Crystallization Behavior of Amorphous Solid DispersionsRole of Nucleation and Nucleation Density
Abstract
The Tnose for nucleation (i.e., the temperature of the maximum nucleation rate without any crystal growth) of flurbiprofen-polyvinylpyrrolidone amorphous solid dispersions (ASDs) was determined using the time−temperature−transformation (TTT) diagram. Varying levels of nucleation were induced in ASDs by annealing for different time periods at Tnose for nucleation. Synchrotron X-ray diffractometry was utilized for real-time monitoring of the crystallization behavior upon wetting the ASDs with water. An increase in the nucleation density shortened the lag time and also accelerated drug crystallization. Williamson−Hall analysis of the X-ray data revealed a progressive reduction in the lattice strain (increased lattice order) of the crystallizing phase with increasing contact time with water. From performance perspectives, actualizing the solubility advantage of the amorphous drug necessitates retaining supersaturation for a sufficiently long period to allow absorption from the gastrointestinal tract. However, the presence of nuclei, by facilitating crystallization, can negate the solubility and the consequent bioavailability advantage of ASDs. A systematic framework for evaluating the “health” of ASDs was established, highlighting that the absence of nuclei would be an essential attribute of robust ASDs.