Orally Disintegrating Tablets: Formulation Development, Novel Engineering Solutions and Fixed Dose Combinations Thomas James Dennison Doctor of Philosophy Aston University November 2016 ©Thomas James Dennison, 2016 Thomas James Dennison asserts his moral right to be identified as the author of this thesis This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright belongs to its author and that no quotation from the thesis and no information derived from it may be published without appropriate permission or acknowledgement 1 Thesis Summary Aston University Orally Disintegrating Tablets: Formulation Development, Novel Engineering Solutions and Fixed Dose Combinations Thomas James Dennison Doctor of Philosophy 2016 Thesis Summary Orally disintegrating tablets (ODTs) are an attractive solid dosage form for patients who suffer from dysphagia, a difficulty in swallowing, which is particularly prevalent in paediatric and geriatric populations. ODTs and fixed dose combination (FDC) formulations are popular as they improve patient compliance and combination of the two has not previously been explored. The requirement for ODTs to disintegrate rapidly whilst also being mechanically robust means that high drug loading is a significant challenge. An ODT formulation for the beta- lactam antibiotic flucloxacillin was developed at doses of 250 and 125 mg. ODTs were mechanically robust, however this limited disintegration to within 3 mins, with mannitol fragmentation being a major limitation. Polymeric film coating was devised as a potential technique to enhance ODT mechanical properties. Due to high attrition during fluidisation a novel stationary coating technique was developed as a proof of concept. ODTs coated in this way, coupled with a post- coating curing step, demonstrated an increase in hardness of almost double and essentially zero friability. This novel coating technique could prove hugely beneficial in the formulation of high dose or poorly compactable drugs. The application of ODTs for FDCs was tested with four model drugs: amlodipine (5 mg), atorvastatin (10 mg), isoniazid (50 mg) and rifampicin (75 mg). ODT formulations for single and FDCs showed rapid disintegration and good mechanical properties. Comparison of single and FDC dissolution profiles was performed using FDA recommended f1 and f2 testing. Bioavailability from ODTs was assessed using in vitro Caco-2 permeability and dissolution data and in silico physiologically based pharmacokinetic modelling. Bioequivalence was demonstrated between single and FDC for each drug in both fed and fasted states, whilst atorvastatin showed a positive food effect (enhanced peak plasma concentration and area under the curve), due to reduced metabolism by CYP3A4. 2 Acknowledgements Acknowledgements I would like to begin by thanking my supervisor Prof Afzal Mohammed for providing me with the opportunity to undertake this PhD and for his continued support, advice and expertise. His confidence and trust in me has undoubtedly allowed me to develop as a researcher and has grown the assurance that I hold in my own ability. Above all, his optimism and passion for this field of study has helped me on many occasions and for this I am extremely grateful. I would also like to thank my second supervisor Dr Raj Badhan for his contribution and knowledge and for being available whenever I needed help. I am very appreciative to the financial support supplied to me by the Medical Research Council and Viridian Pharma, without which this PhD would not have been possible. I would also like to thank the technical team at Aston University, particularly Jiteen Ahmed and Christine Jakeman for their unwavering assistance and knowhow. I am also very grateful to Dr Michael Hofmann from the University of Birmingham for his contribution in micro-CT imaging. I would also like to extend my sincerest thanks to my colleagues within our research group: Jas Koner, Dr Affiong Iyire, Dr Eman Dahmash, Hamad Alyami, Ansarr Warraich and Habtom Ftuwi and to other members of the lab team, past and present. Getting to know you all over the past 4 years has been a pleasure. Special thanks goes to my family. To my parents, you have been an incredible support over the past 4 years and long before. I would not have achieved this without the faith you have placed in me and I am eternally grateful for everything you have done for me; I couldn’t have asked for anything more or anyone better as parents. To Charlie and Arch, thank you for always being there and for your patience, especially towards the end of this work. I am incredibly lucky and the past four years would have been unthinkable without you. To Lauren and Katy, Scott, Evie and George, thanks for your support and for always making me smile. 3 List of Contents List of Contents Thesis Summary .......................................................................................................... 2 Acknowledgements ...................................................................................................... 3 List of Contents ............................................................................................................ 4 List of Abbreviations ....................................................................................................12 List of Tables ...............................................................................................................13 List of Figures ..............................................................................................................18 Publications List ..........................................................................................................30 Chapter 1 - Introduction ...............................................................................................32 1.1 Paediatric Medicines .....................................................................................33 1.1.1 Legislation, Regulations and Incentives .................................................33 1.1.2 Excipient Considerations ........................................................................34 1.1.3 Considerations for Paediatrics................................................................35 1.1.4 Paediatric Relevant Dosage Forms ........................................................36 1.2 Orally Disintegrating Tablets .........................................................................38 1.3 Technologies Involved in ODT Manufacture ..................................................40 1.3.1 Moulding ................................................................................................40 1.3.1.1 Compression Moulding ...................................................................40 1.3.1.2 Heat Moulding .................................................................................40 1.3.1.3 No-Vacuum Lyophilisation ...............................................................41 1.3.1.4 Advantages and Challenges of Moulding ........................................41 1.3.2 Freeze Drying/Lyophilisation ..................................................................41 1.3.3 Mass Extrusion ......................................................................................42 1.3.4 Cotton Candy Process ...........................................................................42 1.3.5 Granulation and Spray Drying ................................................................43 1.3.5.1 Wet Granulation ..............................................................................43 1.3.5.2 Melt Granulation ..............................................................................43 1.3.5.3 Spray Drying ...................................................................................44 1.3.5.4 Advantages and Challenges of Granulation ....................................44 1.3.6 Post-Compression Treatment.................................................................45 1.3.6.1 Sublimation .....................................................................................45 4 List of Contents 1.3.6.2 Humidity Treatment .........................................................................45 1.3.6.3 Sintering ..........................................................................................46 1.3.6.4 Advantages and Challenges of Post Compression Treatment .........46 1.4 Direct Compression .......................................................................................47 1.4.1 Advantages and Challenges of Direct Compression ...............................47 1.4.2 Importance of Excipients ........................................................................48 1.4.3 Patented Systems ..................................................................................49 1.5 Excipients Suitable for Compressed ODTs ....................................................51 1.6 Film Coating ..................................................................................................61 1.6.1 History of Tablet Coating ........................................................................61 1.6.2 Applications and Objectives of Film Coating...........................................62 1.6.3 Conventional Coating Process ...............................................................63 1.6.4 Recent Tablet Coating Technologies......................................................64 1.6.5 Polymers for Film Coating ......................................................................65