UNDERSTANDING INTERPARTICLE INTERACTIONS IN DRY POWDER INHALATION: GLASS BEADS AS AN INNOVATIVE MODEL CARRIER SYSTEM DOCTORAL THESIS SUMBITTED IN FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR IN NATURAL SCIENCES AT KIEL UNIVERSITY, GERMANY by Niklas Ludwig Renner Kiel 2017 Referee: Prof. Dr. Regina Scherließ Co-Referee: Prof. Dr. Thomas Kunze Date of Exam: 13.10.2017 Accepted for publication: 13.10.2017 Prof. Dr. Natascha Oppelt (Dean) Published research articles contributing to the present thesis: Renner, N.; Steckel, H.; Urbanetz, N.A.; Scherließ, R. Tailoring the surface topography of a model carrier to alter dry powder inhaler performance Dalby, R.N. (Ed.), RDD Europe 2017 2 (2017), 195-200 Renner, N; Steckel, H.; Urbanetz, N.A.; Scherließ, R. Nano- and microstructured model carrier surfaces to alter dry powder inhaler performance International Journal of Pharmaceutics 518 (2017), 20-28 Conference contributions: Renner, N.; Steckel, H.; Urbanetz, N.A.; Scherließ, R. Tailoring the surface topography of a model carrier to alter dry powder inhaler per- formance Respiratory Drug Delivery, Nice, France (2017) Renner, N.; Steckel, H.; Urbanetz, N.A.; Scherließ, R. A deeper insight into the impact of chemical surface properties on inhalation perfor- mance Drug Delivery to the Lungs 27, Edinburgh, Scotland (2016) Renner, N.; Scherließ, R.; Steckel, H. Glass beads as model carriers in dry powder inhalers: the influence of chemical sur- face properties on inhalation performance International Congress on Particle Technology, Nurnberg, Germany (2016) Renner, N.; Scherließ, R.; Steckel, H. Investigating the influence of carrier surface roughness on drug delivery in DPIs 10th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Tech- nology, Glasgow, Scotland (2016) Renner, N.; Kutelova, Z.; Scherließ, R.; Steckel, H. Modified glass beads as model carriers to understand the performance of interactive powder blends Drug Delivery to the Lungs 26, Edinburgh, Scotland (2015) “If we knew what we were doing it would not be called research, would it?” Albert Einstein Meinen Eltern gewidmet Lack of specific mark or a reference to a trademark or a patent does not imply that this work or part of it can be used or copied without copyright permission. I Table of Contents 1 Introduction and Objectives........................................................... 1 1.1 Introduction ................................................................................................ 1 1.2 Objectives ................................................................................................... 2 2 Theoretical Background ................................................................. 4 2.1 The Human Respiratory Tract ................................................................... 4 2.2 Pulmonary Drug Delivery .......................................................................... 5 2.2.1 General Considerations for Inhalation Products ................................................. 5 2.2.2 Drug Application Devices ................................................................................... 7 2.2.2.1 Nebulisers ...................................................................................................................... 7 2.2.2.2 Pressurised Metered-Dose Inhalers .............................................................................. 8 2.2.2.3 Soft Mist Inhalers ........................................................................................................... 8 2.2.2.4 Dry Powder Inhalers ...................................................................................................... 8 2.3 Formulation Strategies for Dry Powder Inhalation ................................. 9 2.3.1 Manufacturing of Drug Particles for Inhalation ................................................... 9 2.3.2 Carriers in Pulmonary Drug Delivery ................................................................ 10 2.3.2.1 α-Lactose Monohydrate ............................................................................................... 11 2.3.2.2 Other Organic Carriers ................................................................................................. 11 2.3.2.3 Model Carrier System: Glass Beads ............................................................................ 11 2.3.3 Interparticle Interactions ................................................................................... 12 2.3.3.1 General Considerations for DPI Formulations ............................................................. 12 2.3.3.2 Impact of Particle Properties on Interparticle Interactions ........................................... 15 2.3.4 The Inhalation Device ...................................................................................... 17 3 Materials and Methods ................................................................. 19 3.1 Materials ................................................................................................... 19 3.1.1 Model Drugs .................................................................................................... 19 3.1.1.1 Budesonide .................................................................................................................. 19 3.1.1.2 Formoterol Fumarate ................................................................................................... 20 II 3.1.1.3 Ipratropium Bromide .................................................................................................... 21 3.1.1.4 Tiotropium Bromide ...................................................................................................... 21 3.1.2 Glass Beads .................................................................................................... 22 3.1.3 Tungsten Carbide ............................................................................................ 23 3.1.4 Hydrofluoric Acid .............................................................................................. 23 3.1.5 Capsules.......................................................................................................... 23 3.1.6 Inhalation Devices ........................................................................................... 24 3.1.6.1 Cyclohaler .................................................................................................................... 24 3.1.6.2 Unihaler/Modular Inhaler .............................................................................................. 24 3.2 Statistical Methods .................................................................................. 26 3.2.1 Design of Experiments ..................................................................................... 26 3.2.2 General Statistical Considerations ................................................................... 28 3.3 Preparative Methods ................................................................................ 29 3.3.1 Spray Drying of Model Drugs ........................................................................... 29 3.3.1.1 Budesonide .................................................................................................................. 30 3.3.1.2 Formoterol Fumarate ................................................................................................... 31 3.3.1.3 Tiotropium Bromide ...................................................................................................... 31 3.3.1.4 Ipratropium Bromide .................................................................................................... 31 3.3.2 Modification of Glass Beads............................................................................. 31 3.3.2.1 Chemical Surface Modification .................................................................................... 32 3.3.2.2 Alteration of Surface Topography ................................................................................ 32 3.3.3 Working Under Controlled Ambient Conditions ................................................ 34 3.3.4 Calculation of Carrier Surface Coverage-Theoretical Considerations ............... 34 3.3.5 Preparation of Interactive Mixtures................................................................... 36 3.4 Analytical Methods .................................................................................. 38 3.4.1 API and Carrier Characterisation ..................................................................... 38 3.4.1.1 Laser Diffraction ........................................................................................................... 38 3.4.1.2 Dynamic Image Analysis .............................................................................................. 38 3.4.1.3 Scanning Electron Microscopy ..................................................................................... 39 3.4.1.4 Contact Angle Measurements ...................................................................................... 40 III 3.4.1.5 Atomic Force Microscopy ............................................................................................. 40 3.4.1.6 Density Measurements ................................................................................................ 43 3.4.1.7 Dynamic Vapour Sorption ............................................................................................ 43 3.4.1.8 X-Ray Powder Diffraction ............................................................................................