Understanding and mitigating the consequences of undesired crystallization phenomena taking place during filtration and washing of active pharmaceutic

A well-designed pharmaceutical crystallization produces rather pure crystals of the active pharmaceutical ingredient (API) suspended in mother liquor containing; by-products, un-reacted starting materials, unused reagents, solvents, and miscellaneous impurities. The product is recovered by filtration at the end of which impure solution fills the voids in the filter cake and covers the surfaces of the crystals. This mother liquor must be removed by washing to avoid the impurities being incorporated in the product when the wet cake is dried. This project aims to mitigate the undesired crystallization phenomena occurring during the washing process. As the wash solvent is forced through the wet cake to displace the mother liquor it triggers multiple processes as the solution composition varies along the axis of flow. Where under saturation arises API dissolves reducing yield and modifying the particle size distribution; where supersaturation increases, particularly towards the end of washing, dissolved product may be forced out of solution potentially causing particles to agglomerate modifying both particle size distribution and powder flow characteristics; throughout the process there is the potential to precipitate dissolved impurities compromising product quality.
Potentially all these phenomena occur during washing of any API as the wash front passes through the filter cake. This PhD will include developing; a systematic methodology to evaluate these problems, modelling tools and an optimisation strategy to identify the least damaging API washing process with the aim of industrial deployment to reduce the cost of API manufacture and to improve product quality. Presuming the approaches under evaluation are validated this PhD program will deliver data and understanding to build the case for industrial exploitation.
Initially paracetamol will be evaluated since its solubility and those of eight main impurities of synthesis have already been determined in a range of potential crystallization and wash solvents within the research group establishing a critical foundation for the project. The work will be extended to industrial partner's compounds with differing attributes to verify the wider applicability of the approach.
This research is part of the core program of the Centre for Continuous Manufacturing and Advanced Crystallization (CMAC) Future Manufacturing Research Hub.