PG granules (Table 18). At condition HH, moisture
content of the granules at the granule bed reached a maximum level of approximately
6 %, w/w for both PG and TG (Figures 29c and 29d) with a higher AUCmoisture
observed for PG. Yet again, the rate and amount of ASA degradation found was
significantly lower for PG granules than for TG granules (Table 18).
Using the results obtained, the ratio of the amount of ASA degradation in PG to TG
was calculated and defined in Equation (17) as the ASA degradation index. ASA
158
degradation indices were found to be 52.7 % and 31.5 % at condition LL and
condition HH, respectively (Table 18). An ASA degradation index of 52.7 %
indicated that only approximately half the amount of degradation that occurred in TG
took place in PG at condition LL. With employment of a high binder spray rate and
high inlet air temperature at condition HH, the ASA degradation index was reduced to
31.5 %.
The stability of ASA was observed to be better in PG compared to TG at both
conditions LL and HH. The findings suggested that the effect of the amount of
moisture retained in granule beds was less influential than the effect of system fluid
dynamics on ASA stability at comparable process drying efficiencies. It appeared that
as long as the rate of moisture addition was sufficiently low (or removal of moisture
was sufficiently high) to maintain a reasonably dry granule bed, the extent and
duration of exposure to heat from the drying air had greater impact on the kinetics of
hydrolysis of ASA as compared to bed moisture content. The different modes of air
distribution in the two systems subjected ASA to a comparatively shorter duration and
a smaller extent of exposure to heat in the PG process. When the process did expose
the granules to the heated drying air while they were in the drying zone, it occurred
when the granules were very wet. The heat was therefore efficiently dissipated by the
latent heat of evaporation as moisture was removed from the wetted granules and the
granules did not get heated up unduly.
Comparing results within the PG process, the rate and amount of ASA degradation
was found to be lower at condition HH than that at condition LL (Table 18). The
results indicated that even though a larger amount of moisture was introduced per unit
159
time with usage of a high binder spray rate at condition HH, it was effectively
removed by the use of a high inlet air temperature. Thus, both conditions LL and HH
allowed the attainment of similar levels of 6 %, w/w moisture content before the start
of the drying phase (Figures 29a and Figure 29c). The rates of ASA degradation at
condition LL and condition HH in PG were found not to be vastly different. Therefore
the lower amount of ASA degradation (Table 18) at condition HH in PG was largely
due to a shortening in processing time with the higher wetting rate offset by a higher
rate of moisture removal, attributed to the high inlet air temperature employed. This
was indicated by the lower AUCmoisture and AUCheat values observed at condition HH
compared to condition LL (Table 18). As the liquid binder was sprayed at a faster rate,
the granulation phase was shortened. This reduced processing time and consequently,
the stress on ASA stability. To minimize the amount of ASA degradation in PG,
usage of a combination of high inlet air temperature and high binder spray rate was
observed to be a suitable approach.
The converse was seen within the TG process. In contrast to PG, the rate of ASA
degradation in this process was observed to be comparatively much higher at
condition HH than at condition LL (Table 18). Despite the shortened processing time
at condition HH, the amount of ASA degradation was found to be significantly higher.
At condition HH, moisture content in the TG granule bed reached an approximate
maximum level of 6 %, w/w (Figure 29d) in contrast to the approximate maximum
level of 3 %, w/w at condition LL (Figure 29b) before the start of drying. These
observations could again be attributed to the less ordered particle circulation pattern
and even distribution of heated drying air in TG. The higher amount of heat from the
use of a higher inlet air temperature (at condition HH) could not be specifically
160
“targeted” at drying the wetted granules, as suggested by the comparative increase in
AUCmoisture at this condition. Hence, usage of a combination of high inlet air
temperature and high binder spray rate was less favoured for TG. Instead, for the TG
process, the results suggested that moisture should be slowly introduced into and
gently removed from the system to reduce processing stress on ASA stability.
D2. Factors influencing processing conditions and ASA stability in PG
Since the PG process was shown to be superior to TG at minimizing the amount of
ASA degradation, process variables influencing the conditions at the spray
granulation zone and drying zone were studied. This is to provide better insights and
an in-depth understanding of how the stability of a moisture sensitive ASA could be
improved during PG. The variables investigated include AAI diameter, inlet air
temperature and binder spray rate. AAI diameter affected the air velocity of the drying
air, whereas inlet air temperature and binder spray rate indicated the amount of heat
and moisture introduced into the system respectively.
From Table 19, the influences of the investigated variables on the amount of ASA
degradation (YASA) were fitted to Equation (25). After fitting of the observed data, the
regressed equation (R2 = 0.877) below was obtained. The constant term and
coefficients of the inlet air temperature term (Xheat) and binder spray rate term (Xmoisture)
were found to have a level of significance of p < 0.001. The coefficient of the AAI
term (XAAI) was found have a p value of more than 0.05 and hence suggested that this
variable had no significant influence on ASA stability.
YASA = 5.55 + 0.00764XAAI – 0.0938Xheat + 0.129Xmoisture (31)
161
Table 19. Influence of variables on processing conditions, granule properties and amount of ASA degradation in PG.
AAI Inlet air Binder Capacity for Residual moisture

