Synthon Hierarchies in Crystal Forms Composed of Theophylline and Hydroxybenzoic Acids: Cocrystal Screening via Solution-Mediated Phase Transformation

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• 作者：Dejan-Kre拧imir Bu膷ar ; Rodger F. Henry ; Geoff G. Z. Zhang ; Leonard R. MacGillivray
• 刊名：Crystal Growth & Design
• 出版年：2014
• 出版时间：October 1, 2014
• 年：2014
• 卷：14
• 期：10
• 页码：5318-5328
• 全文大小：578K
• ISSN：1528-7505

文摘

Theophylline, a pharmaceutical model compound, was screened for cocrystal formation using nine (di)hydroxybenzoic acids as cocrystal formers, namely, 2-, 3-, 4-hydroxybenzoic- and 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-dihydroxybenzoic acids. The experiments were conducted using an efficient, reliable, and fast screening method based on thermodynamically driven solution-mediated phase transformation and revealed the formation of eight cocrystals and one salt. The theophylline-based solids were identified using powder and structurally characterized via single-crystal X-ray diffraction. The obtained solids are sustained by theopylline-carboxylic acid heterosynthons, in addition to both theophylline and carboxylic acid homosynthons. The results are a part of a systematic study of xanthine-alkaloid cocrystals that aims to establish synthon hierarchies in cocrystals comprised of molecules with multiple hydrogen-bonding functional groups. Structural features and synthon hierachies are discussed and compared to those in a series of published caffeine cocrystals.