The Production and Characterization of Fluoroquinolone Amorphous Solid Dispersions A dissertation submitted for the degree of Doctor of Philosophy at the School of Pharmacy & Pharmaceutical Sciences, Trinity College Dublin, the University of Dublin, Ireland by Hanah N. Mesallati Under the supervision of Dr. Lidia Tajber June 2017 Declaration I declare that this thesis has not been submitted as an exercise for a degree at this or any other university. A small proportion of the work described in this thesis was carried out by others, and this is duly acknowledged in the text wherever relevant. I declare that all other work is entirely my own. I agree to deposit this thesis in the University’s open access institutional repository or allow the Library to do so on my behalf, subject to Irish Copyright Legislation and Trinity College Library conditions of use and acknowledgement. Hanah Mesallati Table of Contents Summary ................................................................................................................................ i Acknowledgements ............................................................................................................. iii Publications and Presentations .......................................................................................... iv List of Abbreviations and Symbols ................................................................................... vi Chapter 1: General Introduction ....................................................................................... 1 1.1 Bioavailability .............................................................................................................. 2 1.1.1 Classification of Drugs ......................................................................................... 2 1.1.2. Solubility and Dissolution ................................................................................... 3 1.1.3 Permeability .......................................................................................................... 4 1.1.4 Methods of Improving Bioavailability ................................................................. 6 1.2 Amorphous Solids ........................................................................................................ 9 1.2.1 Stability of Amorphous Solids .............................................................................. 9 1.2.2 Amorphous Solid Dispersions ............................................................................ 11 1.2.2.1 Stability of ASDs ......................................................................................... 11 1.2.2.1.1 Miscibility ............................................................................................. 12 1.2.2.2 Solubility and Dissolution of ASDs............................................................. 15 1.2.3 Methods of Producing Amorphous Solids .......................................................... 17 1.2.3.1 Milling ......................................................................................................... 18 1.2.3.2 Spray Drying ................................................................................................ 20 1.3 Ciprofloxacin ............................................................................................................. 21 1.3.1 Ciprofloxacin Formulations ................................................................................ 23 1.3.2 Enrofloxacin ........................................................................................................ 25 1.4 Project Aims .............................................................................................................. 26 Chapter 2: The Two Faces of Ciprofloxacin: Investigation of Proton Transfer in Solid State Transformations ....................................................................................................... 29 2.1 Introduction ................................................................................................................ 30 2.2 Experimental Section ................................................................................................. 32 2.2.1 Materials ............................................................................................................. 32 2.2.2 Methods .............................................................................................................. 33 2.2.2.1 Production of Amorphous Ciprofloxacin .................................................... 33 2.2.2.1.1 Ball Milling ........................................................................................... 33 2.2.2.1.2 Cryomilling ........................................................................................... 33 2.2.2.1.3 Spray Drying ......................................................................................... 33 2.2.2.2 Solid-State Characterization ........................................................................ 33 2.2.2.2.1 Powder X-ray Diffraction (PXRD) ....................................................... 33 2.2.2.2.2 Differential Scanning Calorimetry (DSC) ............................................ 34 2.2.2.2.3 High-Speed DSC (HSDSC) .................................................................. 34 2.2.2.2.4 Temperature-Modulated Differential Scanning Calorimetry (StepScan) .............................................................................................................................. 34 2.2.2.2.5 Thermogravimetric Analysis (TGA) ..................................................... 34 2.2.2.2.6 Solid-State Fourier Transform Infrared Spectroscopy (FTIR) ............. 35 2.2.2.3 Thermal Degradation Study ......................................................................... 35 2.2.2.4 High-Performance Liquid Chromatography (HPLC) .................................. 35 2.2.2.5 Dynamic Vapor Sorption (DVS) ................................................................. 36 2.2.2.6 Crystallographic Analysis ............................................................................ 36 2.2.2.7 Computational Methods ............................................................................... 36 2.2.2.8 Statistical Analysis ....................................................................................... 37 2.3 Results and Discussion .............................................................................................. 37 2.3.1 Crystal Forms of Ciprofloxacin .......................................................................... 37 2.3.2 Production of Amorphous Ciprofloxacin............................................................ 40 2.3.2.1 Ball Milling at Room Temperature .............................................................. 41 2.3.2.2 Cryomilling .................................................................................................. 42 2.3.2.3 Spray Drying ................................................................................................ 43 2.3.3 Quench Cooling - Thermal Degradation Studies ................................................ 44 2.3.4 Solid-State Fourier Transform Infrared Spectroscopy ........................................ 45 2.3.5 Conventional Thermal Analysis ......................................................................... 48 2.3.6 Investigation of Proton Transfer in CIP .............................................................. 52 2.3.7 Physical Stability in Humid Conditions .............................................................. 56 2.4 Conclusions ................................................................................................................ 58 Chapter 3: Amorphous Polymeric Drug Salts as Ionic Solid Dispersion Forms of Ciprofloxacin ...................................................................................................................... 59 3.1 Introduction ................................................................................................................ 60 3.2 Experimental Section ................................................................................................. 61 3.2.1 Materials ............................................................................................................. 61 3.2.2 Methods .............................................................................................................. 63 3.2.2.1 Ball Milling .................................................................................................. 63 3.2.2.2 Solid-State Characterization ........................................................................ 63 3.2.2.2.1 Powder X-ray Diffraction ..................................................................... 63 3.2.2.2.2 Solid-State Fourier Transform Infrared Spectroscopy .......................... 64 3.2.2.2.3 Differential Scanning Calorimetry ........................................................ 64 3.2.2.2.4 Temperature-Modulated Differential Scanning Calorimetry (StepScan) ............................................................................................................................. 64 3.2.2.2.5 Calculation of Theoretical Glass Transition Values with Gordon-Taylor Equation ............................................................................................................... 64 3.2.2.2.6 Thermogravimetric Analysis ................................................................ 65 3.2.2.3 Dynamic Vapor Sorption ............................................................................