Marsh, Georgina E.
(2018)
Utilising micron-scale 3D printing to investigate particulate interactions for respiratory applications.
PhD thesis, University of Nottingham.
Abstract
In order to achieve drug delivery via the respiratory route, an understanding of particulate interactions is of vital importance. For successful delivery to the distal airways, an aerodynamic diameter of less than 5 µm must be achieved. However, particles of this size presents a difficult formulation challenge, due to the inherent cohesiveness between particles and adhesion to the device, due to the high surface to volume ratio of such small particles, causing the particles to clump together. This tendency will thereby cause a reduction in dispersion, aerosolisation and device efficiency; for this reason dry powder inhalers (DPIs) invariably fail to achieve a fine particle fraction efficiency above 15%.
There are a wide variety of factors which affect particulate interactions including; surface roughness, surface chemistry, particle size or shape and particle mechanical properties. However, these factors are highly interrelated and so previous attempts to investigate their effect on particle adhesion generally have difficulty isolating the impact of each factor. For instance, investigating the effect of morphology on particulate interactions invariably utilise destructive techniques to alter the roughness, which is likely to alter other factors like surface energy and provide limited control for optimisation. With the rise of 3D printing (additive manufacturing) there is now the capability to produce sub- micron morphologies, and so a bottom-up approach to studying the effect of morphology on particulate interactions can be achieved.
The aims of this thesis are therefore twofold. Firstly, to identify, optimise and evaluate a suitable additive manufacturing technique to produce well-defined micron scale morphologies appropriate for furthering the understanding of the importance of morphology on particle adhesion. This is a scale which is at least two orders of magnitude improvement on current state of the art 3D inkjet printers. Secondly, to measure the effect on particle adhesion and deposition to these morphologies, both on an individual particle and on a bulk powder basis, allowing elucidation and understanding of the effect of surface roughness on particle adhesion, with a specific focus on respiratory drug delivery.
Printing well defined geometries of an appropriate micron scale size range for particle adhesion testing has been achieved, using two photon polymerisation (TPP). TPP is a novel 3D printing technique which as its name suggests involves the curing of usually acrylate containing polymer resins by the absorption of two infra-red photons in the focus of the laser beam. TPP has been shown to produce a sub-diffraction limit lateral resolution of 120 nm. By optimising the printer parameters and experimentation with differing structure fill and input settings the creation of a well- defined curve on a micron scale was achieved. The initial test morphologies comprised of a ridge with a semi-circular top with a diameter of 1 µm, which were shown to be reproducibly printed. These morphologies were then varied in a controllable fashion with varying ridge height and spacing between the ridges. A uniform and consistent surface chemistry was created using a plasma polymerised hexane (ppHex) coating.
In order to evaluate particulate interactions relevant to pulmonary drug delivery both an understanding of the effect of morphology on both individual particle adhesion and bulk powder deposition in a fluid environment is needed. Individual particle-surface adhesion was achieved by testing the TPP structures against three particle types using single particle colloidal probe microscopy (polystyrene beads diameter 10 µm and 5 µm and a lactose particle designed for inhalation formulations). The analysis of this data provides evidence of a clear trend between particle contact area and adhesion recorded both on the ppHex control and the TPP coated morphologies. The TPP morphologies are shown to locally reduce the overall adhesion, in comparison to the flat substrate. The ridge height is also seen to have a significant effect on particle adhesion, with 5 µm < 3 µm < 1 µm for the polystyrene beads, but 3 µm < 5 µm < 1 µm for the Respitose SV003 lactose particle for all ridge spacings. Varying the ridge spacing produced two differing trends in adhesion to the polystyrene beads. If the particle was unable to penetrate the valleys of the roughness, for the 1 µm high ridges, a significant effect on particle adhesion was seen with 3 µm < 1 µm for the polystyrene beads. In contrast, the 3 µm and 5 µm high ridges showed the opposite trend when the particle is unable to descend between the ridges with 1 µm < 3 µm < 8 µm for the polystyrene beads.
Investigation of the bulk powder deposition of the particles on the TPP structures and any subsequent re-entrainment in a fluid environment was then achieved using a novel methodology developed during the course of this work. This combines the use of a standard next generation impactor, which generally is used to separate out a respiratory formulation based on aerodynamic diameter, with the TPP substrates. This shows that ridge height has a significant effect on particle adhesion with 3 µm < 1 µm < 5 µm. In contrast, the different spacings of the ridges were not shown to produce a significant difference in particle deposition. This is likely due to the conflicting effect of asperity spacing on the processes of particle deposition and re-entrainment.
This thesis therefore highlights the capability of TPP, to produce well-defined micron scale structures with varying morphologies. It then shows that these can be successfully utilised to provide valuable insight into the effect of surface morphology on particle- surface interactions, specifically; adhesion, deposition and re-entrainment.
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