Study on the recovery of post compaction matrices

i


STUDY ON THE RECOVERY OF
POST-COMPACTION MATRICES




TAN BING XUN
(B.Sc. (Pharm.)(Hons.), NUS)




A THESIS SUBMITTED
FOR THE DEGREE OF DOCTOR OF PHILOSOPHY
DEPARTMENT OF PHARMACY
NATIONAL UNIVERSITY OF SINGAPORE

2014
ii

i




DECLARATION

I hereby declare that this thesis is my original work and it has been written by me in

its entirety. I have duly acknowledged all the sources of information which have been
used in the thesis.

This thesis has also not been submitted for any degree in any university previously.



_________________________
Tan Bing Xun
01 Aug 2014
ii

ACKNOWLEDGEMENTS

I would like to express my heartfelt gratitude to my supervisor, Assistant Professor
Celine Valeria Liew for her guidance, support and encouragement throughout my
candidature. I am similarly indebted to Associate Professor Paul Heng for his
leadership, ideas and advice during my time under his care in the laboratory. I would
also like to thank Associate Professor Chan Lai Wah and Associate Professor TRR
Kurup for their guidance of my research and thesis.
In addition, I am grateful to the Department of Pharmacy, Faculty of Science and
National University of Singapore for their generous research scholarship and
administrative support.
My special appreciation to Mrs. Teresa Ang and Ms. Wong Mei Yin for their
invaluable advice and technical assistance during the course of my candidature. I
would also like to acknowledge Dr. Wang Likun, Dr. Loh Zhi Hui, Dr. Christine
Cahyadi, Dr. Srimanta Sarkar, Ms. Lim Pei Qi and Mr. Goh Hui Ping for their
valuable contributions to this research.
To my dear co-workers in GEA-NUS PPRL, Professor Lucy Wan and other GEA-
NUS PPRL alumni whom I have had the pleasure of meeting during the course of my

candidature, I greatly treasure your friendship and companionship. Our shared
moments are precious memories that I will always keep close to my heart.
Finally, I wish to thank my parents, my sisters and Shu Fang for their love, faith,
support and understanding. I share the joy of this hard-earned personal milestone with
all of you.

With gratitude,
Bing Xun
2014
iii

TABLE OF CONTENTS
DECLARATION i
ACKNOWLEDGEMENTS ii
TABLE OF CONTENTS iii
SUMMARY x
LIST OF TABLES xii
LIST OF FIGURES xiv
LIST OF SYMBOLS AND ABBREVIATIONS xix
1 INTRODUCTION 2
1.1 Pharmaceutical tablet manufacture 3
1.1.1 Tablet compaction process 4
1.1.2 Commercial production of pharmaceutical tablets 6
1.1.3 Excipients used in tablet formulations 8
1.1.4 Equipment used in tablet manufacture 9
1.1.5 Batch and continuous manufacture of tablets 12
1.2 Recovery of tablets 13
1.2.1 Immediate recovery and latent recovery 13
1.2.2 Mechanism of tablet recovery 14
1.3 Latent recovery of post-compaction matrices 15

1.3.1 Effects of latent recovery 15
1.3.2 Factors affecting latent recovery 19
iv

1.3.2.1 Formulation variables affecting latent recovery 19
1.3.2.2 Non-formulation variables affecting latent recovery 25
1.3.3 Characterization of tablet latent recovery 29
1.3.4 Instruments used for measurement of tablet dimensions in evaluation of
tablet latent dimensional recovery 30
1.4 Research gaps in evaluation of tablet latent recovery 34
1.4.1 Characterization of tablet latent recovery through tablet dimensions 35
1.4.2 Mathematical models for analysis of tablet dimensional data 36
1.4.3 Latent recovery of compacted mixtures of excipients 37
1.4.4 Influence of tablet geometry on tablet latent recovery 38
2 HYPOTHESES AND OBJECTIVES 41
3 MATERIALS AND METHODS 45
STUDY A: Development of laser triangulation as a profiling tool for monitoring
dimensional changes in post-compaction matrices 45
3A.1 Preparation of model pharmaceutical Lactose tablets 47
3A.2 Hardware development of the laser profiler 48
3A.3 Data acquisition and processing 51
3A.3.1 Axial profiling 51
3A.3.2 Radial profiling 54
3A.4 Characterization of tablets 54
3A.4.1 Weight 54
3A.4.2 Breaking force 54
v

