Crystallization and Crystal Energy Landscape of Hydrochlorothiazide

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• 作者：Andrea Johnston ; Alastair J. Florence ; Norman Shankland ; Alan R. Kennedy ; K. Shankland ; Sarah L. Price
• 刊名：Crystal Growth & Design
• 出版年：2007
• 出版时间：April 2007
• 年：2007
• 卷：7
• 期：4
• 页码：705 - 712
• 全文大小：379K
• 年卷期：v.7,no.4(April 2007)
• ISSN：1528-7505

文摘

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 thewell-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 thetwo polymorphs, within 12 kJ mol^-1 of the global minimum. This is a consequence of the abundant hydrogen-bonding opportunitiesthat arise from the functional groups present in the molecule. In particular, a range of bimolecular hydrogen-bonding motifs ispredicted, 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 thatunderpin solvate formation, a phenomenon that remains largely unexplained at present. While this is an encouraging step along theway to understanding solvate formation, this investigation also highlights important elements of the prediction methodology thatrequire further development.