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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

d50 particle diameter at the 50 percentile of the cumulative percent


undersize plot

d90 particle diameter at the 90 percentile of the cumulative percent


undersize plot

d99 particle diameter at the 99 percentile of the cumulative percent


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


response surface equation

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


response surface equation

xix
List of symbols

XAS interaction term (air accelerator insert × binder spray rate) in


response surface equation

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


response surface equation

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
Hypothesis and objectives

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
Hypothesis and objectives

(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
Results and discussion – Part A

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
Results and discussion – Part A

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
Results and discussion – Part A

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
Results and discussion – Part A

(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
Results and discussion – Part A

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
Results and discussion – Part A

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.
Results and discussion – Part A

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.
Results and discussion – Part A

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.
Results and discussion – Part A

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 (-).
Results and discussion – Part A

82
Results and discussion – Part A

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
Results and discussion – Part A

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
Results and discussion – Part A

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
Results and discussion – Part A

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
Results and discussion – Part A

(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
Results and discussion – Part A

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
Results and discussion – Part A

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
Results and discussion – Part A

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
Results and discussion – Part A

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
Results and discussion – Part A

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
Results and discussion – Part A

(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
Results and discussion – Part A

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
Results and discussion – Part A

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
Results and discussion – Part B

(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
Results and discussion – Part B

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
Results and discussion – Part B

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
Results and discussion – Part B

(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
Lactose powder blend

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
Results and discussion – Part B

(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
Lactose powder blend

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
Results and discussion – Part B

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
Results and discussion – Part B

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
Results and discussion – Part B

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
Results and discussion – Part B

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
Results and discussion – Part B

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
Results and discussion – Part B

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.


Results and discussion – Part B

108
Results and discussion – Part B

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
Results and discussion – Part B

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
Results and discussion – Part B

(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
Results and discussion – Part B

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
Results and discussion – Part B

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)


Values in parentheses denote inter-batch standard deviations.

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
Results and discussion – Part B

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
Results and discussion – Part B

Lactose powder blend

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)

Values in parentheses denote inter-batch standard deviations.


Results and discussion – Part B

116
Results and discussion – Part B

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
Results and discussion – Part B

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)


Values in parentheses denote inter-batch standard deviations.

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
Results and discussion – Part B

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
Results and discussion – Part C

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
Results and discussion – Part C

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.
Results and discussion – Part C

123
Results and discussion – Part C

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
Results and discussion – Part C

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
Results and discussion – Part C

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
Results and discussion – Part C

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
Results and discussion – Part C

PG tablets TG tablets

(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
Results and discussion – Part C

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
Results and discussion – Part C

(a)

16000

12000
Ra (nm)

8000

4000

0
0 20 40 60 80 100 120 140 160
Compaction pressure (MPa)

(b)
20000

16000

12000
Rq (nm)

8000

4000

0
0 20 40 60 80 100 120 140 160
Compaction pressure (MPa)

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
Results and discussion – Part C

PG tablets TG tablets
(a) (b)
Ra: 12320 nm, Rq: 16890 nm Ra: 14780 nm, Rq: 18560 nm

13 MPa

(c) (d)
Ra: 7660 nm, Rq: 10280 nm Ra: 10080 nm, Rq: 12770 nm

25 MPa

(e) (f)
Ra: 6120 nm, Rq: 8330 µm Ra: 7060 nm, Rq: 9800 nm

38 MPa

(g) (h)
Ra: 5260 nm, Rq: 7520 nm Ra: 6560 nm, Rq: 9500 nm

51 MPa

Figure 25. Three-dimensional plots of micro-surfaces (taken at 20.64 × magnification)


of PG and TG tablets.

131
Results and discussion – Part C

PG tablets TG tablets
(i) (j)
Ra: 4260 nm, Rq: 6030 nm Ra: 4830 nm, Rq: 6230 nm

76 MPa

(k) (l)
Ra: 3330 nm, Rq: 5003 nm Ra: 3630 nm, Rq: 5260 nm

102 MPa

(m) (n)
Ra: 2480 nm, Rq: 3520 nm Ra: 2520 nm, Rq: 3540 nm

127 MPa

(o) (p)
Ra: 2120 nm, Rq: 2940 nm Ra: 2390 nm, Rq: 3550 nm

153 MPa

Figure 25 (continued). Three-dimensional plots of micro-surfaces (taken at 20.64 ×


magnification) of PG and TG tablets.

132
Results and discussion – Part C

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
Results and discussion – Part C

45

40

35
Tablet porosity (%)

30

25

20

15

10
0 20 40 60 80 100 120 140 160
Compaction pressure (MPa)

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
Results and discussion – Part C

3.5

2.5
Tensile strength (N/mm2 )

1.5

0.5

0
0 20 40 60 80 100 120 140 160
Compaction pressure (MPa)

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
Results and discussion – Part C

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 (▲).
Results and discussion – Part C

137
Results and discussion – Part C

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
Results and discussion – Part C

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.
Results and discussion – Part C

140
Results and discussion – Part C

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
Results and discussion – Part C

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
Results and discussion – Part C

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
Results and discussion – Part C

144
Results and discussion – Part C

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.
Results and discussion – Part C

146
Results and discussion – Part C

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
Results and discussion – Part C

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
Results and discussion – Part C

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
Results and discussion – Part D

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.


Results and discussion – Part D

152
Results and discussion – Part D

(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
Results and discussion – Part D

(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
Results and discussion – Part D

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
Results and discussion – Part D

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
Results and discussion – Part D

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
Results and discussion – Part D

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
Results and discussion – Part D

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
Results and discussion – Part D

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
Results and discussion – Part D

“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)
Results and discussion – Part D

162
Values in parentheses denote inter-batch standard deviation.
Results and discussion – Part D

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
Results and discussion – Part D

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
Results and discussion – Part D

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
Results and discussion – Part D

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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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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