Conformational flexibility and polymorphism of the dipeptide sweetener, neotame

Abstract

This thesis reports the conformational flexibility and polymorphism of the dipeptide sweetener, neotame (N-(3,3-dimethylbutyl)-L-aspartyl-L-phenylalanine methyl ester).

Neotame anhydrate is found to exist in multiple polymorphic forms and in several solvates. The crystal structures of the following five forms of neotame were solved: a monohydrate, three organic solvates (methanol, ethanol, and benzene), and an anhydrate polymorph G. Analysis of the molecular conformations in these crystal structures using molecular modeling software (Cerius ^{2, TM}) showed that the neotame molecules take different conformations. The conformational flexibility of the neotame molecule provides the possibility of conformational polymorphism for neotame anhydrate. Among the anhydrate polymorphs, A–G, Forms A, D, F, G were prepared in bulk, and were characterized by various thermal analytical, calorimetric, spectroscopic and crystallographic techniques. Using thermodynamic rules, the thermodynamic relationships among these four polymorphs were determined, i.e., A–G and A–D are enantiotropic pairs, whereas D–F, D–G, F–G are monotropic pairs. The phase transition temperature between A and G is estimated to be 35–70°C. At 70°C, the relative stability of the four polymorphs follows the rank order: G > D > F and G > A. An analytical method employing powder X-ray diffractometry (PXRD) was developed for the accurate quantitative analysis of binary polymorphic mixtures of A and G.

Molecular modeling (Cerius^{2, TM}) was employed to calculate the most stable conformations of the neotame molecule in the gaseous state. These gas-phase conformations have lower conformational energies than those in the five crystal forms, indicating an energetic compromise between conformational flexibility and the geometry of efficient molecular packing in the crystal. By graph-set analysis, the intramolecular ring, S(5), is found to exist in all the above five crystal forms, and the following hydrogen bonding patterns occur in some of them: diad, D, intramolecular rings, S(6) and S(7), chains, C (5) and C(6), and an intermolecular ring, [special characters omitted](12). Cerius^{2, TM} Powder Solve was employed to determine the crystal structure of polymorph G from its PXRD pattern, and the results suggest that an accurate representation of the molecular conformation is essential for deducing the crystal structure from PXRD.