Process drying Amount of ASA
diameter temperature spray rate moisture MMD (µm) Span content
efficiency (%) degradation (%)
(mm) (°C) (g/min) removal (g/min) (%, w/w)
24 60 22 90.4 (1.2) 21.0 (0.2) 423 (19) 1.44 (0.10) 0.19 (0.09) 2.91 (0.09)
30 60 22 93.1 (2.8) 21.3 (1.3) 546 (44) 1.42 (0.12) 0.25 (0.08) 2.82 (0.02)
35 60 22 96.8 (2.9) 22.6 (1.4) 627 (6) 1.78 (0.05) 0.08 (0.08) 3.04 (0.04)
35 65 22 98.8 (0.9) 23.7 (0.7) 513 (25) 1.67 (0.16) 0.21 (0.07) 2.78 (0.35)
35 70 22 100.4 (2.5) 27.4 (1.3) 532 (10) 1.70 (0.05) 0.20 (0.13) 2.07 (0.18)
35 75 22 101.0 (2.4) 30.6 (0.1) 500 (15) 1.61 (0.06) 0.27 (0.05) 1.63 (0.00)
35 80 22 102.8 (1.8) 43.4 (1.2) 450 (22) 1.58 (0.17) 0.22 (0.04) 0.86 (0.05)
35 80 25 101.9 (1.3) 36.4 (2.2) 493 (13) 1.56 (0.04) 0.28 (0.08) 1.82 (0.14)
35 80 28 100.2 (1.6) 30.9 (0.9) 538 (46) 1.69 (0.10) 0.27 (0.09) 2.31 (0.10)
35 80 31 92.3 (3.4) 28.7 (0.5) 620 (79) 1.70 (0.09) 0.19 (0.12) 2.30 (0.16)
35 80 34 86.3 (1.2) 31.8 (1.8) 658 (60) 1.62 (0.06) 0.31 (0.09) 2.76 (0.23)
35 80 37 82.2 (3.5) 31.5 (2.0) 717 (85) 1.50 (0.12) 0.32 (0.08) 2.88 (0.37)
162
Values in parentheses denote inter-batch standard deviation.
D2.1. Influence of AAI diameter
AAI diameter was found not to have significant effect on the amount of ASA
degradation. As shown in Table 20, the usage of different diameters of AAI (24, 30
and 35 mm) resulted in the variation of air velocity through the partition column and
the time taken to transit through the spray granulation and drying zones. The spray
granulation zone and drying zone were estimated to be 15 cm and 30 cm in length
respectively for the calculations of transit time.
Table 20. Influence of AAI diameter on air velocity and transit time.
AAI Transit time through
Air velocity through Transit time through
diameter spray granulation zone
partition column (m/s) drying zone (ms)
(mm) (ms)
24 33.7 (0.0) 4.5 (0.0) 11.9 (0.0)
30 27.8 (0.1) 5.4 (0.0) 14.4 (0.0)
35 17.3 (0.1) 8.7 (0.0) 23.1 (0.0)

