Crystal structure of the low‐humidity form of aspartame sweetener

Abstract: The low‐humidity IB crystal form of aspartame (l ‐α‐aspartyl‐l ‐phenylalanine methyl ester) is prepared via humidity‐induced transition from the highly hydrated IA crystal form and is used widely as a sweetener. The crystal structure of the low‐humidity IB form is determined at 1.05 Å resolution (0.476 Å^?1 in maximum sinθ/λ) from an extremely fine fibrous crystal using synchrotron radiation. There are three aspartame molecules and two water molecules in the asymmetric unit of the monoclinic space group P2₁. Each aspartame molecule adopts an almost identical extended conformation which is commonly observed in other crystal forms of aspartame. Three aspartame molecules are assembled into a triangular trimer, and trimer units are stacked along the b‐axis via hydrogen‐bonding and electrostatic interactions in the main chains and also via hydrophobic contacts in the phenyl side‐chains. Six trimer units are related by pseudo 6₁‐screw axis symmetry and form a hydrophilic channel at their center. The hydrophilic channel in the IB form contains only four water molecules in the unit cell, compared with 16 in the IA form. Although the IB form exhibits a trimer structure similar to that of the IA form, one aspartame molecule is rotated by ≈ 20° from the orientation in the IA form. This arrangement of the molecule implies that the humidity‐induced transition is accompanied by a flapping motion of its methyl ester group. These structural differences may imply the stepwise transition from the IA to the IB forms.