Investigation of polymorphism in aspartame and neotame using solid-state NMR spectroscopy

We have been studying the artificial sweeteners aspartame (L-aspartyl-L-phe nylalanine methyl eater) and neotame (N-(3,3-dimethylbutyl)-L-aspartyl-L-ph enylalanin methyl ester) as compounds which exhibit polymorphism. C-13 CP/M AS NMR shows that aspartame exists in three distinct forms at room temperat ure, depending on preparation conditions. For two of the forms, there exist s three resonances for each carbon, indicating three crystallographically i nequivalent sites and therefore three distinct conformations and/or arrange ments of aspartame molecules within the unit cell. Two-dimensional exchange spectroscopy using high-speed MAS and very high-power H-1 decoupling on un iformly C-13 labeled aspartame is a very powerful tool for unambiguously as signing each resonance in the NMR spectrum of aspartame. Even for forms of aspartame that possesses multiple crystallographically inequivalent sites, it is possible to identify connectivities between the nuclei of each confor mation and/or arrangement of molecules using two-dimensional NMR techniques . C-13 CP/MAS NMR also shows that neotame exists in multiple solid forms. T he most stable form of neotame under ambient conditions is a monohydrate. H owever, other forms can be prepared by heating or using reduced pressures. We have found that high-speed magic-angle spinning can cause a change in po lymorphic forms. Three different forms were produced upon spinning at 29 kH z for several days. The monohydrate was identified as the second form produ ced. Also, altering the crystallization and drying conditions can generate mixtures of the solid forms of neotame. When the monohydrate form of neotam e was heated under vacuum, a mixture of anhydrate forms was produced. In th e reconversion to the monohydrate upon exposure to moisture under ambient c onditions no significant changes were observed in the powder X-ray diffract ion patterns during part of the reconversion process. This suggests that no change in form had occurred. The C-13 CP/MAS NMR spectra, however, indicat ed the presence of many forms of neotame during the reconversion. One possi ble reason that solid-state NMR spectroscopy detected the changes in forms and powder X-ray diffraction did not is that the conformation of the neotam e molecules changes between forms but the unit cell parameters do not chang e significantly. (C) 2000 Elsevier Science Ltd. All rights reserved.