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 i ii 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 i 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 GEANUS 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 ii 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 INTRODUCTION 1.1 Pharmaceutical tablet manufacture . 1.1.1 Tablet compaction process . 1.1.2 Commercial production of pharmaceutical tablets . 1.1.3 Excipients used in tablet formulations 1.1.4 Equipment used in tablet manufacture . 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 iii 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 HYPOTHESES AND OBJECTIVES 41 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 iv 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 v 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 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 vi 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 vii 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 SSHt and SSAUC . 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 SSHt and SSAUC . 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 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International Journal of [...]... focuses on tablet production by compaction using typical formulations and excipients meant for oral administration In this chapter, an overview of the compaction process and excipients used in oral tablet formulations are presented In addition, current limitations and research gaps in the field of tablet compaction with regard to the post- compaction recovery process are further illustrated In Chapter 2, the. .. Based on these models, the quantitative parameters of the steady state value, SSresponse, and the time taken after tablet ejection to attain 50% of SSresponse in the hyperbola/hyperbolic decay phase, t50response, 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... CONCLUSION 166 6 BIBLIOGRAPHY 171 ix 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... (Livingstone, 1970) Most pharmaceutical formulations are mixtures of API(s) and 7 excipients which can segregate or have poor flow Hence, granulation is often required for agglomeration of the fine particles before tableting The decision for wet or dry granulation depends on the sensitivity of the API(s) and excipients to moisture 1.1.3 Excipients used in tablet formulations Tablet formulations typically contain... 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 SSHT 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... 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... increased the speed of tablet production (Gill, 1881) Since then, technological advances have led to a variety of modern tablet presses Almost all of the tablet presses today, regardless of scale, possess similar working principles which involve compaction of particles by a machine fitted with tooling(s) A single station of tooling consists of an upper punch, a lower punch and a die The next section will... step, the upper punch enters the die and the press mechanism brings the upper and lower punches closer together, causing a gradual increase in compression force on the powder bed This reduction in distance between the punches continues until the desired tablet thickness or compression force is reached As the applied compression force increases, particles inside the die go through a sequence of processes... surfaces, adhesion and cohesion forces at non-freely movable binder bridges, molecular and electrostatic attraction forces between solid particles, and mechanical interlocking (Turba and Rumpf, 1964) Finally, in the tablet ejection step, the upper punch is raised and formed tablets are then pushed out of the die by the concurrent upward movement of the lower punch During this step, decompression of the tablet... immediately upon removal of pressure from the upper punch 1.1.2 Commercial production of pharmaceutical tablets Commercial production of tablets encompasses several processes performed sequentially in batches and the processes involved will differ based on the manufacture approach taken, namely wet granulation, dry granulation or direct compaction approach (Aulton and Taylor, 2013) An outline of these three . 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. 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. 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