3A.4.3 Height and diameter 55
3A.5 Statistical analysis 56

STUDY B: Impact of storage temperature and RH conditions on the
physicomechanical properties of post-compaction matrices over time 57
3B.1 Preparation of tablets 57
3B.2 Control of storage conditions 59
3B.3 Characterization of tablets 60
3B.3.1 Height and diameter 60
3B.3.2 Weight 60
3B.3.3 Tensile strength 61
3B.3.4 Disintegration time 61
3B.3.5 Loss on drying 61
3B.4 Evaluation of changes in tablet physicomechanical properties 62
3B.5 Statistical analysis 65
STUDY C: Recovery of post-compaction matrices prepared from multi-component
formulations 66
3C.1 Preparation and blending of excipients 66
3C.2 Preparation of tablets 68
3C.3 Tablet dimensions 68
3C.4 Poisson's ratio 68
3C.5 Tensile strength 69
3C.6 Statistical analysis 69
vi

STUDY D: A line method to evaluate impact of tablet geometry and compression
pressure on recovery of post-compaction matrices 71
3D.1 Duration of material equilibration 71
3D.2 Part 1: Tablet production using a manual single-station press 72
3D.3 Part 2: Tablet production using a motorized rotary multi-station press . 75
3D.4 Characterization of tablets 77
3D.4.1 Height 77
3D.4.2 Weight and breaking force 77

3D.4.3 Loss on drying 77
3D.5 Development of line method for analysis of corrected tablet profiles 78
3D.6 Percentage change in breaking force 80
3D.7 Statistical analysis 80
4 RESULTS AND DISCUSSION 83
STUDY A: Development of laser triangulation as a profiling tool for monitoring
dimensional changes in post-compaction matrices 83
4A.1 Acquisition and processing of data from laser profiler 83
4A.2 Verifying accuracy and precision of the laser profiler 86
4A.2.1 Evaluation of non-deforming aluminum studs 89
4A.2.2 Evaluation of potentially deforming Lactose tablets 90
4A.3 Summary 93
STUDY B: Impact of storage temperature and RH conditions on the
physicomechanical properties of post-compaction matrices over time 94
vii

4B.1 Overview of changes in tablet physicomechanical properties 94
4B.2 Tablet volume and tensile strength 95
4B.2.1 Alternative data handling method and modeling for Δ volume and Δ
TS 95
4B.2.2 Effect of storage conditions on volume and TS of MCC tablets 99
4B.2.3 Effect of storage conditions on volume and TS of PGS tablets 104
4B.2.4 Effect of storage conditions on volume and TS of Lactose tablets 108
4B.3 Effects of storage conditions on DT of tablets 111
4B.4 Implications of results 114
4B.5 Summary 115
STUDY C: Recovery of post-compaction matrices prepared from multi-component
formulations 116
4C.1 Time-dependent changes in tablet height 116
4C.1.1 Excipient effect on Δ height 116

4C.1.2 Effect of compression force on Δ height 124
4C.2 Time-dependent changes in tablet diameter 124
4C.2.1 Excipient effect on Δ diameter 130
4C.2.2 Effect of compression force on Δ diameter 132
4C.3 Poisson's ratio 133
4C.4 Change in tablet TS 138
4C.5 Summary 141
viii

