Prediction of Onset of Crystallization in Amorphous Pharmaceutical Systems: Phenobarbital, Nifedipine/PVP, and Phenobarbital/PVP

The aim of this work is to determine if a stability testing protocol based on the correlations between crystallization onset and relaxation time above the glass transition temperature (T-g) can be used to predict the crystallization onsets in amorphous pharmaceutical systems well below their T-g. This procedure assumes that the coupling between crystallization onset and molecular mobility is the same above and below T-g. The stability testing protocol has been applied to phenobarbital, phenobarbital/polyvinylpyrrolidone (PVP) (95/5, w/w), and nifedipine/PVP (95/5, w/w). Crystallization onsets have been detected by polarized light microscopy examination of amorphous films; molecular mobility has been determined by dielectric relaxation spectroscopy above T-g and by both isothermal calorimetry and modulated differential scanning calorimetry below T-g. We find that small amounts of PVP significantly retard re-crystallization. This dramatic effect of PVP is not related to mobility, so this approach applies, at best, to extrapolation of high temperature data on a given formulation to low temperatures. Variation in molecular mobility at these concentrations of PVP is not the dominant factor in determining variation in propensity for re-crystallization from glassy systems; we suggest surface interactions between PVP and nuclei and/or small crystals slowing growth control variation in crystallization kinetics between formulations. (C) 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3887-3900, 2010