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

精心设计的药物结晶产生悬浮在母液中的相当纯的活性药物成分(API)的晶体，包括副产品、未反应的原料、未使用的试剂、溶剂和各种杂质。产品通过过滤回收，在过滤结束时，杂质溶液填充滤饼中的空隙并覆盖晶体表面。这种母液必须通过洗涤去除，以避免湿蛋糕干燥时产品中的杂质。该项目旨在减轻洗涤过程中出现的不良结晶现象。当洗涤溶剂被强迫通过湿滤饼来取代母液时，它触发了多个过程，因为溶液的组成沿流动轴线变化。在饱和的情况下，API溶解会降低产率并改变粒度分布；当过饱和度增加时，尤其是在洗涤结束时，溶解的产品可能会被迫离开溶液，可能会导致颗粒团聚，从而改变粒度分布和粉末流动特性；在整个过程中，可能会沉淀溶解的杂质，从而影响产品质量。所有这些现象都可能发生在洗涤任何原料药的过程中，因为洗涤正面穿过滤饼。这一博士学位将包括开发评估这些问题的系统方法、建模工具和优化策略，以确定损害最小的原料药洗涤过程，目的是进行工业部署，以降低原料药生产成本和提高产品质量。假设评估中的方法得到验证，该博士项目将提供数据和理解，为工业开发奠定基础。最初将对扑热息痛进行评估，因为已经在研究组内的一系列潜在结晶和洗涤溶剂中确定了其溶解性和合成的八种主要杂质，为该项目奠定了关键基础。这项工作将扩展到具有不同属性的工业伙伴的化合物，以验证该方法的更广泛的适用性。这项研究是连续制造和先进结晶(CMAC)未来制造研究中心核心计划的一部分。

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.