Air velocity within the partition column was averaged across airflow rates of 50, 60, 70, 80, 90, 100
and 110 m3/h. Values in parentheses denote standard deviation among independent runs.
When the diameter of AAI was increased, the longer transit through the spray
granulation zone allowed more time for wetting and increased opportunities for
granule growth. Larger MMD values were hence observed (Table 19). AAI was also
observed to influence the efficiency of moisture removal at the drying zone, as seen
from the higher process drying efficiencies observed (Table 19). Drying of these
wetted granules was improved owing to the slower transit through the drying zone
with usage of AAIs of larger diameters. Therefore, even though wetter conditions
were created when AAIs of larger diameters were used, it did not affect ASA stability.
This accounted for the insignificance of this variable in Equation (31).
163
D2.2. Influence of inlet air temperature
Equation (31) derived indicated an inverse relationship between the amount of heat in
the drying air introduced into the system and the amount of ASA degradation,
whereby an increase in inlet air temperature decreased the amount of ASA
degradation. The results shown in Table 19 also suggested that when inlet air
temperature was increased while AAI diameter and binder spray rate were kept
constant, it caused corresponding increases in process drying efficiencies and
capacities for moisture removal. These increases suggested that a higher amount of
moisture could be removed from the system per unit time.
As a consequence of the higher inlet air temperatures employed, the water saturation
pressures of the drying air was increased and a more efficient rate of mass transfer of
moisture from the wetted granules to the air occurred. This increase in drying kinetics
with usage of increased temperature of the inlet air had been previously reported
(Senadeera et al., 2003; Miranda et al., 2009). When more heat was introduced into
the system with higher temperatures, the capacity for moisture removal during
granulation increased and a more rapid removal of moisture from the wetted granules
was possible. This reduced opportunities for the wetted powder particles to
agglomerate and smaller granules were formed (Table 19). Another contributing
reason to the smaller size granules seen might also be the more pronounced attrition
effect at the annular down flow bed as the dry conditions failed to produce strong
agglomerates. Nonetheless, the more rapid and efficient removal of moisture with the
use of higher inlet air temperature promoted ASA stability and the amount of ASA
degradation markedly decreased (Table 19).
164
D2.3. Influence of binder spray rate
On the other hand, the reverse was found for binder spray rate. When the rate of
moisture introduction into the system was increased while AAI diameter and inlet air
temperature remained unchanged, it was found to be detrimental to ASA stability.
This was indicated by the positive coefficient of the binder spray rate term in
Equation (31). An increasing amount of ASA degradation was observed when the
liquid binder was sprayed at a faster rate (Table 19) and this was caused by the
additional moisture stress introduced into the system. As the system was unable to
cope with the additional moisture stress introduced under similar drying conditions,
corresponding reductions in process drying efficiencies resulted.
Higher binder spray rates reduced overall processing times and the change would be
advantageous for ASA stability. However findings from the present study indicated
that the additional moisture stress introduced by the higher binder spray rates
counteracted the advantages conferred by the shorter processing times needed. When
binder spray rate was increased, the capacity for moisture removal during granulation
was compromised from 43.4 g/min to a stable level of approximately 31 g/min. This
indicated that the maximum rate of moisture removal that the system could attain was
approximately 31 g/min. Therefore excess moisture was introduced into the system
was more than what it could be removed when binder spray rates of 34 and 37 g/min
were used. This resulted in larger granules and an undesirable increase in the amount
of ASA degradation (Table 19).
From Equation (31), it can be inferred that ASA degradation in the PG process
depended on the balance between the amount of heat and moisture introduced into the
165
system. Binder spray rate should be optimized to be as high as can be achieved (with
