Neotame Anhydrate Polymorphs I: Preparation and Characterization

Purpose: To prepare, characterise and compare polymorphs of neotame anhydrate. Methods: Neotame anhydrate polymorphs were prepared from amorphous or crystalline anhydrate by crystallization or suspension in various organic solvents, or by dehydration of neotame monohydrate. The following techniques were used for characterization: differential scanning calorimetry, thermogravimetry, hot-stage microscopy, powder X-ray diffractometry (PXRD), 13 C solid-state nuclear magnetic resonance (SSNMR) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy, dynamic water vapor sorption/desorption, and density measurements. Results: Seven polymorphs (Forms A-G) of neotame anhydrate were prepared and show different thermal properties and PXRD patterns, Two enantiotropically related pairs were identified: B and C; E and A. 13 C SSNMR and FTIR spectroscopy clearly distinguish between Forms A. D, F, and G, which show similar needle-shaped morphology hut distinct differences in dynamic water vapor sorption/desorption and density. The 13 C. SSNMR chemical shifts suggest conformational polymorphism. The stability in the presence of water vapor follows the rank order. G > A > D - F, which resembles the rank orders of the molar volume and of the polarity of the solvents from which they crystallized. Conclusions: The neotame anhydrate polymorphs appear to show different molecular conformations. The less dense polymorphic structures crystallize from solvents of greater polarity and sorb water vapor less rapidly and less completely. Two enantiotropic pairs were discerned.