Investigation of an amide-pseudo amide hydrogen bonding motif within a series of theophylline:amide cocrystals

Mark Eddleston, Mihalis Arhangelskis, Laszlo Fabian, Graham Tizzard, Simon J. Coles, William Jones

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The pharmaceutically active compound theophylline (T) was cocrystallised with the amides formamide (1), acetamide (2), N-methylformamide (3), N,N-dimethylformamide (4), benzamide (5) and pyrazinamide (6), with systems T:1, T:5 and T:6 displaying polymorphic behaviour. The cocrystals with formamide (T:1), acetamide (T:2) and benzamide (T:5), and one polymorph of
the cocrystal with pyrazinamide (T:6-I), contain an R22(9) hydrogen bonding motif between the amide cocrystal formers and the HN-C-C=O moiety of the theophylline molecule (an amide-pseudo amide synthon). This motif was, however, absent from the other polymorph of the pyrazinamide cocrystal (T:6-II), and also from the N-methylformamide cocrystal (T:3) (and is not possible in the N,N-dimethylformamide cocrystal (T:4)). These observations are rationalised using hydrogen bond propensity calculations, although limitations of using such calculations for predicting cocrystallisation are noted. The amide-pseudo amide synthon is favoured when theophylline cocrystallises with both primary amides and with secondary amides which are locked in a cis configuration. On heating, all cocrystals were found to dissociate before melting due to loss of the amide, making stability to dissociation a more meaningful measure of cocrystal stability than melting point for these systems. On dissociation of the cocrystals, theophylline typically crystallises as the commonly observed polymorph Form II. In the case of the acetamide cocrystal (T:2), however, the rarely observed metastable polymorph, Form V, crystallises concomitantly with Form II suggesting that cocrystal dissociation on heating could be a strategy for generating novel polymorphic forms of compounds.
Original languageEnglish
Pages (from-to)51-58
Number of pages8
JournalCrystal Growth & Design
Issue number1
Early online date17 Nov 2015
Publication statusPublished - 6 Jan 2016


  • Cocrystals
  • Polymorphism
  • Stability
  • Hydrogen bonding
  • Crystal chemistry
  • Pharmaceutical

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