Preparation and evaluation of stable amorphous flurbiprofen complexes using two different cyclodextrins

This study aimed to develop stable amorphous inclusion complexes of flurbiprofen (FP, used as a model drug) with two different cyclodextrins (CDs). Specifically, three-component amorphous systems were developed by co-grinding crystalline FP/β-CD complexes with either α- or γ-CD. Among these, the FP/β-CD/γ-CD system exhibited superior physical stability under accelerated humid conditions, whereas rapid crystallization occurred in binary amorphous FP/β-CD system. Notably, even a small amount of γ-CD (β-CD:γ-CD = 1:0.1) was sufficient to inhibit the crystallization of FP/β-CD complex, while α-CD and polyvinylpyrrolidone (PVP) were less effective. This stabilizing effect is likely attributed to the inherently low crystallization tendency of γ-CD. Crystallization inhibition was also observed in vitro dissolution studies, where the amorphous FP/β-CD/γ-CD maintained a supersaturated state for a prolonged period compared to the amorphous FP/β-CD complex. In vivo absorption studies in rats revealed that the amorphous FP/β-CD/γ-CD significantly enhanced the oral absorption of FP, with 2.4-fold and 2.1-fold increases in C_max and AUC, respectively, compared to FP alone. Even a small amount of γ-CD was sufficient to influence the absorption kinetics of FP. These findings demonstrate the utility of γ-CD as an effective stabilizer for amorphous CD-based complexes and highlight the potential of combining two different CDs to improve both the physical stability and oral bioavailability of poorly water-soluble drugs capable of forming inclusion complexes.