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Crystallization of Active Pharmaceutical Ingredients in the Presence of Heterosurfaces

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Crystallization of Active Pharmaceutical Ingredients in the Presence of Heterosurfaces Crystallization of Active Pharmaceutical Ingredients in the Presence of Heterosurfaces Raquel Arribas Bueno Thesis presented for the award of Doctor of Philosophy (PhD) Supervisors: Prof. Kieran Hodnett, Dr. Sarah Hudson, and Dr. Peter Davern Submitted to the Faculty of Science and Engineering, University of Limerick, Ireland, January 2018 1 | P a g e DECLARATION I declare that the work presented in this thesis herein, is entirely my own work and has not been submitted to this or any other university. Due reference and acknowledgment has been made, when necessary, to the work of others. ____________________ Raquel Arribas Bueno 2 | P a g e TABLE OF CONTENTS ABSTRACT ........................................................................................................................ 6 LIST OF PUBLICATIONS ................................................................................................ 8 ABBREVIATIONS AND NOTATIONS ........................................................................ 11 1. CHAPTER 1: INTRODUCTION 1.1.General Introduction .......................................................................................... 17 1.2.Components of a Drug ....................................................................................... 18 1.3.Stages of the Drug Manufacturing Process ....................................................... 18 1.4.The Crystal ........................................................................................................ 20 1.5.Crystallization .................................................................................................... 22 1.6.Polymorphism .................................................................................................... 40 1.7.Bioavailability ................................................................................................... 43 1.8.Crystallization of API’s in the presence of excipients ..................................... 45 1.9.Scope of this Project .......................................................................................... 48 1.10. References ...................................................................................................... 50 2. CHAPTER 2: MATERIALS AND ANALYTICAL TECHNIQUES 2.1.Materials ............................................................................................................ 55 2.1.1. Acetaminophen ........................................................................................... 55 2.1.2. Fenofibrate .................................................................................................. 56 2.1.3. Lactose ........................................................................................................ 58 2.1.4. Mannitol ...................................................................................................... 59 2.1.5. Microcrystalline cellulose ........................................................................... 60 2.1.6. Carboxymethyl cellulose ............................................................................ 61 2.1.7. Polycaprolactone ......................................................................................... 62 2.1.8. Mesoporous silica ....................................................................................... 65 2.1.9. Polycarbonate .............................................................................................. 64 2.1.10. Polymethyl methacrylate .......................................................................... 64 2.1.11. Polytetrafluoroethylene ............................................................................. 65 2.1.11. Methanol ................................................................................................... 65 2.2.Analytical techniques ........................................................................................ 66 2.2.1. Powder X-Ray diffraction .......................................................................... 66 2.2.1.1. The crystal ......................................................................................... 67 3 | P a g e 2.2.1.2 Diffraction peaks and Miller indices .................................................. 68 2.2.1.3. Diffractometer ................................................................................... 72 2.2.1.3.1. Reflection mode ................................................................... 72 2.2.1.3.2. Transmission mode .............................................................. 73 2.2.1.4. Diffraction pattern ............................................................................. 73 2.2.1.5. XRD analysis conducted in this work ............................................... 74 2.2.2 Scanning electron microscopy (SEM) ........................................................ 74 2.2.2.1. SEM analysis conducted in this work ............................................... 76 2.2.3. In situ SEM-Raman and Raman spectroscopy............................................ 77 2.2.3.1. Raman spectroscopy ......................................................................... 77 2.2.3.1.1. Raman analysis conducted in this work ............................... 79 2.2.3.2. In situ SEM-Raman........................................................................... 79 2.2.3.2.1. In situ SEM-Raman analysis conducted in this work .......... 80 2.2.4. Ultraviolet-visible spectrophotometer (UV-Vis) ........................................ 80 2.2.4.1. UV-Vis analysis conducted in this work .......................................... 81 2.2.5. Solid-state Nuclear Magnetic Resonance Spectroscopy (SSNMR) ........... 82 2.2.5.1. SSNMR analysis conducted in this work.......................................... 83 2.2.6. iControl LabMax ......................................................................................... 83 2.2.6.1. Focussed beam reflectance measurement (FBRM) ........................... 84 2.2.6.2. In situ Fourier Transform Infrared (FTIR) ........................................ 85 2.3.References ......................................................................................................... 88 3. CHAPTER 3: INFLUENCE OF PROCESS PARAMETERS ON THE HETEROGENEOUS NUCLEATION OF ACTIVE PHARMACEUTICAL INGREDIENTS ONTO EXCIPIENTS ...................................................................... 91 3.1.Abstract .............................................................................................................. 92 3.2.Introduction ....................................................................................................... 92 3.3.Experimental ...................................................................................................... 96 3.4.Results ............................................................................................................. 101 3.5.Discussion ........................................................................................................ 117 3.6.Conclusion ....................................................................................................... 121 3.7.References ....................................................................................................... 122 4. CHAPTER 4: HETEROGENEOUS CRYSTALLIZATION OF FENOFIBRATE ONTO PHARMACEUTICAL EXCIPIENTS .......................................................... 124 4.1.Abstract ............................................................................................................ 125 4 | P a g e 4.2.Introduction ..................................................................................................... 125 4.3.Experimental .................................................................................................... 129 4.4.Results and discussion ..................................................................................... 137 4.5.Conclusion ....................................................................................................... 160 4.6.Supplementary information ............................................................................. 160 4.7.References ....................................................................................................... 160 5. CHAPTER 5: CRYSTALLIZATION OF ACTIVE PHARMACEUTICAL INGREDIENTS IN THE PRESENCE OF POLYMER COUPONS ....................... 164 5.1.Abstract ............................................................................................................ 165 5.2.Introduction ..................................................................................................... 165 5.3.Materials .......................................................................................................... 168 5.4.Methods ........................................................................................................... 169 5.5.Results ............................................................................................................. 175 5.6.Discussion ........................................................................................................ 191 5.7.Conclusion ...................................................................................................... 196 5.8.References ....................................................................................................... 196 6. CHAPTER 6: COMPARATIVE STUDY OF ACETAMINOPHEN AND FENOFIBRATE CRYSTALLIZATION.................................................................. 198 6.1.Abstract ...........................................................................................................
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