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High-Throughput Nanoscale Crystallisation of Dihydropyridine Active Pharmaceutical Ingredients

Lookup NU author(s): Jess Metherall, Dr Michael HallORCiD, Professor Mike ProbertORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Single crystal X-ray diffraction analysis of small molecule active pharmaceutical ingredients is a key technique in the confirmation of molecular connectivity, including absolute stereochemistry, as well as the solid-state form. However, accessing single crystals suitable for X-ray diffraction analysis of an active pharmaceutical ingredient can be experimentally laborious, especially considering the potential for multiple solid-state forms (solvates, hydrates and polymorphs). In recent years, methods for the exploration of experimental crystallisation space of small molecules have undergone a ‘step-change’, resulting in new high-throughput techniques becoming available. We describe the application of high-throughput encapsulated nanodroplet crystallisation to a series of six dihydropyridines, calcium channel blockers used in the treatment of hypertension related diseases. This approach allowed 288 individual crystallisation experiments to be performed in parallel on each molecule, resulting in rapid access to crystals and subsequent crystal structures for all six dihydropyridines, as well as revealing a new solvate polymorph of nifedipine (1,4-dioxane solvate) and the first known solvate of nimodipine (DMSO solvate). This work further demonstrates the power of modern high-throughput crystallisation methods in the exploration of the solid-state landscape of active pharmaceutical ingredients to facilitate crystal form discovery and structural analysis by single crystal X-ray diffraction.

Publication metadata

Author(s): Metherall JP, Corner PA, McCabe JF, Hall MJ, Probert MR

Publication type: Article

Publication status: Published

Journal: Acta Crystallographica Section B

Year: 2024

Volume: 80

Issue: 1

Print publication date: 01/02/2024

Online publication date: 21/12/2023

Acceptance date: 20/11/2023

Date deposited: 03/01/2024

ISSN (electronic): 2052-5206

Publisher: Wiley-Blackwell Publishing Ltd.


DOI: 10.1107/S2052520623010053


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Engineering and Physical Sciences Research Council
Diamond Light Source