Molecular transport of water and solvents through organic crystal lattices

水和溶剂通过有机晶格的分子传输

• 批准号: 2599632
• 金额: --
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2599632
• 关键词: Molecular; transport; water; solvents; through

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.

大约三分之一的有机分子能够形成水合物和溶剂化物晶体，这包括商业生产和开发中的许多阿斯利康化合物。在制药行业中，干燥操作是一个面临许多挑战且经常被忽视的操作。先前的工作（PROPAT EU项目637232中的利兹工作）已经强调了这种晶体的干燥操作的完成主要是由于对固相内溶剂的传输知之甚少。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。本项目的目的是发展一个包括氮气对流干燥和真空干燥的静态颗粒床干燥的通用理论（目前使用单独的模型）通过传质阻力网络耦合晶格内的传输过程（分子尺度）在床的气相中输送（宏观处理尺度）。在固相中包含传输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，是迈向精确模拟工业过程的重要一步，也是提高数字孪生模型可靠性的重要一步。为了实现该项目的目标并使未来干燥操作的成功设计和操作成为可能，关键是要更好地理解溶剂通过固相的传输，因此需要对水合物脱水的动力学进行建模和测量，因此该项目分为以下目标：-使用合适的软件（例如MATLAB或Python）建立一维阻力模型来描述水合物/溶剂化物的干燥。- 作为溶剂含量的函数的许多水合物/溶剂化物的平衡状态的表征（使用原子力显微镜（AFM）、扫描电子显微镜（SEM）、X射线衍射（XRD）、动态蒸气吸附（DVS））。- 基于前述和初始干燥试验，将构建具有集成近红外光谱（NIR）的小型流化床干燥单元，以监测晶体的溶剂含量，并允许精确测量一系列固体中的溶剂传输速率，由此可以推断固相传质阻力。- 使用X射线断层扫描（XRT）观察溶剂去除过程中晶体结构的变化，以深入了解解释所观察到的传质阻力的物理原因（与罗伊斯研究所合作）。- 生成的数据将用于通知基于平衡热力学和基本传输参数的新的气固（维斯）传输模型，这些模型一旦集成到我们的一维干燥模型中，将通过使用阿斯利康材料的模型系统和工业实例进行验证。该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，最终旨在优化干燥操作的吞吐量和效率，降低其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，干燥时间的准确测定将是至关重要的，允许在干燥器中的磨损和团聚，以更准确地预测。因此，水合物和溶剂化物干燥模型的开发是提高颗粒设计和过程效率的重要一步。本项目与EPSRC的以下研究领域相联系：颗粒技术-水合物/溶剂化物流体颗粒系统的处理、测量、表征和多尺度建模;分析科学-现有技术在分析化学系统方面的新应用，例如，将近红外技术纳入流化床单元，以监测水分含量;和工程设计-理论，方法和工具，用于建模，优化，模拟和推理水合物/溶剂化物系统。