Abstract

Aim: The study aims to develop a 3^rd generation amorphous solid dispersion (ASD) of Apremilast (APST) employing the Design of Experiment (DoE) methodology, followed by a thorough assessment including in silico pharmacokinetics.

Background: APST, classified as a BCS-Class IV molecule due to its low solubility and permeability, exhibits highly variable oral bioavailability across different species.

Objective: In this study, a 3^rd generation ASD of APST was developed using the DoE approach.

Methods: The miscibility of APST within polymers was assessed using solubility parameters and Flory Huggin equation. Phase solubility studies were conducted to identify the most suitable polymer-surfactant combination for maximizing drug solubility. The produced solid dispersions were characterized using FTIR, DSC, XRD, DVS, and SEM.

Results: The combination of APST and Soluplus^® in a 1:5 ratio resulted in the highest improvement in solubility and dissolution, with vitamin E TGPS being identified as the most efficient surfactant. Stability studies were carried out, and findings revealed that the ASD remained stable under accelerated conditions for up to 3 months, suggesting its suitability for scaling up for industrial applications. In silico predictions of the pharmacokinetics of APST following oral administration of solid dispersion formulations were determined by PBBM using GastroPlus™.

Conclusion: The simulation of oral absorption profiles for APST showed a significant improvement in both Cmax and AUC for the solid dispersion formulations compared to plain drugs. This study makes a significant contribution to the field of pharmaceutical science by addressing the formulation complexities inherent in poorly water-soluble compounds like APST.

Keywords: Amorphous solid dispersion, DoE, simulation, population modelling, GastroPlus, apremilast.