Unveiling polyamorphism and polyamorphic interconversions in pharmaceuticals: the peculiar case of hydrochlorothiazide

08 June 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


Active pharmaceutical ingredient
Glass transition temperature
Pair distribution function
Molecular Dynamics simulations
Structural relaxation

Supplementary materials

Electronic Supplementary Information (ESI)
The Electronic Supplementary Information (ESI) contains detailed description for all experimental techniques and computational methods used. Supplementary data, including TGA, DSC, PXRD, HPLC, PDF, radial distribution function and dihedral angle distributions are also provided.


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