A comparative study on in vitro and in vivo characteristics of enzalutamide nanocrystals versus amorphous solid dispersions and a better prediction for bioavailability based on "spring-parachute" model

This study systematically compared enzalutamide (ENZ) nanocrystals and amorphous formulation (Xtandi (R) Tablets) and proposed an effective method for predicting pharmacokinetic behavior. ENZ nanosuspensions were prepared by anti-solvent precipitation (ENZ/NS-AS) and wet milling (ENZ/NS-WM) under optimal conditions and were solidified by spray drying and further tableting. Spray dried ENZ/NS-WM was confirmed to exist in crystalline state by DSC and PXRD, while spray dried ENZ/NS-AS was amorphous form. The dissolution testing revealed that ENZ/NS-WM tablets exhibited significantly faster dissolution rate than the physical mixture of untreated ENZ and HPMCAS-HG (1:1) prepared by gently grinding with a mortar and pestle for 2 min and were comparable to Xtandi (R) Tablets. However, the pharmacokinetic study in beagle dogs indicated that ENZ/NS-WM tablets displayed 0.43-fold lower Cmax and area under the curve from 0 d to 14 d (AUC0-14 d) than Xtandi (R) Tablets. This difference was well explained by the "spring-parachute" testing, where ENZ/NS-WM tablets exhibited a worse supersaturation performance with 0.46-fold lower supersaturated level (Cspring) and 0.42-fold lower area under the curve of "spring-parachute" process in pH6.8 (AUSPC2-24h) compared to Xtandi (R) Tablets, indicating that Cspring and AUSPC2-24h obtained from "spring-parachute" testing were better indicators for pre-dicting in vivo behavior than the dissolution rate. Overall, despite the fact that the current nanocrystal formu-lation did not exhibit advantageous bioavailability, the study provided valuable information and direction for oral drug delivery system based on nano-technology.