Comparison of Solid-State ¹³C NMR Spectroscopy and Powder X-ray Diffraction for Analyzing Mixtures of Polymorphs of Neotame

Polymorphism is defined as the ability of a compound to adopt two or more conformations and/or arrangements in its crystalline state. Polymorphism and pseudopolymorphism (i.e., a change in solvation state) are important because the different crystal forms of a compound can have different physical properties, such as density, melting point, and solubility. Powder X-ray diffraction is currently the most common method for determining the existence of polymorphism in crystalline organic compounds. Solid-state 13 C NMR spectroscopy has emerged as another powerful analytical technique for determining polymorphism. Both solid-state 13 C NMR spectroscopy and powder X-ray diffraction have been used to analyze mixtures of the solid forms of neotame. Neotame, N -(3,3-dimethylbutyl)- l -aspartyl- l -phenylalanine methyl ester, is a new high-potency sweetener that exists in multiple solid forms. The most stable form of neotame under ambient conditions in the presence of moisture is a monohydrate. Altering the crystallization and drying conditions can generate mixtures of solid forms of neotame. A systematic study has been performed to observe the conversion under vacuum of the monohydrate to a mixture of forms and then reconversion to the monohydrate upon exposure to moisture under ambient conditions. No significant changes were observed in the powder X-ray diffraction patterns during part of the reconversion process, suggesting that no change in form had occurred. The solid-state 13 C NMR spectra, however, indicated the presence of many forms of neotame during the reconversion. One possible reason that solid-state 13 C NMR spectroscopy detected the changes in forms and powder X-ray diffraction did not is that the conformation of the neotame molecules changes between forms but the unit cell parameters do not change significantly.