Neotame anhydrate polymorphs. II: Quantitation and relative physical stability

Purpose. To study the relative thermodynamic and kinetic stabilities of neotame anhydrate polymorphs A, D, F, and G, and to develop a quantitative method for analyzing polymorphic mixtures of A and G by powder X-ray diffractometry (PXRD).Methods. Based on the melting points, heats of fusion, and densities of the four polymorphs, thermodynamic rules were applied to study their thermodynamic relationships. The phase transition temperature of Forms A and G was estimated from their heats of solution and intrinsic dissolution rates (J) in 2-propanol. Using PXRD, a method for the quantitative analysis of polymorphic mixtures of Forms A and G was developed. Binary polymorphic mixtures of Forms A, D, F, or G were stored under zero relative humidity at 23 or 70°C, and their compositions were monitored by PXRD.Results. The endothermic enthalpy of solution of A, D, F, and G follows the rank order: G (29.71 ± 0.82 kJ/mol, n = 4) > A (28.48 ± 0.51 kJ/mol, n = 4) > D (20.43 ± 0.45 kJ/mol, n = 4) > F (18.77 ± 0.31 kJ/mol, n = 4). The van't Hoff plots of ln(J) against 1/T for A and G show good linearity between 25°C and 32°C. At 23°C polymorphic mixtures remain unchanged for 4 months. However, at 70°C the phase transition is fast and the relative stability of the four polymorphs follows the rank order: G > D > F and G > A.Conclusions. PXRD provides a reliable and accurate technique for the quantitative analysis of polymorphic mixtures of Forms A and G. Among the four polymorphs, 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 lies within the range 35-70°C.