STUDY D: A line method to evaluate impact of tablet geometry and compression
pressure on recovery of post-compaction matrices 142
4D.1 Part 1: Tablet production using a manual single-station press 142
4D.1.1 Effects of tablet geometry and compression pressure on Δ height 142
4D.1.2 Effects of tablet geometry and compression pressure on Δ AUC of
corrected tablet profiles 144
4D.1.3 Effects of tablet geometry and compression pressure on SS
Ht
and
SS
AUC
148
4D.1.4 Effects of tablet geometry and compression pressure on changes in
tablet breaking force 152
4D.1.5 Relationship between changes in axial dimensions and breaking force
154
4D.2 Part 2: Tablet production using a motorized rotary multi-station press154
4D.2.1 Effects of tablet geometry and compression pressure on Δ height 154
4D.2.2 Effects of tablet geometry and compression pressure on Δ AUC of
corrected tablet profiles 156
4D.2.3 Effects of tablet geometry and compression pressure on SS

Ht
and
SS
AUC
160
4D.2.4 Effects of tablet geometry and compression pressure on changes in
tablet breaking force 162
4D.2.5 Relationship between changes in axial dimensions and breaking force
162
4D.3 Summary 164
ix

5 CONCLUSION 166
6 BIBLIOGRAPHY 171


x

SUMMARY
Evaluation of recovery in post-compaction matrices involves characterization of
changes in compact physicomechanical properties over time. This research work
addressed the need to develop suitable tools and methods for monitoring dimensional
changes in post-compaction matrices. Laser-optical sensors, which operate on laser
triangulation principles, were successfully employed in a setup that was developed
and used to measure and profile time-dependent height and diameter changes in
multiple compact samples simultaneously. The non-contact, semi-automatic, quasi-
continuous performance of the laser profiler was equivalent, if not preferable, to
conventional contact measurement tools in terms of accuracy and functionality.
Changes in tablet dimensions and tensile strength were observed to follow 4 distinct
hyperbolic models when plotted against time. Based on these models, the quantitative

parameters of the steady state value, SS
response
, and the time taken after tablet ejection
to attain 50% of SS
response
in the hyperbola/hyperbolic decay phase, t50
response
, were
derived and used for statistical comparison. In further analysis of the tablets' axial
dimensional data obtained from the laser profiler, a line method was proposed to
elucidate the homogeneity of axial dimensional changes across a tablet surface.
Non-formulation variables affecting recovery in post-compaction matrices such as
storage temperature and relative humidity conditions, compression force, tablet press
type and tablet geometry were investigated in compacts produced from both binary
and multi-component formulations of common pharmaceutical excipients. A complex
relationship was revealed which underlined several important considerations when
reviewing and comparing data of tablet recovery.
xi

Overall, this research work provided analytical tools and highlighted key
considerations in the study of recovery in post-compaction matrices. The knowledge
gained will be invaluable in troubleshooting potential issues that can arise from
continuous pharmaceutical manufacturing.
xii

LIST OF TABLES
Table 1. Model Lactose tablets produced to three levels of hardness. 46
Table 2. The respective true densities of materials and targeted weights of tablets. 59
Table 3. Sampling frequency for tablet characterization. 60
Table 4. LOD conditions as specified in BP for the respective excipients. 62

Table 5. Excipients evaluated in study on latent recovery of multi-component tablets.
67
Table 6. Mean LOD results for the excipients in powder form at different time
intervals. 72
Table 7. Factor combinations in Part 1 (using manual single-station press) 74
Table 8. Factor combinations used in Part 2 (using motorized rotary multi-station
press). 76
Table 9. Physical characteristics of the three batches of model tablets manufactured.
90
Table 10. Measurements of tablet height and diameter made by the laser-optical
sensors (L
1
) and the micrometer screw gauge (M). 91
Table 11. Measurements of tablet height and diameter made by the laser-optical
sensors before (L
1
) and after (L
2
) use of the micrometer screw gauge. 92
Table 12. Model-fits proposed for Δ volume of MCC tablets under the respective
storage conditions. 100
Table 13. Model-fits proposed for Δ TS of MCC tablets under the respective storage
conditions. 100
Table 14. Model-fits proposed for Δ volume of PGS tablets under the respective
storage conditions. 104
Table 15. Model-fits proposed for Δ TS of PGS tablets under the respective storage
conditions. 105
Table 16. Model-fits proposed for Δ TS of Lactose tablets under the respective
storage conditions. 109
Table 17. Time required to reach steady state in Δ DT (tSS

