Molecular transport of water and solvents through organic crystal lattices

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.