Dissolution of amorphous solid dispersions across broad parameter space in semi-infinite slab simulations

Abstract

A large fraction of the active pharmaceutical ingredients in drug development pipelines suffer from low solubility in aqueous solutions. Addressing this issue and improving drug bioavailability for patients requires innovative materials and chemical formulations. Amorphous solid dispersions (ASDs) have emerged as one of these innovative materials, where the insoluble drug is dispersed in its amorphous form within a polymer matrix. ASDs have been effectively utilized in industry for drug delivery. However, there is a lack of understanding of how polymer and drug chemistry affects the ASD dissolution process, which hinders the design and formulation of ASDs. Previous studies have narrowly focused on specific polymer-drug combinations. On a broader scale, the field lacks a phenomenological model for how varying the interactions between ASD components affects dissolution. Therefore, in this work, we have aimed to provide such a model through molecular dynamics simulations in a semi-infinite slab geometry, where dissolution occurs along the long axis. We built the system using a modified Lennard-Jones potential called the Ashbaugh-Hatch potential. In our simulations, we varied a large number of Lennard-Jones interaction strength parameters (ε values) and length scale parameters (σ values). We found that size mismatch between drug molecules and monomers greatly hinders drug transport. We also found that polymer hydrophilicity and drug size were the main factors governing polymer and drug transport properties, drug release, and water penetration into the ASD. This study serves as a guide for which parameters are most important to tune during ASD development. We offer a qualitative perspective on how polymer hydrophilicity and drug size, along with other less critical parameters, should be chosen to achieve desired ASD dissolution behavior.