DT
). 111
Table 18. Mean tablet TS and mean percentage change in TS of tablets compacted
from each formulation using three compression forces. 139
xiii

Table 19. Mean SS
Ht
and SS
AUC
values for tablets compacted from each factor
combination using the manual single-station press. 149
Table 20. Mean tablet breaking force at different time intervals and percentage
change in mean tablet breaking force over 24-hour period for tablets compacted from
each factor combination using the manual single-station press. 153
Table 21. Mean SS
Ht
and SS
AUC
values for tablets compacted using the motorized
rotary multi-station press for each factor combination. 161
Table 22. Mean tablet breaking force at different time intervals and percentage
change in mean tablet breaking force over 24-hour period for tablets compacted from
each factor combination using the motorized rotary multi-station press. 163

xiv

LIST OF FIGURES
Fig. 1. Typical secondary manufacture process of tablets by the ( ) direct compaction
approach or ( ) wet/dry granulation approach. 7

Fig. 2. Viscoelastic behavior of a powder compact represented by Maxwell and
Voigt’s spring and dashpot mechanical model. 14
Fig. 3. Pictorial representations of the developed laser profiler showing (A) a
schematic layout and photograph of turntable and laser-optical sensors in the setup,
and (B) schematic of rotating turntable with the marker platform labeled as S0 and the
seventeen sample platforms labeled as S1 through S17; (C) Photograph of the laser
profiler enclosed within an acrylic chamber. 49
Fig. 4. Typical plots of axial data depicting the (A) raw profile, (B) baseline profile,
(C) fitted complete baseline profile, and (D) corrected tablet profile. 51
Fig. 5. Schematic representations of (A) the axial laser triangulation sensor scanning
the unloaded platform surface, and (B) top view of the radial laser triangulation sensor
scanning the tablet band surface. 53
Fig. 6. Measurement of (A) tablet height and (B) tablet diameter using the micrometer
screw gauge positioned at the points labeled by the pairs of block arrows. 55
Fig. 7. Possible general plots of (A) positive and (B) negative percentage changes in
tablet physicomechanical properties. 64
Fig. 8. Tablet geometries evaluated in Part 1 (using manual single-station press). 73
Fig. 9. Typical corrected tablet profile produced from the laser triangulation setup at a
single time point. Changes in the height and AUC of the profile, and mean "height"
within each of the twenty segments were monitored with time 79
Fig. 10. Possible plots of Δ height and Δ AUC. SS
Ht
and SS
AUC
for each tablet were
extrapolated from the plateau 79
Fig. 11. Collected (A) axial; and (B) radial profiles of aluminum studs loaded on the
turntable platforms, where the studs are represented by the seventeen troughs, S1
through S17, located between two marker troughs, S0. (C) Axial; and (D) radial
profiles collected from one stud-loaded platform, where the measured corresponding

sections i through v are graphically represented in schematic (E) 84
Fig. 12. A typical stud outline from the (A) axial direction obtained by subtracting the
blank profile from the stud profile of a single platform as illustrated by the dashed
arrow path in schematic (B). A typical stud outline from the (C) radial direction
obtained by subtracting the blank profile from the stud profile of a single platform as
illustrated by the dashed arrow path in schematic (D) 87
Fig. 13. Measurements of mean stud height (○) and diameter (□) from the developed
setup (laser triangulation) were plotted against the corresponding mean micrometer
xv

