Prediction of the relaxation behavior of amorphous pharmaceutical compounds. I. Master curves concept and practice.

Variability in the time to crystallization is a major technical and economic hurdle in using amorphous solids in dosage forms. It is hypothesized that amorphous solids "age", and that the older they are, the more relaxed they are and the higher the probability of crystallization. At present, there is no method that allows the "effective age" of an amorphous raw material to be assessed relative to its unrelaxed initial condition. A method has been developed that may satisfy this unmet need and provide a first step in subsequent investigation of the crystallization "event". This method consists of using master curves to enable the determination of the effective age ("aging") of an amorphous compound given normal excursions in storage conditions. The present study shows that master curves can be prepared for different storage conditions and subsequently be used to predict the relaxation or aging behavior of amorphous compounds with expected variations in storage conditions. Given the constraint that the system remain within the area enclosed by the equilibrium supercooled liquid line and the glass on the enthalpy-temperature diagram, experimental results using indomethacin and salicin as model compounds show that master curves can be used to predict aging behavior under nonisothermal conditions, with temperature excursions as large as 10 degrees C. The nonisothermal relaxation behavior can be modeled by combining the Kohlrausch-Williams-Watts (KWW) stretched exponential function, the relaxation function, and a shift factor. In addition, a model was developed that extends the range of applicability to time/temperature regions in which partial crystallization occurs.