Engineering Downstream Processes to Enhance Processability of Crystallized Products

设计下游工艺以增强结晶产品的加工性能

• 批准号: 2856572
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2856572
• 关键词: Engineering; Downstream; Processes; Enhance; Processability

In the production chain of active pharmaceutical ingredients (API), a crystallization step is an integral part for separation and purification purposes. A typical solution crystallization step is followed by the so-called downstream processing steps. These correspond to a solid-liquid separation step, i.e. filtration, a washing step to remove the mother liquor from the filter cake, and finally a drying step to evaporate the wash solvent. The dried powder is eventually blended with excipients and in some cases formulated as tablets or granules to obtain the final solid product. The performance of these steps is often dictated by the crystallization step, namely through the particle size and shape distribution (PSSD), the moisture content, the surface properties (e.g. cohesive/adhesive interactions), to name a few, of the crystallized product.The aforementioned downstream steps have been studied both experimentally and computationally in detail for many different applications, e.g. pharmaceuticals, agrochemicals, paper and pulp, etc. Experimental and modeling studies that aim to provide an empirical relationship between the PS(S)D (mostly on size and rarely on shape) and the final filter cake porosity have been reported. Despite its significance, washing has been scarcely explored over the years, with the focus being on developing rules of thumb and empirical models that work under a narrow range of operating conditions for specific compounds. When it comes to drying, many of the reported works have looked into understanding the impact of the solvent/wash solvent content, agitation of filter cakes, size of particles, to name a few, on the effectiveness of the drying process in terms of time and the extent of breakage or agglomeration. Even though these downstream steps have been studied for a long time, they have not been done in an integrated framework with the upstream crystallization step. Much less studied is the impact of the PSSD of the crystallized product on the downstream processability of the product. This can be mainly attributed to the unavailability of reliable and accurate size and shape characterization tools. Most importantly, even if this link is established there are only a handful of processes reported in the literature that have the ability to tune the size and shape of the crystals to enhance its downstream processability.This project is aimed at bridging the gap between the upstream crystallization step and the downstream steps by using a multiscale approach. We will develop predictive microscopic and macroscopic models backed by experimental data for all the three aforementioned downstream steps (filtration, washing and drying) to improve our understanding and in turn develop efficient processes. These models will pave way to integrate the entire process chain, where given a PSSD one could quantitatively gauge the processability of the crystallized product in terms of both processing time and energy consumption.

在活性药物成分(API)的生产链中，结晶步骤是用于分离和纯化目的的不可或缺的一部分。典型的溶液结晶步骤之后是所谓的下游处理步骤。这些步骤对应于固液分离步骤，即过滤、从滤饼中去除母液的洗涤步骤，以及最后蒸发洗涤溶剂的干燥步骤。干燥的粉末最终与辅料混合，在某些情况下制成片剂或颗粒，以获得最终的固体产品。这些步骤的性能通常由结晶步骤决定，即通过结晶产品的颗粒大小和形状分布(PSSD)、水分含量、表面性质(例如，粘合/粘合相互作用)等。上述下游步骤已在许多不同的应用中进行了详细的实验和计算研究，例如制药、农用化学品、纸张和纸浆等。实验和模拟研究的目的是提供PS(S)D(主要是大小，很少是形状)与最终滤饼孔隙率之间的经验关系。尽管洗涤具有重要意义，但多年来几乎没有人对其进行探索，重点是开发在特定化合物的狭窄操作条件下工作的经验规则和经验模型。在干燥方面，许多已报道的工作都着眼于了解溶剂/洗涤溶剂含量、滤饼的搅拌、颗粒大小等对干燥过程的有效性在时间和破碎或团聚程度方面的影响。尽管这些下游步骤已经研究了很长时间，但它们还没有与上游结晶步骤在一个完整的框架内完成。结晶产品的PSSD对产品的下游加工性的影响的研究要少得多。这主要可以归因于无法获得可靠和准确的尺寸和形状表征工具。最重要的是，即使建立了这种联系，文献中报道的能够调节晶体尺寸和形状以增强其下游加工性的工艺也屈指可数。该项目旨在通过使用多尺度方法来弥合上游结晶步骤和下游步骤之间的差距。我们将为上述三个下游步骤(过滤、洗涤和干燥)开发有实验数据支持的预测性微观和宏观模型，以提高我们的理解，进而开发高效的工艺。这些模型将为整合整个工艺链铺平道路，在给定PSSD的情况下，人们可以根据加工时间和能源消耗来定量衡量结晶产品的加工性。