screw gauge measurements of stud height (∆) and diameter (◊) to illustrate the
former’s precision and accuracy. 90
Fig. 14. An example of profiles showing the status of steady state attainment in (A) Δ
volume, (B) Δ TS, and (C) Δ DT of tablets stored at various temperature and RH
conditions over a period of 4 weeks after tablet ejection. 94
Fig. 15. Plots of (A) Δ volume and (B) Δ TS of MCC tablets stored over a period of 4
weeks after tablet ejection under different RH conditions: (i) < 25% RH, (ii) 43% RH,
and (iii) 75% RH, and temperature conditions: () < 5 °C, () 25 °C, () 40 °C. A
control tablet (—) was included for measurements of Δ volume. 96
Fig. 16. Plots of (A) Δ volume and (B) Δ TS of PGS tablets stored over a period of 4
weeks after tablet ejection under different RH conditions: (i) < 25% RH, (ii) 43% RH,
and (iii) 75% RH, and temperature conditions: () < 5 °C, () 25 °C, () 40 °C. A
control tablet (—) was included for measurements of Δ volume. 97
Fig. 17. Plots of (A) Δ volume and (B) Δ TS of Lactose tablets stored over a period of
4 weeks under different RH conditions: (i) < 25% RH, (ii) 43% RH, and (iii) 75%
RH, and temperature conditions: () < 5 °C, () 25 °C, () 40 °C. A control tablet
(—) was included for measurements of Δ volume. 98
Fig. 18. Diagrammatic representation of (A) monophasic hyperbola model Ia: two
parameter single hyperbola; (B) monophasic hyperbolic decay model Ib: three
parameter hyperbolic decay; (C) biphasic hyperbola model IIa: initial linear decrease

followed by three parameter single hyperbola; and (D) biphasic hyperbolic decay
model IIb: initial linear increase followed by three parameter hyperbolic decay. 99
Fig. 19. Main effects of temperature and RH on (A) SS
V
with p = 0.899 and p <
0.001* respectively; (B) t50
V
with p = 0.187 and p = 0.166 respectively; (C) SS
TS

with p < 0.001* and p < 0.001* respectively; and (D) t50
TS
with p = 0.886 and p =
0.161 respectively of MCC tablets. (*: denotes statistically significant effects) 101
Fig. 20. LOD plot of MCC tablets stored over a period of 4 weeks under different
conditions. Storage conditions: () < 5 °C, < 25% RH; () 25 °C, < 25% RH; ()
40 °C, < 25% RH; () < 5 °C, 43% RH; () 25 °C, 43% RH; () 40 °C, 43% RH;
() < 5 °C, 75% RH; () 25 °C, 75% RH; and () 40 °C, 75% RH. 102
Fig. 21. Interaction plot of temperature and RH on SS
TS
showing a statistically
significant interaction effect (p = 0.034). 103
Fig. 22. Main effects of temperature and RH on (A) SS
V
with p = 0.895 and p <
0.001* respectively; (B) t50
V
with p = 0.099 and p = 0.013* respectively; (C) SS
TS

with p = 0.175 and p = 0.017* respectively; and (D) t50
TS
with p = 0.435 and p =
0.249 respectively of PGS tablet. (*: denotes statistically significant effects) 106
Fig. 23. LOD plot of PGS tablets stored over a period of 4 weeks after tablet ejection
under different storage conditions. Storage conditions: () < 5 °C, < 25% RH; ()
25 °C, < 25% RH; () 40 °C, < 25% RH; () < 5 °C, 43% RH; () 25 °C, 43% RH;
() 40 °C, 43% RH; () < 5 °C, 75% RH; () 25 °C, 75% RH; and () 40 °C, 75%
RH 107
xvi

Fig. 24. Main effects of temperature and RH on (A) SS
TS
with p < 0.001* and p <
0.001* respectively; and (B) t50
TS
with p = 0.769 and p = 0.078 respectively of
Lactose tablets. Interaction plots of temperature and RH on (C) SS
TS
with p < 0.001*;
and (D) t50
TS
with p = 0.004*. (*: denotes statistically significant effects) 110
Fig. 25. (A) SS
DT
of (i) MCC, (ii) PGS, and (iii) Lactose tablets at respective storage
conditions. Storage temperature: ( ) < 5 °C ( ) 25 °C ( ) 40 °C. (B) Main effects
plot of (i) temperature (p < 0.001*) and RH (p < 0.001*) on SS
DT
of MCC tablets; (ii)

