Drying of Pharmaceutical Powders Using An Agitated Filter Dryer Wei Li Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds Institute of Particle Science and Engineering December 2014 The candidate confirms that the work submitted is his/her own and that appropriate credit has been given where reference has been made to the work of others. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. The right of Wei Li to be identified as Author of this work has been asserted by her in accordance with the Copyright, Designs and Patents Act 1988. - ii - Acknowledgements I would first like to express my gratitude to Professor Kevin J. Roberts and Tariq Mahmud for their help and supervision throughout the course of this research work. I very appreciate that I spent such a fulfilled time to work in the field of Chemical Engineering especially in process engineering an area that I am so interested in. I am deeply grateful to them that they introduced me to the field of chemical engineering a discipline that I am much more proficient in. I would also like to thank the technical staff in School of Chemical and Process Engineering, in particular Steve Caddick, Peter Dawson, John Cran and Simon Lloyd for their support in building up the experimental facilities needed for this research as well as for carrying out repairs and relocating to the filter dryer rig. I would also like to extend my appreciation to Stephen Terry from electronics workshop for his help for developing and implementing the LabVIEW system needed to control the experimental rigs used. I wish to thank all my colleagues in my group and Ulrike for providing such a pleasant working atmosphere. I am grateful to my industrial supervisor, Dr. Mayling Yeow from Pfizer, Sandwich, UK and to Dr. David Am Ende, and Dr Mark Maloney from Pfizer, Groton, CT, USA who used to or still being worked in Pfizer company by giving me their valuable time and support during designing the drying rigs as well as though the most of research work. I would like to thank the David Slate from Process Systems Enterprise (PSE) for helping me to implement and inspect the models developed in this work using gPROMS software. I would also like to thanks Samal Mukayeva, who finished her master degree in University of Leeds in October, 2014, for her help in carrying out the experimental work on particle drying from mixed-solvents. The financial support provided by EPSRC and Pfizer is gratefully acknowledged through the award of Dorothy Hodgkin Scholarship. I am indebted to my mum for her continuous emotional and spiritual support, providing me with a sheltered harbour and for being as brilliant a guide as I could ever have wished for. - iii - Abstract The drying of pharmaceutical powders following their isolation via crystallization and filtration is examined using a laboratory-scale agitated filter dryer (AFD). Vacuum contact and through-circulation convective drying with and without agitation of aspirin powders with pure and mixed solvents are studied through an integrated experimental and modelling approach. Experiments were carried out under different operating conditions by using aspirin particles and water/water-ethanol as typical solid-solvent systems. Two approaches were used to study the drying behaviour of aspirin: 100 µL small-scale drying using thermal gravimetric analysis (TGA) and 5 L medium-scale drying in a laboratory AFD. While the TGA tests provided a better understanding of drying kinetics as functions of temperature, vacuum level, solvent type and particle size, the AFD study revealed the effects of industry-relevant operating parameters (such as the heating rate, vacuum level, agitation speed and regime, gas flow rate, and initial solvent content) on the drying of aspirin particles. In the TGA experiments, the constant and falling rate periods are observed for drying with pure water, while only the falling rate period is observed for pure ethanol and water-ethanol mixed solvents. In the laboratory-scale AFD experiments, drying cycle time is found to decrease with increasing agitation speed, vacuum level, heating power supplied and gas flow. The critical solvent content is determined by identifying the transition point on the temperature-time and the torque-time plots during the drying process. Particle size distribution and morphology analysis of aspirin particles before and after drying with agitation indicate that the particles tend to agglomeration at lower stirring speeds while they are prone to attrition at higher speeds. An increase of the circularity of the particles with the increase of the agitation speed is observed due to attrition effect. Drying models based on a lumped-parameter (LPM) approach are developed for the static and agitated bed vacuum contact drying and combined LMP and distributed-parameter model (DPM) for the convective drying. Within this modelling approach, only one parameter that is the critical solvent content needs to be estimated from experimental results compared to other LPMs which greatly reduced the degree of parameter estimation. These computationally expedient models can be used for the prediction of drying time in a fast and reliable way. The model equations are implemented - iv - in gPROMS software and the models are applied to simulate the experiments carried out in the 5 L AFD. The vacuum contact drying experiments were also simulated using a DPM embedded in the gPROMS software. The modelling results of LPM were compared with that obtained using the DPM. Overall, a good agreement between the calculated and measured drying curves is obtained and the measured drying times are well predicted at varied drying conditions. This research presented the following improvements over the current studies on powder bed drying with limited research on organic crystalline materials and mixed solvent: holistic studies on drying behaviour with varied external drying conditions as well as internal material properties using different scale apparatus: TGA and AFD. Over the previous LPMs on powder bed drying, the modelling approach presented the following improvements: the models developed in this work need less parameter estimation. Three consistent approaches to measure the required parameter at the laboratory scale have been described in this work. The models provide a potential for industrial application on AFD drying. - v - Table of Contents Acknowledgements ..................................................................................... ii Abstract……. .............................................................................................. iii Table of Contents ........................................................................................ v List of Tables ............................................................................................... x List of Figures ............................................................................................ xi Nomenclature ............................................................................................ xx List of Abbreviations ............................................................................... xxv Chapter 1 Introduction ............................................................................ 1 1.1 Research background ................................................................. 1 1.2 Motivation ................................................................................... 5 1.3 Aims and objectives .................................................................... 6 1.4 Project management ................................................................... 8 1.5 Layout of the thesis ................................................................... 10 Chapter 2 Drying theory ........................................................................ 11 2.1 Introduction ............................................................................... 11 2.2 Basic drying theory ................................................................... 11 2.3 Drying types .............................................................................. 16 2.4 Transport mechanisms ............................................................. 17 2.5 Dryer types ............................................................................... 19 2.6 Drying periods .......................................................................... 22 2.7 Conclusion ................................................................................ 26 Chapter 3 Literature review .................................................................. 27 3.1 Experimental work .................................................................... 27 3.1.1 Solid-solvent binding and sticky issues .......................... 27 3.1.2 Factors involved in drying ............................................... 31 3.1.2.1 Crystallization effect ........................................... 31 3.1.2.2 Operating conditions .......................................... 32 3.1.2.3 Characterization of powders involved in drying ................................................................. 34 3.1.2.4 Scale up problems ............................................. 35 3.1.3 Material and solvent types .............................................. 36 3.2 Modelling work .......................................................................... 42 3.2.1