Structure, dynamics, and stability of β-cyclodextrin inclusion complexes of aspartame and neotame

Studies of the high-intensity sweetener aspartame show that its stability is significantly enhanced in the presence of β-cyclodextrin (β-CyD). At a 5:1 β-CyD/aspartame molar ratio, the stability of aspartame is 42% greater in 4 mM phosphate buffer (pH 3.1) compared to solutions prepared without β-CyD. Solution-state ¹H NMR experiments demonstrate the formation of 1:1 β-CyD/aspartame complexes, stabilized by the interaction of the phenyl-ring protons of aspartame with the H3 and H5 protons of β-CyD. Inclusion complex formation clearly accounts for the observed stability enhancement of aspartame in solution. The formation of inclusion complexes in solution is also demonstrated for β-CyD and neotame, a structural derivative of aspartame containing an N-substituted 3,3-dimethylbutyl group. These complexes are stabilized by the interaction of β-CyD with both phenyl-ring and dimethylbutyl protons. Solid-state NMR experiments provide additional characterization, clearly demonstrating the formation of inclusion complexes in lyophilized solids prepared from solutions of β-CyD and either aspartame or neotame.