Molecular transport of water and solvents through organic crystal lattices

大约三分之一的有机分子能够形成水合物和溶剂化晶体，这包括一些正在商业生产和开发中的阿斯利康化合物。在制药行业中，干燥操作是一项面临许多挑战的操作，而且经常被忽视。以前的工作(利兹在PROPAT EU项目637232中的工作)强调，这种晶体的干燥操作的完成主要是由于对溶剂在固相内的传输知之甚少。目前的干燥模型通过实验干燥曲线以经验的方式解释了这种传输。本项目的目的是通过传质阻力网络耦合晶格内(分子尺度)内的传输过程以在床的气相(宏观处理尺度)中传输，从而发展包括氮气对流干燥和真空干燥(目前使用的是分开的模型)的静态颗粒床干燥的普遍理论。在固相中加入输送阻力是传统干燥模型的扩展，旨在更有信心地优化干燥操作，是实现准确模拟工业过程以及提高数字孪生兄弟的可靠性的重要一步。为了实现这一项目目标，并使未来的干燥操作能够成功地设计和运行，提高对固相中溶剂传输的了解是关键，因此需要对水合物脱水的动力学进行建模和测量，因此该项目被分成以下目标：-使用合适的软件，例如，MATLAB或PYTHON，建立一个描述水合物/溶剂的干燥的一维阻力模型。-表征一些水合物/溶剂的平衡状态(使用原子力显微镜(AFM)、扫描电子显微镜(SEM)、X射线衍射(XRD)、动态蒸汽吸附(DVS))作为溶剂含量的函数。-在前述和初步干燥试验的基础上，将建造一个带有集成近红外光谱(NIR)的小型沸腾干燥室，以监控晶体中的溶剂含量，并允许准确测量一系列固体中的溶剂传输速率，由此可以推断出固相传质阻力。-使用X射线层析成像(XRT)观察溶剂去除过程中晶体结构的变化，以深入了解观察到的传质阻力的物理原因(与罗伊斯研究所合作)。-生成的数据将用于基于平衡热力学和基本传输参数的新固体蒸气(VIS)传输模型，一旦集成到我们的1D干燥模型中，将通过模型系统和使用阿斯利康材料的工业实例进行验证。这个拟议项目的潜在好处是能够使用新的干燥模型准确预测晶体干燥时间，最终目标是优化干燥操作的产量和效率，降低它们的成本，并提高制药和其他高附加值制造工艺的可持续性。此外，准确确定干燥时间对于更准确地预测干燥器中的磨损和团聚将是至关重要的。因此，开发水合物和溶剂的干燥模型是改进颗粒设计和工艺效率的重要步骤。本项目与以下EPSRC研究领域相联系：颗粒技术-水合物/溶剂流体-颗粒系统的加工、测量、表征和多尺度建模；分析科学-现有技术在分析化学体系方面的新应用，例如集成到流动床池中以监测水分含量的近红外光谱；以及工程设计-关于水合物/溶剂体系的建模、优化、模拟和推理的理论、方法和工具。

Around one third of organic molecules are able to form hydrate and solvate crystals and this includes a number of AstraZeneca compounds in commercial manufacture and in development. Within the pharmaceutical industry, the drying operation is one that presents many challenges and is often overlooked. Previous work (Leeds work in PROPAT EU project 637232) has highlighted that the completion of drying operations of such crystals is dominated by the poorly understood transport of solvent within the solid phase. Current drying models account for this transport in an empirical manner via an experimental drying curve.The aim of this project is to develop a universal theory of drying in static particle beds that encompasses both nitrogen convective drying and vacuum drying (currently separate models are used) by way of a mass transfer resistance network to couple the transport processes within the crystal lattice (molecular scale) to transport in the gas phase of the bed (macro processing scale). The inclusion of transport resistances within the solid phase is an extension of conventional drying models, and intends to allow for optimisation of drying operations with more confidence and is an important step towards accurate simulations of industrial processes, as well as increasing the reliability of a digital twin. To achieve this project aim and enable the successful design and operation of future drying operations, an improved understanding of solvent transport through the solid phase is key, hence there is a need to model and measure the kinetics of hydrate dehydration and so the project is split into the following objectives:- Build a 1D resistance model to describe the drying of hydrates/solvates using suitable software, e.g. MATLAB or Python. - Characterisation of the equilibrium state of a number of hydrates/solvates (using Atomic Force Microscopy (AFM), Scanning Electron Microscopy (SEM), X-Ray Diffraction (XRD), Dynamic Vapor Sorption (DVS)) as a function of solvent content. - Based on the preceding, and initial drying trials, a small fluid bed drying cell with integrated Near-Infrared Spectroscopy (NIR) will be built to monitor the solvent content of crystals and allow accurate measurement of solvent transport rates in a range of solids, from which solid phase mass transfer resistances can be inferred. - Observe changes within the crystal structure during solvent removal using X-Ray tomography (XRT) to get an insight into the physical reasons that explain observed mass transfer resistances (Collaboration with the Royce institute). - The generated data will be used to inform new vapour-in-solid (ViS) transport models based on equilibrium thermodynamics and fundamental transport parameters, which once integrated into our 1D drying model, will be validated via model systems and industrial examples using AstraZeneca materials. The potential benefit of this proposed project is the ability to accurately predict crystal drying time using the new drying model, which ultimately aims to optimise throughput and efficiency of drying operations, reducing their cost and improving the sustainability of pharmaceutical and other high value added manufacturing processes. Also, accurate determination of drying time will be vital in allowing attrition and agglomeration in dryers to be predicted more accurately. Therefore, development of a drying model for hydrates and solvates is an important step in improving particle design and process efficiency.This project links to the following EPSRC research areas: Particle Technology-processing, measurement, characterisation and multi-scale modelling of hydrate/solvate fluid-particle systems; Analytical Science-novel application of existing techniques to analyse chemical systems, e.g. NIR integrated into a fluid bed cell to monitor moisture content; and Engineering Design-theories, methods and tools for modelling, optimising, simulating and reasoning about the hydrate/solvate system.