concurrent employment of high inlet air temperature) without compromising the
process drying efficiency of the system. Thus, a finely balanced granulation process
will provide optimized conditions and minimize the adverse conditions for
granulation of a moisture sensitive drug. The spray rate of liquid binder should always
be adjusted to balance the capacity of the conditions set for moisture removal so as
not to produce an unduly wet process (a condition detrimental to the stability of ASA)
and for a successful granulation run.
Clearly, use of higher inlet air temperatures in the PG process was beneficial by the
higher capacities for moisture removal. Therefore, between heat and moisture, the
amount of moisture present during the process was probably the major factor that
caused ASA degradation. Nevertheless, the amount and extent of heat exposure was
also important for hydrolytic breakdown, and the desirable manner in which heat was
“targeted” at removing moisture from the wetted particles in PG was advantageous for
minimizing degradation of moisture sensitive drugs.
166
PART V:
CONCLUSION
167
Conclusion
V. CONCLUSION
From the results of the factorial study, the dominating influence of fluid dynamics on
granule growth in PG was established. The size and shape of PG granules were
observed to be significantly influenced by AAI diameter and partition gap. Critically,
a larger AAI diameter reduced air velocity through the spray granulation zone. The
increased residence time of powder particles at the spray granulation zone hence gave
rise to granule batches of larger mean size. The partition gap regulated particle entry
into the spray granulation zone and affected process yields. An optimal partition gap
was found to be important to obtain high process yields and highly spherical granules.
It was observed that granule shape was also affected when different wetting
conditions were created by various liquid binder spray rates. An increase in wetting
resulted in the formation of granules that were more spherical.
The strong influence of fluid dynamics on granule growth in PG was further
supported by the findings from a comparative study of PG and conventional TG
where investigations examined the influence of binder spray rate on granule
properties. A relative insensitivity of growth in PG to wetting was observed, and
granule size characteristics of granule batches were interestingly shown to be
relatively unaffected by changes in binder spray rate within the conditions
investigated. In comparison, growth in conventional TG was shown to be less robust
towards wetting, where an increase in binder spray rate resulted in the formation of
higher amounts of lumps and larger granules. Unlike the conventional process,
granule growth in PG is mainly dependent on the system’s fluid dynamics. Flexible
control of granule size, shape and flow in PG is therefore possible with its unique
fluid dynamics that can be easily modulated.
168
Conclusion
Owing to the more ordered particle circulation pattern in PG, distinct phases of
wetting, growth and drying were present in each cycle. This led to layered growth as
liquid binder layers formed and solidified around particle surfaces. TG granules
formed preferentially by solidification of liquid bridges between particles due to the
more random particle circulation pattern and indistinct stages of wetting, growth and
drying. This mode of growth in TG gave rise to poorer drug content uniformity in
smaller sized TG granules and thus, poorer overall weighted batch drug content
uniformity during the spray deposition of a low dose, poorly soluble micronized drug.
Binder spray rate and feed material characteristics were found to influence the granule
drug content uniformity of smaller sized TG granules whereas PG granules were
relatively unaffected by changes in these variables.
Due to the layered mode of growth in PG and the presence of shear force at the spray
granulation zone that aided coalescence and consolidation, the granules formed were
found to be generally less porous and more spherical than TG granules. Thus, PG
granules exhibited better flow and a denser die filling during tabletting. Differing
compaction behaviour between the two types of granules were hence seen, in which
PG granules were observed to rearrange less and yielded more readily through plastic
deformation during the volume reduction process. This resulted in PG tablets of
slightly higher tensile strength. Generally, the tablets produced using both PG and TG
granules had similar characteristics but consideration of their differences in granule
