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

Eddleston, Mark, Arhangelskis, Mihalis, Fabian, Laszlo, Tizzard, Graham, Coles, Simon J. and Jones, William (2016) Investigation of an amide-pseudo amide hydrogen bonding motif within a series of theophylline:amide cocrystals. Crystal Growth & Design, 16 (1). pp. 51-58. ISSN 1528-7483

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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.

Item Type: Article
Uncontrolled Keywords: cocrystals,polymorphism,stability,hydrogen bonding,crystal chemistry,pharmaceutical
Faculty \ School: Faculty of Science > School of Pharmacy
UEA Research Groups: Faculty of Science > Research Groups > Drug Delivery and Pharmaceutical Materials (former - to 2017)
Faculty of Science > Research Groups > Pharmaceutical Materials and Soft Matter
Depositing User: Pure Connector
Date Deposited: 20 Jan 2016 13:00
Last Modified: 22 Oct 2022 00:32
DOI: 10.1021/acs.cgd.5b00905

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