Pushing Technique Boundaries to Probe Conformational Polymorphism

Martin R Ward; Christopher R Taylor; Matthew T Mulvee; Giulio I Lampronti; Ana M Belenguer; Jonathan W Steed; Graeme M Day; Iain D H Oswald

doi:10.1021/acs.cgd.3c00641

Pushing Technique Boundaries to Probe Conformational Polymorphism

Cryst Growth Des. 2023 Aug 30;23(10):7217-7230. doi: 10.1021/acs.cgd.3c00641. eCollection 2023 Oct 4.

Authors

Martin R Ward¹, Christopher R Taylor², Matthew T Mulvee³, Giulio I Lampronti⁴, Ana M Belenguer⁵, Jonathan W Steed³, Graeme M Day², Iain D H Oswald¹

Affiliations

¹ Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, U.K.
² Computational Systems Chemistry, School of Chemistry, University of Southampton, Southampton SO17 1BJ, U.K.
³ Department of Chemistry, Durham University, South Road, Durham DH1 3LE, U.K.
⁴ Department of Materials Science & Metallurgy, University of Cambridge, 27 Charles Babbage Rd, Cambridge CB3 0FS, U.K.
⁵ Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.

Abstract

We present an extensive exploration of the solid-form landscape of chlorpropamide (CPA) using a combined experimental-computational approach at the frontiers of both fields. We have obtained new conformational polymorphs of CPA, placing them into context with known forms using flexible-molecule crystal structure prediction. We highlight the formation of a new polymorph (ζ-CPA) via spray-drying experiments despite its notable metastability (14 kJ/mol) relative to the thermodynamic α-form, and we identify and resolve the ball-milled η-form isolated in 2019. Additionally, we employ impurity- and gel-assisted crystallization to control polymorphism and the formation of novel multicomponent forms. We, thus, demonstrate the power of this collaborative screening approach to observe, rationalize, and control the formation of new metastable forms.