Energy/temperature diagram and compression behavior of the polymorphs of D-mannitol

Three modifications of D-mannitol were produced and investigated: mod. I (mp 166.5°C, heat of fusion 53.5 kJ mol^-1), mod. II (mp 166°C, heat of fusion 52.1 kJ mol^-1), and mod. III (mp incongruent 150-158°C, heat of transition, III to I 0.2 kJ mol^-1). The measured densities are 1.490 ± 0.000 gcm^-3 [95% confidence interval (CI)] for mod. I, 1.468 ± 0.002 g cm^-3 (95% CI) for mod. II, and 1.499 ± 0.004 gcm^-3 (95% CI) for mod. III. It was possible to relate the different modifications given in the literature to one of the three pure crystal forms or to mixtures of two or all three modifications. The thermodynamic relationship among the crystal forms is represented in a semi-schematic energy/temperature diagram. From these data we can conclude that mod. III is thermodynamically stable at absolute zero. It is enantiotropically related to mod. I and mod. II. FTIR and Raman spectra, differential scanning calorimetry curves, and X-ray powder patterns of these crystal forms are depicted for doubtless assignment in the future. The water uptake of the three modifications at 92% relative humidity and 25°C is less than 1%. The differences of the heat capacities and the heats of solution between mod. II and III are not significant, whereas mod. I shows small significant differences compared with the other modifications. In addition, compaction studies of these crystal forms were performed by means of an instrumented hydraulic press. The results show that mod. III should have the best tableting behavior under these conditions. (C) 2000 Wiley-Liss, Inc. and the American Pharmaceutical Association.