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

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

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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.

Original language	English
Pages (from-to)	7217-7230
Number of pages	14
Journal	Crystal Growth and Design
Volume	23
Issue number	10
Early online date	30 Aug 2023
DOIs	https://doi.org/10.1021/acs.cgd.3c00641
Publication status	Published - 4 Oct 2023

Funding

The authors would like to acknowledge Dmitry S. Yufit for the crystal structure elucidation of the Gelator G2 and Solvates S1 and S2. G.M.D. and C.R.T. would like to acknowledge David P. McMahon for contributions to the flexible-molecule CSP work. G.M.D. and C.R.T. acknowledge the use of the IRIDIS High-Performance Computing Facility and associated support services at the University of Southampton, as well as the use of the ARCHER2 U.K. National Supercomputing Service (https://www.archer2.ac.uk) provided by our membership of the U.K.’s HEC Materials Chemistry Consortium, funded by EPSRC (EP/L000202, EP/R029431). Part of this work was carried out in the CMAC National Facility supported by UKRPIF (U.K. Research Partnership Fund) award from the Higher Education Funding Council for England (HEFCE) (grant no. HH13054). We acknowledge Diamond Light Source for time on Beamline I11 via Rapid Access Proposal CY25007. The authors would like to acknowledge that all data underpinning the characterization of the two pure phases and salt forms are openly available from the University of Strathclyde KnowledgeBase (DOI: 10.15129/ba2d77ef-6958-4561-9281-a87dc51e10b9) and Durham University Collections (DOI: 10.15128/r13b5918658). The data set of CSP-generated structures is available from the University of Southampton Pure service (DOI: 10.5258/SOTON/D2604). The authors would like to acknowledge Dmitry S. Yufit for the crystal structure elucidation of the Gelator G2 and Solvates S1 and S2. G.M.D. and C.R.T. would like to acknowledge David P. McMahon for contributions to the flexible-molecule CSP work. G.M.D. and C.R.T. acknowledge the use of the IRIDIS High-Performance Computing Facility and associated support services at the University of Southampton, as well as the use of the ARCHER2 U.K. National Supercomputing Service ( https://www.archer2.ac.uk ) provided by our membership of the U.K.’s HEC Materials Chemistry Consortium, funded by EPSRC (EP/L000202, EP/R029431). Part of this work was carried out in the CMAC National Facility supported by UKRPIF (U.K. Research Partnership Fund) award from the Higher Education Funding Council for England (HEFCE) (grant no. HH13054). We acknowledge Diamond Light Source for time on Beamline I11 via Rapid Access Proposal CY25007. The authors would like to acknowledge that all data underpinning the characterization of the two pure phases and salt forms are openly available from the University of Strathclyde KnowledgeBase (DOI: 10.15129/ba2d77ef-6958-4561-9281-a87dc51e10b9) and Durham University Collections (DOI: 10.15128/r13b5918658). The data set of CSP-generated structures is available from the University of Southampton Pure service (DOI: 10.5258/SOTON/D2604). Engineering and Physical Sciences Research council: grant no. EP/N015401/1 to I.D.H.O. and M.R.W. and grant no. EP/R013373/1 to J.W.S. and G.M.D., supporting M.T.M. and C.R.T.

Keywords

polymorphism
chlorpropamide
crystal structure calculation
milling
gels
spray drying

Access to Document

10.1021/acs.cgd.3c00641Licence: CC BY 4.0

Ward-etal-CGD-2023-Pushing-technique-boundaries-to-probeFinal published version, 6.74 MBLicence: CC BY 4.0

Cite this

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title = "Pushing technique boundaries to probe conformational polymorphism",

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.",

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doi = "10.1021/acs.cgd.3c00641",

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T1 - Pushing technique boundaries to probe conformational polymorphism

AU - Ward, Martin R.

AU - Taylor, Christopher R.

AU - Mulvee, Matthew T.

AU - Lampronti, Giulio I.

AU - Belenguer, Ana M.

AU - Steed, Jonathan W.

AU - Day, Graeme M.

AU - Oswald, Iain D. H.

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N2 - 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.

AB - 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.

KW - polymorphism

KW - chlorpropamide

KW - crystal structure calculation

KW - milling

KW - gels

KW - spray drying

UR - https://pubs.acs.org/journal/cgdefu

U2 - 10.1021/acs.cgd.3c00641

DO - 10.1021/acs.cgd.3c00641

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VL - 23

SP - 7217

EP - 7230

JO - Crystal Growth and Design

JF - Crystal Growth and Design

IS - 10

ER -

Pushing technique boundaries to probe conformational polymorphism

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Pressure-Induced Nucleation for the Continuous Manufacture of Supramolecular assemblies

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Pushing technique boundaries to probe conformational polymorphism

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