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

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

Bottom-up Chemoenzymatic Synthesis Towards Novel Fluorinated Cellulose-like Materials

Understanding the fine details of self-assembly of building blocks into complex hierarchical structures represents a major challenge en route to the design and preparation of soft matter materials with specific properties. Enzymatically-synthesised cellodextrins are known to have limited water solubility beyond DP9, a point at which they self-assemble into particles resembling the anti-parallel cellulose II crystalline packing. We have prepared and characterized a series of site-selectively fluorinated cellodextrins of different degrees of fluorination and substitution patterns by chemoenzymatic synthesis. The structural characterization of these materials at different length scales, combining advanced NMR and microscopy methods, showed that multiply 6-fluorinated cellodextrin chains assembled into particles presenting morphological and crystallinity features that are unprecedented for cellulose-like materials. In contrast, the introduction of a single fluorine atom per cellodextrin chain had a minor impact on materials structure. Our work emphasizes the strength of combining chemoenzymatic synthesis, fluorinated building blocks and advanced NMR and microscopy methods for the thorough characterization of hierarchical structures, leading to the controlled design of new biomaterials with specific properties

Bottom-up Chemoenzymatic Synthesis Towards Novel Fluorinated Cellulose-like Materials

Understanding the fine details of self-assembly of building blocks into complex hierarchical structures represents a major challenge en route to the design and preparation of soft matter materials with specific properties. Enzymatically-synthesised cellodextrins are known to have limited water solubility beyond DP9, a point at which they self-assemble into particles resembling the anti-parallel cellulose II crystalline packing. We have prepared and characterized a series of site-selectively fluorinated cellodextrins of different degrees of fluorination and substitution patterns by chemoenzymatic synthesis. The structural characterization of these materials at different length scales, combining advanced NMR and microscopy methods, showed that multiply 6-fluorinated cellodextrin chains assembled into particles presenting morphological and crystallinity features that are unprecedented for cellulose-like materials. In contrast, the introduction of a single fluorine atom per cellodextrin chain had a minor impact on materials structure. Our work emphasizes the strength of combining chemoenzymatic synthesis, fluorinated building blocks and advanced NMR and microscopy methods for the thorough characterization of hierarchical structures, leading to the controlled design of new biomaterials with specific properties