properties and compaction behaviour should be given when used with certain
disintegrants.
169
Conclusion
The highly ordered circulation pattern and unique fluid dynamics in PG processing
was also found to confer a greater advantage on the stability of moisture sensitive
drugs over conventional TG. The granulation process could be carried out rapidly by
the employment of a high inlet air temperature and a high binder spray rate in PG,
achieving a reduction in processing time and less processing stress on drug stability.
A lower amount of drug degradation was found in PG granules containing ASA in
contrast to TG granules, whereby usage of high inlet air temperature and high binder
spray rate were shown to instead cause more drug degradation. Using the derived
equation for ASA degradation, it can be inferred that drug degradation in the PG
process depended on the heat and moisture introduced into the system, whereas the air
velocity of the drying air played a less influential role. A high inlet air temperature
should be employed to promote moisture removal while binder spray rates should be
concurrently optimized as high as possible to minimize moisture contact time and
drug degradation, without compromising process drying efficiency.
In conclusion, this study demonstrated consistent and generally better drug content
uniformity in PG granules that were spray deposited with a drug. Reduced
degradation of a moisture sensitive drug was also found in PG granules. Therefore the
PG process may potentially be applied for (i) spray deposition of a low dose, poorly
soluble drug and (ii) wet granulation of a moisture sensitive drug. Additionally, the
PG process was shown to be an attractive alternative to the conventional TG process
with greater process control capability and resultant granules with comparable
tabletting properties as those of TG.
170
PART VI:
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Zhao, N., Augsburger, L.L., 2005. The influence of swelling capacity of
superdisintegrants in different pH media on the dissolution of hydrochlorothiazide
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208
References
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209
PART VII:
LIST OF PUBLICATIONS
210
List of publications
VII. LIST OF PUBLICATIONS
Journal publications
1. Liew, C.V., Er, D.Z.L., Heng, P.W.S., 2009. Air-dictated bottom spray process:
Impact of fluid dynamics on granule growth and morphology. Drug Dev. Ind.
Pharm. 35(7), 866-876.
2. Er, D.Z.L., Liew, C.V., Heng, P.W.S., 2009. Layered growth with bottom-spray
granulation for spray deposition of drug. Int. J. Pharm. 377(1-2), 16-24.
Conference presentations
1. Er, D.Z.L., Liew, C.V., Heng, P.W.S. A comparative study on the compactibility
of granules prepared by bottom-spray and top-spray granulation. Poster
presentation. American Association of Pharmaceutical Scientists (AAPS) Annual
Meeting and Exposition 2009, 8th to 12th November 2009, Los Angeles, California,
USA.
2. Er, D.Z.L., Liew, C.V., Heng, P.W.S. Air-dictated bottom spray process for
granulation of moisture sensitive drugs. Oral presentation. ASEAN Scientific
Conference in Pharmaceutical Technology 2008, 1st to 3rd June 2008, Penang,
Malaysia.
3. Er, D.Z.L., Liew, C.V., Heng, P.W.S. A study on granule growth behaviour in top
and bottom fluidized bed granulations. Poster presentation. Asian Association of
Colleges of Pharmacy (AASP) Conference 2007, 25th to 28th October 2007, Makati
City, Philippines.
211
List of publications
4. Ng, Y., Er, D.Z.L., Liew, C.V., Heng, P.W.S. Influence of the characteristics of
starting material on fluidized bed granules properties. Poster presentation. 2nd
AAPS-NUS Student Chapter Symposium, 5th March 2007, Singapore.
5. Er, D.Z.L., Liew, C.V., Heng, P.W.S. Precision granulation: a promising bottom
spray fluid bed granulation process. Poster presentation. Asian Pharmaceutics
Graduate Congress, 25th to 27th September 2006, Singapore.
6. Er, D.Z.L., Liew, C.V., Heng, P.W.S. A comparative study of the influence of fluid
dynamics and thermodynamics on the properties of granules prepared by precision
granulation. Poster presentation. American Association of Pharmaceutical
Scientists (AAPS) Annual Meeting and Exposition 2006, 29th October to 2nd
November 2006, San Antonio, Texas, USA.
7. Er, D.Z.L., Liew, C.V., Heng, P.W.S. Cocurrent and countercurrent binder spray
orientation on growth kinetics in fluid bed granulation processes. Poster
presentation. Asian Association of Colleges of Pharmacy (AASP) Conference
2005, 14th to 17th November 2005, Bangkok, Thailand.
212

