An investigation into the feasibility of Fused DepositionModelling for 3D printing oral pharmaceuticalsJehad NasereddinThesis submitted in fulfilment of the requirements for the degree of Doctor ofPhilosophy, University of East Anglia. Norwich, United Kingdom This copy of the thesis has been supplied on condition that anyone who consults it is understood torecognise that its copyright rests with the author and that use of any information derived therefrom must bein accordance with current UK Copyright Law. In addition, any quotation or extract must include fullattribution.

AcknowledgementsI dedicate this work to the memory of my grandfather, Jehad Hasan Nasereddin, whopassed on the morning on January 3rd, 2018. I’m sorry you didn’t get to see it through,but I trust that as you look down on me, you feel pride in who you left behind. And thankyou for the name you passed on to me. I will wear it proudly till the last of my days. Mayyour memory live forever.I would like to thank my supervisors. Dr. Sheng Qi, Prof. Peter Belton and my adoptive supervisor,Dr. Muqdad Alhijjaj. You have been the most patient of souls. Through your help and guidance,I could see myself grow into my own both as a researcher and a person. To that, I extend thewarmest gratitude.I also would like to take a moment to thank my brothers in arms, Dr. Janine Wilkinson, ZuzanaHlaskova, (hopefully, by the time of this writing Dr.) Salman Rahman, Randa Ziqlam, Chak Tam,and Sherif Ismail. In the words of Kurt Cobain, our little group has always been and always willuntil the end.My family, my greatest gift. Mom, Dad, Sara, Amer, Lara. I love you all, and thank you for yourendless love and support. I would’ve never made it this far without you.And to those who extended a hand of friendship and guidance throughout this journey, Ithank you all. Dr. Laszlo Fabian, Dr. Klaus Wellner, Prof. Yaroslav Khimyak, Alex,Veronica, Noelia, Muhammad, Sara, the lovely team at PCE Automation, thank you!2

AbstractFused Deposition Modelling (FDM) is a variant of 3D Printing (3DP) that relies on themelt extrusion of thermoplastic polymers for the fabrication of objects. Using FDM,objects with customised geometries, mass, shapes, and dimensions can be printed ondemand. This customisability makes FDM a robust method for creating patient-tailored,personalised dosage forms. Therefore, the past few years have seen an increase in researchdemonstrating the use of FDM to produce solid dosage forms. Various research effortshave demonstrated the capacity of FDM to create dosage forms with customisedgeometries, tailored release profiles, and polypills containing multiple drugs. However,there remains no commercially available products are produced by FDM. This may bedue to reported works describing the use of FDM as a pharmaceutical manufacturingprocess often employ a trial-and-error approach to arrive at a formulation, with little workdemonstrating a thorough understanding of the FDM process and the involved parameterinteractions as a whole. The work presented herein describes an investigation into theparameters involved in FDM, and their impact on the perceived quality parameters of 3Dprinted solid dosage forms, which should help to guide towards a more rational approachtowards FDM printable dosage forms.The work conducted herein investigated material properties, and FDM printing speed,printing temperature, and infill density, and their impact on perceived quality attributesof the printed dosage forms. Optimising the mechanical properties of the filament wasfound to be the rate limiting in creating a printable formulation. Chapter 3 describes amethod developed to predetermine the mechanical suitability of a filament for FDM.Chapter 4 describes an investigation into the critical quality parameters of FDM, in whichprinting speed was found to have greater impact on the quality of printed dosage formsthan printing temperature. Furthermore, a distortion effect related to material melt flowwas observed and described, which is dubbed the First Layer Effect. Chapter 5demonstrated how the use of the infill process parameter can be used to manipulate thedrug release rate from a 3D printed dosage form and tune the formulation to a range ofrelease characteristics ranging from an immediate release formulation to a sustainedrelease and even a delayed release formulation without the need to alter the constituentsof the printed dosage form.3

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Table of ContentsAcknowledgements . 2Abstract . 3Table of Contents . 4List of Publications . 9List of Figures . 10List of Tables . 16Chapter 1 Introduction . 171.1.3D printing for oral solid dosage forms, the solution to Personalised Medicine? personalised medicine challenge: . 18Pharmaceutical 3D printing: current advancements and trends . 211.2.1.Powder-bed 3D printing: . 221.2.2.Stereolithographic 3D printing:. 231.2.3.Selective Laser Sintering: . 251.2.4.Semi-solid Extrusion: . 251.2.5.Fused Deposition Modelling: . printing terminology: . 311.3.Phases of the solid state: crystalline and amorphous solids, and amorphoussolid dispersions . 321.3.1.Crystalline versus amorphous: short, and long-range molecular order andits impact on dissolution properties: . 321. Dispersions: . 36Aims and objectives . 38Chapter 2 Materials and Methods . 392.1.Materials . 402.1.1.Acrylonitrile Butadiene Styrene and High-Impact Polystyrene: . 402.1.2.Polyvinyl alcohol: . 414

2.1.3.Polycaprolactone: . 412.1.4.Polyethylene Glycol/Polyethylene Oxide: . 422.1.5.Polysorbate 80: . 432.1.6.Hypromellose acetate succinate: . 432.1.7.Eudragit EPO: . 442.1.8.Soluplus :. 452.1.9.Copovidone : . 462.1.10. Hydroxypropyl cellulose: . 462.1.11.Paracetamol: . 472.1.12.Acetylsalicylic acid: . 472.1.13.Sodium bicarbonate:. 482.2.Methods . 492.2.1.Hot-Melt Extrusion: . 492.2.2.Material Characterisation Methods: . 502.2.3.Texture Analysis: . 552.2.4.Principal Component Analysis: . 56Chapter 3 Investigating the mechanical properties of melt-extruded filaments and theirsuitability for 3D printing . 573.1.Introduction . 583.2.Materials and Methods . 613.2.1.Materials:. 613.2.2.Preparation of in-house filaments: . 613.2.3.Filament Characterisation: . 623.2.4.FDM feedability testing: . 633.2.5.Texture analysis:. 633.2.6.Data manipulation and statistical analysis: . 633.3.Results . 643.3.1.Materials characterisation: . 643.3.2.Filament feedability tests: . 705

3.3.3.Texture Analysis screening tests: . 713.3.4.Correlation Analysis: . 753.3.5.Principal Component Analysis: . 763.4.Discussion . 793.4.1.Intrepretation of the Texture Analysis Flexibility Profile: . 793.4.2.Correlation between mechanical properties and feedability: . 813.4.3.Using flexibility profile towards screening . 843.4.Conclusion . 86Chapter 4 Investigating the impact of printing temperature and printing speed onpharmaceutically-relevant quality attributes . 874.1.Introduction: . 884.2.Materials and methods . 904.2.1.Materials:. 904.2.2.Preparation of drug loaded filaments by HME: . 904.2.3.FDM 3D printing of commercial filaments and drug-loaded filaments: 904.2.4.Melt Flow Index measurements: . 924.2.5.Levelling of the build plate of the printer: . 934.2.6.Printing on different surfaces . 944.2.7.Characterization of printed solid dosage forms . 944.2.8.Statistical Analysis . 954.3.Results . 964.3.1.Materia