Calorimetric Relaxation in Pharmaceutical Molecular Glasses and Its Utility in Understanding Their Stability Against Crystallization

Glassy states of three pharmaceuticals, acetaminophen, griseofulvin, and nifedipine, and an acetaminophen−aspirin (1:1 mol) alloy were made by slow cooling of the melt and studied by calorimetry. Measurements were performed by cooling and heating at significantly slow rates of 20 K/h, which were comparable to the rate used in adiabatic calorimetry. The results were modeled in terms of a nonexponential, nonlinear structural relaxation. The calorimetric relaxation of all four pharmaceutical samples were less nonexponential than those of polymeric or inorganic glasses, and this finding was attributed to additional contributions to energy change that would arise from temperature and time dependent variation in the hydrogen bond population, the extent of isomerization, and/or the ionic equilibria that exist in these materials. Four calculated and relevant parameters for the pharmaceutical samples were, ln A = −183, β = 0.75, x = 0.4, and Δh* = 457 kJ/mol for acetaminophen, ln A = −170, β = 0.75, x = 0.45, and Δh* = 516 kJ/mol for griseofulvin, ln A = −189, β = 0.69, x = 0.39, and Δh* = 503 kJ/mol for nifedipine, and ln A = −160, β = 0.70, x = 0.50, and Δh* = 363 kJ/mol for the acetaminophen−aspirin alloy. The significance of these parameters and, in particular, their values are discussed in the context of the stability of the pharmaceuticals against crystallization and compared against the significance of the localized motions of the JG relaxation in the same context. Acetaminophen was found to be significantly more prone to crystallization on heating than the other two pharmaceuticals as well as the acetaminophen−aspirin alloy.