Modelling dry powder inhaler operation with the discrete element method

Dry powder inhalers (DPI) are a common asthma treatment. Despite the number of commercial devices available, little is known about their internal operation: the process of fluidising a powder dose into an inhalation airflow. This PhD aims to investigate this process, and demonstrate that it can be modelled computationally. . Experimental work is described to record high speed video of the dose fluidisation from simplified DPls. Typical DPI powders such as lactose are tested, along with cohesionless glass spheres and aluminium flakes. Two distinct dose fluidisation mechanisms are identified, labelled 'fracture' and 'erosion'. Lactose exhibits a fracture mechanism -- large agglomerates are produced as the powder bed cracks along lines of weakness. Glass or aluminium particles exhibit an erosion mechanism: powder is entrained into the flow as individual particles from the bed surface. The recorded video is quantitatively analysed to determine fluidisation timescales and pressures. Shear cell test results show that predicting the mechanism of fluidisation is not possible using averaged bulk powder properties. This suggests any DPI model must include the fundamental particle interactions. The discrete element method (OEM) is introduced as a computational technique capable of predicting DPI behaviour from individual particle properties. The numerical accuracy of the method is assessed, showing that time integration is limited to a maximum of 2nd order accuracy due to discontinuities in particle contact forces. A sensitivity analysis shows inter-particle cohesion is the dominant factor affecting OEM predictions. OEM is used to create a simple model of the dose fluidisation that occurs within a DPI. The results are compared with real powder behaviour. OEM is shown to capture the realistic fluidisation of both lactose and glass powder doses. It is concluded that OEM is a promising technique to predict DPI behaviour, although further work is required to quantify inter--particle cohesive parametersImperial Users onl

Formulation Pre-screening of Inhalation Powders Using Computational Atom–Atom Systematic Search Method

The synthonic modeling approach provides a molecule-centered understanding of the surface properties of crystals. It has been applied extensively to understand crystallization processes. This study aimed to investigate the functional relevance of synthonic modeling to the formulation of inhalation powders by assessing cohesivity of three active pharmaceutical ingredients (APIs, fluticasone propionate (FP), budesonide (Bud), and salbutamol base (SB)) and the commonly used excipient, α-lactose monohydrate (LMH). It is found that FP (−11.5 kcal/mol) has a higher cohesive strength than Bud (−9.9 kcal/mol) or SB (−7.8 kcal/mol). The prediction correlated directly to cohesive strength measurements using laser diffraction, where the airflow pressure required for complete dispersion (CPP) was 3.5, 2.0, and 1.0 bar for FP, Bud, and SB, respectively. The highest cohesive strength was predicted for LMH (−15.9 kcal/mol), which did not correlate with the CPP value of 2.0 bar (i.e., ranking lower than FP). High FP–LMH adhesive forces (−11.7 kcal/mol) were predicted. However, aerosolization studies revealed that the FP–LMH blends consisted of agglomerated FP particles with a large median diameter (∼4–5 μm) that were not disrupted by LMH. Modeling of the crystal and surface chemistry of LMH identified high electrostatic and H-bond components of its cohesive energy due to the presence of water and hydroxyl groups in lactose, unlike the APIs. A direct comparison of the predicted and measured cohesive balance of LMH with APIs will require a more in-depth understanding of highly hydrogen-bonded systems with respect to the synthonic engineering modeling tool, as well as the influence of agglomerate structure on surface–surface contact geometry. Overall, this research has demonstrated the possible application and relevance of synthonic engineering tools for rapid pre-screening in drug formulation and design

European Radioisotope Thermoelectric Generators (RTGs) and Radioisotope Heater Units (RHUs) for Space Science and Exploration

Radioisotope power systems utilising americium-241 as a source of heat have been under development in Europe as part of a European Space Agency funded programme since 2009. The aim is to develop all of the building blocks that would enable Europe to launch and operate deep space and planetary missions in environments where use of solar power or alternative power generation technologies is challenging. Although some technical and policy work activity predate the ESA programme, the maturity of the technology has now reached a level that it can be incorporated in mission studies and roadmaps targeting the period from the mid 2020s onwards. This paper describes the state of the art in European radioisotope thermoelectric generators and radioisotope heater units. This paper includes: the evolution of the technical programme in detail; descriptions of the design; evolution of RTG and RHU devices from laboratory prototypes to more advanced fully functional systems; and experimental data obtained to date. This paper also outlines the technical challenges and multidisciplinary skills required to develop what is a world leading, original, significant and transformative technology solution for planetary science and exploration missions from the mid 2020s onwards.JRC.G.I.3-Nuclear Fuel Safet