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Crystallization and crystal energy landscape of hydrochlorothiazide

Johnston, Andrea and Florence, Alastair J. and Shankland, Norman and Kennedy, Alan R. and Shankland, K. and Price, Sarah L. (2007) Crystallization and crystal energy landscape of hydrochlorothiazide. Crystal Growth and Design, 7 (4). pp. 705-712. ISSN 1528-7483

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A search for physical forms of the diuretic compound hydrochlorothiazide, utilizing automated parallel crystallization, identified two polymorphs and seven novel organic solvates (1:1 with aniline, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, and methyl acetate and 1:2 with N,N-dimethylacetamide and N-methyl-2-pyrrolidone). The majority of crystallizations produced the well-known polymorphic form I, with the recently reported metastable form II obtained from a subset of crystallization conditions. An accompanying computational search found that five rigid body conformations generated ca. 60 crystal structures, including the two polymorphs, within 12 kJ mol(-1) of the global minimum. This is a consequence of the abundant hydrogen-bonding opportunities that arise from the functional groups present in the molecule. In particular, a range of bimolecular hydrogen-bonding motifs is predicted, and these motifs are also prevalent among the solvated crystal structures. The value of the crystal structure predictions is, therefore, not restricted to nonsolvated forms but has been extended to provide a more complete view of the favorable motifs that underpin solvate formation, a phenomenon that remains largely unexplained at present. While this is an encouraging step along the way to understanding solvate formation, this investigation also highlights important elements of the prediction methodology that require further development.