temperature (p = 0.003*) and RH (p = 0.001*) on SS
DT
of PGS tablets; and (iii)
temperature (p = 0.042*) and RH (p < 0.001*) on SS
DT
of Lactose tablets. (*: denotes
statistically significant effects) 113
Fig. 26. Δ height over 24 hours for (A) Lactose, (B) MCC and (C) DCP tablets
compacted with (—) 1.5 tons, (—) 2.0 tons and (—) 2.5 tons of compression force. A
(—) negative control was also included for each set of analysis. 117
Fig. 27. Δ height over 24 hours for (A) PGS, (B) corn starch and (C) tapioca starch
tablets compacted with (—) 1.5 tons, (—) 2.0 tons and (—) 2.5 tons of compression
force. A (—) negative control was also included for each set of analysis. 118
Fig. 28. Δ height over 24 hours for (A) potato starch, (B) HPMC K4M and (C)
HPMC K15M tablets compacted with (—) 1.5 tons, (—) 2.0 tons and (—) 2.5 tons of
compression force. A (—) negative control was also included for each set of analysis.
119
Fig. 29. Δ height over 24 hours for (A) PVP K25, (B) PVP K90 and (C) X-PVP XL
tablets compacted with (—) 1.5 tons, (—) 2.0 tons and (—) 2.5 tons of compression
force. A (—) negative control was also included for each set of analysis. 120
Fig. 30. Δ height over 24 hours for (A) Ac-Di-Sol, (B) SSG and (C) mannitol tablets
compacted with (—) 1.5 tons, (—) 2.0 tons and (—) 2.5 tons of compression force. A
(—) negative control was also included for each set of analysis. 121
Fig. 31. SS
HT
for all 15 formulations compacted at compression forces of ( )1.5 tons,
( )2.0 tons and ( )2.5 tons. 123
Fig. 32. Δ diameter over 24 hours for (A) Lactose, (B) MCC and (C) DCP tablets
compacted with (—) 1.5 tons, (—) 2.0 tons and (—) 2.5 tons of compression force. A
(—) negative control was also included for each set of analysis. 125

Fig. 33. Δ diameter over 24 hours for (A) PGS, (B) corn starch and (C) tapioca starch
tablets compacted with (—) 1.5 tons, (—) 2.0 tons and (—) 2.5 tons of compression
force. A (—) negative control was also included for each set of analysis. 126
Fig. 34. Δ diameter over 24 hours for (A) potato starch, (B) HPMC K4M and (C)
HPMC K15M tablets compacted with (—) 1.5 tons, (—) 2.0 tons and (—) 2.5 tons of
compression force. A (—) negative control was also included for each set of analysis.
127
xvii

Fig. 35. Δ diameter over 24 hours for (A) PVP K25, (B) PVP K90 and (C) X-PVP XL
tablets compacted with (—) 1.5 tons, (—) 2.0 tons and (—) 2.5 tons of compression
force. A (—) negative control was also included for each set of analysis. 128
Fig. 36. Δ diameter over 24 hours for (A) Ac-Di-Sol, (B) SSG and (C) mannitol
tablets compacted with (—) 1.5 tons, (—) 2.0 tons and (—) 2.5 tons of compression
force. A (—) negative control was also included for each set of analysis. 129
Fig. 37. SS
Dia
for all 15 formulations compacted at compression forces of ( )1.5 tons,
( )2.0 tons and ( )2.5 tons. 131
Fig. 38. Change in Poisson's ratio over 24 hours for (A) Lactose, (B) MCC, (C) DCP ,
(D) PGS and (E) corn starch tablets compacted at (—) 1.5 tons, (—) 2.0 tons and (—)
2.5 tons of compression force. 134
Fig. 39. Change in Poisson's ratio over 24 hours for (A) tapioca starch, (B) potato
starch, (C) HPMC K5M, (D) HPMC K15M and (E) PVP K25 tablets compacted at
(—) 1.5 tons, (—) 2.0 tons and (—) 2.5 tons of compression force. 135
Fig. 40. Change in Poisson's ratio over 24 hours for (A) PVP K90, (B) X-PVP XL, (C)
Ac-Di-Sol, (D) SSG and (E) mannitol tablets compacted at (—) 1.5 tons, (—) 2.0 tons
and (—) 2.5 tons of compression force. 136
Fig. 41. Plots of mean Δ height of tablets compacted using the manual single-station
press from each factor combination over the 24-hour period. Compression pressures:

