Investigation of an Amide-Pseudo Amide Hydrogen Bonding Motif within a Series of Theophylline:Amide Cocrystals

The
pharmaceutically active compound theophylline (T) was
cocrystallized 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 behavior. 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 rationalized
using hydrogen bond propensity calculations, although limitations
of using such calculations for predicting cocrystallization are noted.
The amide-pseudo amide synthon is favored when theophylline cocrystallizes
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 crystallizes as the commonly
observed polymorph Form II. In the case of the acetamide cocrystal
(T:2), however, the rarely observed metastable polymorph,
Form V, crystallizes concomitantly with Form II suggesting that cocrystal
dissociation on heating could be a strategy for identifying novel
polymorphic forms of compounds.