Demonstration of the terms enantiotropy and monotropy in polymorphism research exemplified by flurbiprofen

The thermodynamic terms enantiotropy and monotropy are demonstrated by means of solid-state analytical results of polymorphous flurbiprofen (FBP). Vibrational spectra, differential scanning calorimetry (DSC), and thermomicroscopy investigations as well as X-ray powder patterns for three modifications of FBP are described. The melting points are mod. I 113-114 degreesC (enthalpy of fusion 27.9 +/- 0.2 kJ mol-1) for modification I (mod. I), 92 degreesC for mod. II, and 87 degreesC for mod. III. The true densities of mod. I (1.279 +/- 0.001 g cm-3) and mod. II (1.231 +/- 0.002 g cm-3) were measured at 25 degreesC. Modification I (commercial product) is the thermodynamically stable crystal form from absolute zero to its melting point. Modification II was crystallized on a gram scale from a warm saturated solution of FBP in n-heptane and rapid cooling of the solution to -18 degreesC. Modification I is monotropically related to mod. II and mod. III, due to application of the density rule and the entropy-of-fusion rule. The thermodynamic relationships between the three modifications are demonstrated by a semischematic energy/temperature diagram. Theoretical vapor pressure/temperature diagrams and energy/temperature diagrams are compared and briefly discussed.