In-line PXRD characterisation of the reactive crystallisation of Calcium Sulphate within a millilitre-scale continuous-flow reactor Raphael Stone [1][2] , Nina Patel [1] ,Thomas Turner [1] , Richard Bourne [1][2] , Fiona Meldrum [1] , Nikil Kapur [3] . 1 School of Chemistry, University of Leeds, UK 2 School of Chemical and Process Engineering, University of Leeds, UK 3 School of Mechanical Engineering, University of Leeds, UK The use of powder x-ray diffraction (PXRD) in an in situ or in-line manner has, in recent work, proven to be an effective experimental technique for the study of crystallisation processes and their associated kinetics, mechanisms, and solid-state pathways [1][2] . The main benefit of such a characterization technique is the elimination of sampling errors associated with the isolation of products for off-line analysis, where this isolation and drying step can induce unwanted polymorphic or solid-state transitions, which may mask the true crystallization pathway of the material. This technique can be exploited in combination with a continuous-flow crystallization platform, which results in a well-controlled process reaction environment, excellent time-resolution, and the ability to rapidly explore parameter space. However, such studies have often made use of either very small microfluidic chips or large scale, complex continuous-flow platforms, and often take place at Synchrotron sources. To further explore the potential utility of such a combination of continuous crystallization platforms and lab-based, in-line PXRD analysis, the reactive crystallization of Calcium Sulphate from solution has been studied within a 10 milliliter-scale multiple-continuous stirred-tank reactor (CSTR) platform – the fReactor [3] . A lab-based PXRD instrument was used for in-line analysis of reactive crystallisations, demonstrating how such sources can potentially alleviate the need for Synchrotron-based experiments. Both a custom-designed flow-cell and X-ray transparent polyimide tubing have been used to measure in-line PXRD patterns of Calcium Sulphate during precipitation, to rapidly assess polymorphic outcomes across a range of operating conditions without the requirement for sample isolation and preparation. As a demonstration of the platform’s ability to enable the rapid exploration of different crystallization conditions, the effect of water activity on the phase transitions and crystallization kinetics of Calcium Sulphate has been quantified. Induction times have also been quantified through the use of the in-line analysis set-up, with the addition of inorganic additives shown to suppress nucleation. Growth rates have also been measured across supersaturations and in the presence of additives by developing a quantitative relationship between Calcium Sulphate solids content and PXRD diffraction peak intensities. The fReactor continuous crystallization platform shows excellent solids handling abilities, and enables a wide-range of parameter space to be explored. References
1. Levenstein et al., Analytical Chemistry , 92 (11), 2020. 2. Turner et al., Crystal Growth &Design , 18 (2), 2018. 3. Chapman et al., Organic Process Research and Development , 21 (9), 2017
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