(A) 300 MPa and (B) 150 MPa. Excipients: (i) PGS, (ii) RetaLac® and (iii) Tapioca
starch. Tablet geometries: (—) R-FFBE, (—) R-STD, (—) R-DEEP, (—) C-FFBE and
(—) C-STD. 143
Fig. 42. Plots of mean Δ AUC of tablets compacted using the manual single-station
press from each factor combination over the 24-hour period. Compression pressures:
(A) 300 MPa and (B) 150 MPa. Excipients: (i) PGS, (ii) RetaLac® and (iii) Tapioca
starch. Tablet geometries: (—) R-FFBE, (—) R-STD, (—) R-DEEP, (—) C-FFBE and
(—) C-STD. 145
Fig. 43. Surface plots of Δ segmented height profiles of round-shaped PGS tablets
compacted at 300 MPa using the manual single-station press. Tablet geometries: (A)
R-FFBE, (B) R-STD and (C) R-DEEP. Round convex tablets were likely to exhibit
uneven axial dimensional changes across the tablet surface, particularly at the edges.
147
Fig. 44. Surface plots of Δ segmented height profiles of capsule-shaped PGS tablets
compacted at 300 MPa using the manual single-station press. Tablet geometries: (A)
C-FFBE and (B) C-STD. FFBE tablets generally had more uniform axial dimensional
changes across the tablet surface than convex tablets. Convex tablets were likely to
have greater increase in axial dimensions at the edges compared to the middle region.
148
Fig. 45. Interaction plots of tablet geometry and compression pressure on (A) SS
Ht
and
(B) SS
AUC
. Excipients: (i) PGS, (ii) RetaLac® and (iii) Tapioca starch. Compression
pressures: (—) 300 MPa and (—) 150 MPa. 151
xviii

Fig. 46. Plots of mean Δ height of tablets compacted using the motorized rotary multi-
station press from each factor combination over the 24-hour period. Compression

pressures: (A) 300 MPa, (B) 200 MPa and (C) 100 MPa. Tablet geometries: (—) R-
FFBE, (—) R-STD, (—) C-FFBE and (—) C-STD. 155
Fig. 47. Plots of mean Δ AUC of tablets compacted using the motorized rotary multi-
station press from each factor combination over the 24-hour period. Compression
pressures: (A) 300 MPa, (B) 200 MPa and (C) 100 MPa. Tablet geometries: (—) R-
FFBE, (—) R-STD, (—) C-FFBE and (—) C-STD. 157
Fig. 48. Surface plots of Δ segmented height for C-FFBE tablets compacted using the
motorized rotary multi-station press. Compression pressures: (A) 300 MPa and (B)
200 MPa. Contraction of axial dimensions at the tablet edges decreased Δ AUC over
time, while Δ height remained unaffected. 158
Fig. 49. Surface plots of Δ segmented height of PGS tablets compacted at 300 MPa
using the motorized rotary multi-station press. Tablet geometries: (A) R-FFBE and
(B) R-STD. FFBE tablets showed more uniform axial dimensional changes than
convex tablets, albeit to a lesser extent than that of corresponding PGS tablets in Part
1 159

xix

LIST OF SYMBOLS AND ABBREVIATIONS
(r
A
, Ψ)
Radial coordinate and angular coordinate of the laser spot
(R,θ)
Polar coordinate of the laser spot
(r
0
, φ)
Radial coordinate and angular coordinate of the tablet center
(X, Y)

Coordinates perpendicular to the direction of Z
°C
Degree Celsius
a, b, c
Coefficients to be fitted in equation (5)
Ac-Di-Sol
Croscarmellose sodium
ANOVA
Analysis of variance
API
Active pharmaceutical ingredient
AR
Axial recovery
AUC
Area under the curve
BP
British Pharmacopoeia
C-FFBE
Capsule flat-faced bevel-edged
cm
Centimeter
C-STD
Capsule standard convex
D
Tablet diameter
d
Distance between sensor and laser spot
D
c

