An experimental and theoretical study of mechanical properties in pharmaceutical materials

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In pharmaceutical drug product development drug candidates can exhibit sub-optimal behaviour and physical properties, making the development of commercial scale, robust manufacturing processes challenging. A key stage in this development is the selection of the solid form, as different polymorphs of an active pharmaceutical ingredient can have different physico-chemical properties, thus impacting the success of the final dosage form. While solid form is routinely controlled during the particle formation process, the impact of typical manufacturing operations when making tablets via compression is much less well understood. By creating tools to connect the structural features of a solid form with an understanding of how this can be modified under manufacturing conditions it will be possible to unlock new opportunities to accelerate manufacturing development and prevent costly failures. This project will investigate the impact of pressure on pharmaceutical materials. The rationale for this investigation can be found during the processing of the products during micronisation and tabletting of the product. Under these circumstances the solid form in exposed to pressures in excess of 150 MPa and hence understanding the changes that may occur in a solid under these conditions can aid a global understanding. This is especially powerful when taking into account a larger number of compounds. By surveying many different molecules we will be able to explore the impact that different molecular functionalities have on the compression of the pharmaceutical materials. We will be able to follow changes in solid forms as a function of pressure using a diamond anvil cell where the diamonds are transparent to X-ray radiation. Through single-crystal analysis the structures of the pharmaceutical materials can be followed under compression, in particular, under a hydrostatic environment. Non-hydrostatic compression (which is closer to a "working" environment) will be explored using X-ray powder diffraction, nanoindentation and spectroscopic methods. Computational methods will be used to provide energetic information on the system.