Abstract
Polyamorphism has been a controversial and highly debated solid-state phenomenon in both material and pharmaceutical communities. Although some evidence of this fascinating phenomenon has been reported for several inorganic systems, and more recently also for a few organic compounds, the occurrence of polyamorphism is poorly understood and the molecular-level organization of polyamorphic forms is still unknown. Here we have investigated the occurrence of polyamorphism and polyamorphic interconversions in hydrochlorothiazide (HCT), using both experimental and computational methods. Three distinct HCT polyamorphs, presenting distinct physical and thermal stabilities as well as distinct relaxation properties, were systematically prepared using spray-drying (SD), quench-cooling (QC) and ball milling (BM) methods. HCT polyamorph II (obtained by QC) was found to be more physically stable than polyamorphs I and III (obtained by SD and BM, respectively). Furthermore, polyamorphs I and III could be converted into polyamorph II after QC, while polyamorph II did not convert to any other polyamorph after SD or BM. Molecular dynamics simulations show that HCT dihedral angle distributions are significantly different for polyamorphs I and II, which is postulated as a possible explanation for their different physicochemical properties.
Original language | English |
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Journal | Chemical Science |
Volume | 14 |
Issue number | 41 |
Pages (from-to) | 11447-11455 |
Number of pages | 9 |
ISSN | 2041-6520 |
DOIs | |
Publication status | Published - 2023 |
Bibliographical note
Funding Information:The authors acknowledge the Independent Research Fund Denmark for funding the project 0135-00103A “Organic Polyamorphism: Existence – Formation – Relevance”, NordForsk (Nordic POP) for financial support travelling to conferences and workshops, and DESY (Hamburg, Germany), a member of the Helmholtz Association HGF, for the provision of experimental facilities. PDF of this research were carried out at PETRA III beamline P02.1. Beamtime was allocated for proposal(s) I-20210421-EC.
Publisher Copyright:
© 2023 The Royal Society of Chemistry.