Diameter of tablet under maximum load
DCP
Dibasic calcium phosphate dihydrate
D
e

Diameter of ejected tablet
D
o

Tablet diameter at Time 0
DT
Disintegration time
dy
Day
xx

F
Mean breaking force
FFBE
Flat-faced bevel-edged
g
Gram
g/cm
3

Gram per cubic centimeter
H
Tablet height
H

c

Height of tablet under maximum load
H
e

Height of ejected tablet
H
o

Tablet height at Time 0
HPMC
Hydroxypropyl methylcellulose
hr
Hour
IBC
Intermediate bulk containers
i
M

Measurement index
kHz
Kilohertz
kN
Kilonewtons
l
Distance between the radial laser sensor and the center of the
turntable
L
1

Measurement by laser profiler before micrometer screw
gauge measurement
L
2

Measurement by laser profiler after micrometer screw gauge
measurement
L
3

Repeated measurement by laser profiler without micrometer
screw gauge measurement
Lactose
α-lactose monohydrate
LOD
Loss on drying
LVDT
Linear voltage displacement transducer
M
Measurement by micrometer screw gauge
MCC
Microcrystalline cellulose
xxi

mg
Milligram
MgSt
Magnesium stearate
mL

Milliliter
mm
Millimeter
mm/s
Millimeter per second
MPa
Megapascal
N
Newton
n
Sample size
NIR
Near-infrared
nm
Nanometer
PAT
Process analytical technology
PGS
Pregelatinized starch
PVP
Polyvinylpyrrolidone
QbD
Quality by design
r
Pearson correlation coefficient
R
2

Coefficient of determination
R-DEEP

Round deep convex
R-FFBE
Round flat-faced bevel-edged
RH
Relative humidity
RMSE
Root mean square error
R
o

Tablet physicomechanical property at Time 0
rpm
Revolutions per minute
RR
Radial recovery
R-STD
Round standard convex
xxii

R
x

Tablet physicomechanical property at Time x
S0
Marker platform on laser profiler
S1 to S17
Sample platforms on laser profiler
SS
AUC

Steady state value of Δ AUC
SS
Dia

Steady state value of Δ diameter
SS
DT

Steady state value of Δ DT
SSG
Sodium starch glycolate
SS
Ht

Steady state value of Δ height
SS
response

Steady state value of Δ response
SS
TS

Steady state value of Δ TS
SS
V

Steady state value of Δ volume
t50
response

Time to reach 50% of SS
response

t50
TS

Time to reach 50% of SS
TS

t50
V

Time to reach 50% of SS
V

TS
Tensile strength
tSS
DT

Time to reach SS
DT

tSS
response

Time to reach SS
response

VES

Viscoelastic strain
VR
Volumetric recovery
W
1

Weight of ground tablets before drying
W
2

Weight of ground tablets after drying
wk
Week
X-PVP
Cross-linked polyvinylpyrrolidone
Z
Distance between axial sensor and unloaded platform surface
xxiii

γ
Angular coordinate when the laser starts to reach the tablet
surface
Δ AUC
Percentage change in area under the curve
Δ diameter
Percentage change in tablet diameter
Δ DT
Percentage change in tablet disintegration time
Δ height
Percentage change in tablet height

Δ response
Percentage change in tablet physicomechanical property
Δ segmented
height
Percentage change in tablet segmented height
Δ TS
Percentage change in tablet tensile strength
Δ volume
Percentage change in tablet volume
ΔD
x

Change in tablet height at Time x relative to Time 0
ΔH
x

Change in tablet diameter at Time x relative to Time 0
κ
Proportional constant
μm
Micrometer
μm/s
Micrometer per second
ρ
App

Apparent density
ρ
True

True density
υ
Poisson's ratio
x
laser,i

Laser profiler measurement of the i
th
sample
x
micrometer,i

Micrometer screw gauge measurement of the i
th
sample
x
model,i

Predicted Δ response value
x
obs,i

Δ response value for the i
th
observation