Effect of amorphous phase separation and crystallization on the in vitro and in vivo performance of an amorphous solid dispersion

摘要

In this study, the performance of phase separated and crystallized amorphous solid dispersions (ASDs) was evaluated by non-sinkin vitrodissolution testing in fasted-state simulated intestinal fluid (FaSSIF) andin vivoin rats. The amorphous phase-separated or crystallized ASDs were prepared by mixing an ASD of the model drug celecoxib (CCX) in polyvinylpyrrolidone (PVP) with pure amorphous or micronized crystalline CCX at 20, 40, 60 or 100% of the total drug load (25:75 w/w CCX:PVP), respectively. As expected, crystallization of CCX in the ASDs generally had a negative influence on both the area under the curve of the dissolution curve(in vitroAUC) and the plasma concentration-time profile (in vivoAUC) in rats compared to the pure ASD. However, the difference between thein vivoAUC of the pure ASD and the 20% and 40% crystallized ASDs was not statistically significant, which could indicate that a low fraction of crystallization of a drug in an ASD may only have limited impact onin vivoperformance and hence bioavailability. In comparison, amorphous phase separation of CCX in the ASDs did not negatively influence thein vitroAUC andin vivoAUC to the same degree as crystallization and the dissolution profiles of all the amorphous phase-separated ASDs were similar to that of the pure ASD. In fact, even though a slight decrease ofin vivoAUC with increasing fraction of amorphous phase separation was observed, the 20% and 40% amorphous phase-separated ASDs were bioequivalent with the pure ASD.