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The polymorphism of furosemide has been extensively investigated and characterized using X-ray powder diffractometry, differential scanning calorimetry, infrared and Fourier transform infrared spectroscopy, elemental analysis, hot-stage microscopy and scanning electron microscopy. Comparative analysis of the results reported by Doherty and York (1988) with the present data was performed to a high degree of precision in order to determine the points of agreement and difference between the two studies. The aforementioned authors investigated only two polymorphs (one stable and one metastable form), contrasting with our findings of five new types of modification (two polymorphs, two solvates and one amorphous form) in addition to the crystal forms. Among the seven modifications, enantiotropism was observed between two stable forms (low- and high-temperature-stable forms). On heating, the two metastable forms underwent transformation directly to the high-temperature-stable form whereas the situation in the case of the solvates involved progression via the intermediate stage of the low-temperature-stable form. The thermodynamic stability of these four polymorphs is discussed in relation to the activation energy and heat of transformation. A distinctly different degree of physicochemical photostability (coloration) was evident among the modifications; although the stable form did not show significant coloration even when irradiated with intense light, the other crystal forms were very susceptible to coloration. One of the metastable forms (form (III)) far surpassed any of the other crystal forms in dissolution properties.

The physicochemical properties of amorphous forms of frusemide, prepared by spray-drying at 50 or 150°C, and their hygroscopic stability at temperatures of 25 and 40°C, and at 0 and 75% relative humidity were investigated. The glass transition temperature of the amorphous form A was 44·2°C as measured by differential scanning calorimetry, while that of the amorphous form B was 54·4°C. The activation energies for glass transition and crystallization processes were calculated from the differential scanning calorimetry thermograms of amorphous forms A and B, respectively. Stability determined by X-ray diffraction at 0% relative humidity, 25 and 40°C suggested that form B was more stable than form A. However, the stability of form A at 75% relative humidity and 25 and 40°C was similar to that of form B.

The polymorphic transformations of phenylbutazone from metastable forms alpha and beta to stable form delta were studied quantitatively at four temperature and five humidity levels by X-ray powder diffractometry. The transformation of form alpha conformed with the Avrami-Erofe'ev kinetic model and form beta conformed with apparent first-order kinetics. In the two transformation systems, the induction periods depended on the storage conditions and were prolonged with lowering of temperature and humidity. The transformation rate of form alpha was not affected by humidity, whereas that of form beta increased according to a rise in humidity. The temperature dependency of the transformation rate constant was remarkable. The Arrhenius treatment was applicable to the beta----delta transformation at low temperatures. The overall half-life, including induction period, revealed that form alpha was more stable than form beta under any storage condition. A good linear relationship existed between the induction period and the transformation rate constant, irrespective of the storage conditions. The scanning electron photomicrographs of forms alpha and beta demonstrated that acicular crystals of form delta grew as the transformation progressed. This could be confirmed as the change in particle diameter of the samples.

The kinetics of the isothermal transition of tolbutamide polymorphic forms (form B at 65, 70, 75 and 80°C), as well as mefenamic acid (form I at 142.5, 145, 147.5 and 150°C) were investigated by means of differential scanning calorimetry. Kinetic analysis according to the method of Hancock and Sharp indicated that the transition of form B to form A of tolbutamide proceeds by the mechanism of three-dimensional diffusion (Jander equation). The activation energy for this transition calculated from the slope of the Arrhenius plots was 37.3 kcal/mol. On the other hand, the transition of form I to form II of mefenamic acid appeared to follow the zero-order mechanism (Polany-Winger equation). The activation energy for this transition was calculated to be 86.4 kcal/mol.