An integrated computational methodology with data-driven machine learning, molecular modeling and PBPK modeling to accelerate solid dispersion formulation design.

Abstract Drug in solid dispersion (SD) takes advantage of fast and extended dissolution thus attains a higher bioavailability than the crystal form. However, current development of SD relies on a random large-scale formulation screening method with low efficiency. Current research aims to integrate various computational tools, including machine learning (ML), molecular dynamic (MD) simulation and physiologically based pharmacokinetic (PBPK) modeling, to accelerate the development of SD formulations. Firstly, based on a dataset consisting of 674 dissolution profiles of SD, the random forest algorithm was used to construct a classification model to distinguish two types of dissolution profiles “spring-and-parachute” and “maintain supersaturation”, and a regression model to predict the time-dependent dissolution profiles. Both of the two prediction models showed good prediction performance. Moreover, feature importance was performed to help understand the key information that contributes to the model. After that, the vemurafenib (VEM) SD formulation in previous report were used as an example to validate the models. MD simulation was used to investigate the dissolution behavior of two SD formulations with two polymers (HPMCAS and Eudragit) at the molecular level. The results showed that HPMCAS-based formulation resulted in faster dissolution than the Eudragit formulation, which agreed with the reported experimental results. Finally, a PBPK model was constructed to accurately predict the human pharmacokinetic profile of the VEM-HPMCAS SD formulation. In conclusion, an combined computational tools have been developed to in silico predict formulation composition, in vitro release and in vivo absorption behavior of SD formulations. The integrated computational methodology will significantly facilitate pharmaceutical formulation development than the traditional trial-and-error approach in the laboratory.