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A STUDY ON BOTTOM-SPRAY GRANULATION AND

ITS POTENTIAL APPLICATIONS

ER ZHI LIN DAWN

NATIONAL UNIVERSITY OF SINGAPORE

ITS POTENTIAL APPLICATIONS

ER ZHI LIN DAWN

FOR THE DEGREE OF DOCTOR OF PHILOSOPHY

NATIONAL UNIVERSITY OF SINGAPORE

during the course of my study.

technologists during my course of study for their technical assistance.

For my parents, Chin Lam and Hwee Kiang

DEDICATION ............................................................................................................. iii

TABLE OF CONTENTS .............................................................................................. iv

LIST OF TABLES .......................................................................................................xii

LIST OF FIGURES .................................................................................................... xiv

LIST OF SYMBOLS .................................................................................................xvii

A1. Significance of granulation ......................................................................... 2

A2. Types of granulation ................................................................................... 4

A2.1. Dry granulation processes ................................................................... 4

A2.2. Wet granulation processes ................................................................... 5

B. FLUIDIZED BED GRANULATION ............................................................... 9

B1. Techniques of spray .................................................................................. 11

B2. Advantages and challenges ....................................................................... 14

B3.1. Material related factors ...................................................................... 17

B3.2. Process related factors during the liquid binder addition

phase ............................................................................................... 20

C. RECENT ADVANCES IN FLUIDIZED BED GRANULATION ................ 25

C1.1. Moisture content ................................................................................ 26

C1.2. Particle size ........................................................................................ 27

C1.3. Composition of bed material ............................................................. 28

C1.4. Solid state transformations ................................................................ 28

C2. Fluidized bed granulation methods ........................................................... 29

C2.1. Fluidized bed melt granulation .......................................................... 29

C2.2. Fluidized bed binderless granulation ................................................. 31

C2.3. Bottom-spray granulation .................................................................. 32

II. HYPOTHESIS AND OBJECTIVES .............................................................. 40

A. HYPOTHESIS ................................................................................................ 40

B. OBJECTIVES ................................................................................................. 41

III. EXPERIMENTAL ......................................................................................... 44

A. MATERIALS .................................................................................................. 44

A1. Feed material ............................................................................................. 44

A2. Liquid binder ............................................................................................. 44

A3. Model drugs .............................................................................................. 44

A4. Tablet excipients ....................................................................................... 45

A5. Chemicals for dissolution media preparation and high

performance liquid chromatography (HPLC) analyses ............................. 46

B. METHODS ..................................................................................................... 47

B1. Feed material ............................................................................................. 47

B1.1. Blending of powder ........................................................................... 48

B1.2. Determination of powder particle size ............................................... 48

B1.3. Determination of powder flow with angle of repose ......................... 48

B2. Liquid binder ............................................................................................. 49

B2.1. Micronization of HCT ....................................................................... 49

B2.2. Determination of particle size of micronized HCT ........................... 50

B2.3. Preparation of HCT-incorporated liquid binder ................................ 50

B3. Granulation process ................................................................................... 50

B3.1. Real-time measurement of process conditions .................................. 52

B3.2. Determination of process drying efficiency ...................................... 54

B3.3. Determination of granule bed temperature profiles ........................... 54

B3.4. Determination of capacity for moisture removal ............................... 55

B3.5. Determination of granule bed moisture content profiles ................... 55

B3.6. Determination of air velocity within partition column ...................... 56

B3.7. Determination of process yield .......................................................... 56