The Determination Of Physical And Chemical Stability Of Pressurised Metered Dose Inhaler Formulations

Abstract

The main aim of this body of work was to develop alternative physical property detection methods to probe drug propellant interactions. A secondary aim of this thesis was to understand if there was any association between the interaction of drug and propellant on a micro-scale with the key performance attributes of a metered dose inhaler. An isothermal calorimetry technique was developed to dose model propellant vapour and probe the surface of the API. This approach was taken to investigate the crystallization kinetics of two structurally dissimilar yet commonly utilized APIs, salbutamol sulphate and beclomethasone dipropionate. Following on from this work, three APIs from the corticosteroid class were chosen as model drugs to further investigate isothermal microcalorimetry as a tool to predict API-propellant interactions and compare this against aerodynamic particle size distribution studies. Canisters containing API in HFA134a were manufactured to study the correlation between API behaviour in 2H,3H-decafluoropentane with APSD data using the NGI. The in situ crystallisation kinetics of mometasone furoate and beclomethasone dipropionate in 2H,3H-decafluoropentane and HFA-134a respectively was explored via synchrotron radiation in the last section of this work. The in situ crystallisation kinetics of beclomethasone dipropionate in pressurised HFA-134a was studied using a custom built synchrotron cell designed to hold the slurry under pressure. The in situ transformation of spray dried beclomethasone dipropionate in pressurized HFA-134a was observed within 70 seconds and the crystallisation event itself was complete in 3 seconds in pressurised HFA-134a. The transformation of beclomethasone dipropionate to a crystalline intermediary structure was captured using X-ray diffraction in one second frame shots.