In vivo pharmacokinetic study and PBPK modeling: Comparison between 3D-printed nanocrystals and solid dispersions

Abstract

The solubility of drugs remains one of the most challenging aspects of formulation development. Several technologies exist to enhance the properties of poorly soluble drugs, with nanocrystal (NC) and solid dispersion (SD) technologies being among the most important. This work compared NCs and SDs under identical conditions using albendazole as a model drug and 3D printing technology as the delivery method. SDs were initially prepared and characterized, and then compared to the NCs system. Techniques such as TGA, DSC, XRD, FTIR, SEM, and confocal Raman microscopy were employed to assess the solid-state properties and formulation homogeneity. Solubility and dissolution profiles were evaluated under simulated gastric and intestinal conditions. An in vivo pharmacokinetic study was performed in dogs comparing 3D-printed formulations (NC-3D and SD-3D) with a control group treated with the pure drug (ABZ-C). A PBPK model was developed also in dogs to further analyse the results. While no statistically significant differences were observed in the in vitro dissolution profiles in 0.1 N HCl, differences emerged in precipitation time and solubility at intestinal pH (6.8). The pharmacokinetic study revealed improvements in the pharmacokinetic profile of both systems compared to the control, as expected. Between the NCs and the SD, the NC system demonstrated significantly superior pharmacokinetic parameters of interest. The PBPK model helped to explain the differences observed in the in vivo study. The results suggest that nanocrystal technology is more effective at enhancing the in vivo performance of Class II drugs, at least when using albendazole as the model drug.

Keywords: 3D-printing technology; Albendazole; Bioequivalence analysis; Dogs; MESO-PP; PBPK model; Parameter Sensitivity Analysis; Pharmacokinetic study.