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

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.