First Crystal Structure of an Aspartame Cocrystal

Aspartame crystallizes as very long, thin needles. The crystallization behavior of extreme needle formers not only causes problems in industrial processing and handling but is also of interest in fundamental research. Cocrystallization is a popular approach to expand the solid-state landscape of a compound and often leads to improved physicochemical properties such as stability, dissolution behavior, particle size, and morphology. No crystal structure of an aspartame cocrystal has been reported in the literature up to now. In this work, a comprehensive screening study for aspartame cocrystals was performed. Cocrystals with fumaric acid and 4-hydroxybenzoic acid were detected by powder X-ray diffraction analysis. Growing X-ray suitable cocrystals, however, proved extremely difficult, as both cocrystals, like aspartame, crystallized as very fine needles. Nevertheless, in the case of 4-hydroxybenzoic acid, crystals of sufficient quality for single-crystal X-ray analysis could be grown, and the first crystal structure of an aspartame cocrystal is reported. In the cocrystal aspartame·4-hydroxybenzoic acid dihydrate (1), the coformer forms the OH···^–OOC synthon with aspartame. The aspartame zwitterions in 1 are connected through charge-assisted NH₃⁺···^–OOC hydrogen bonds into a spiral along a 2₁ screw axis, the same structural feature that drives the needle growth of aspartame and that seems to be the reason why the isolation of X-ray-quality cocrystals of aspartame is so challenging.

Aspartame·4-hydroxybenzoic acid dihydrate is the first cocrystal of aspartame for which complete single crystal data could be obtained. Similar to aspartame, strong charge-assisted hydrogen bonding combined with van der Waals contact stacking result in an extreme anisotropic growth and needle morphology.