Molecular insights into kinetic stabilization of amorphous solid dispersion of pharmaceuticals

Abstract

Poor aqueous solubility of crystalline active pharmaceutical ingredients (APIs) restricts their bioavailability. Amorphous solid dispersions with biocompatible polymer excipients offer a solution to overcome this problem, potentially enabling a broader use of many drug candidate molecules. This work addresses various aspects of the in silico design of a suitable combination of an API and a polymer to form such a binary solid dispersion. Molecular interactions in such bulk systems are tracked at full atomic resolution within molecular-dynamics (MD) simulations, enabling to identify API–polymer pairs that exhibit the most beneficial interactions. Importance of these interactions is manifold: increasing the mutual miscibility, kinetic stabilization of their amorphous dispersions and impedance of the spurious recrystallization of the API component. MD tools are used to investigate the structural and cohesive properties of pure compounds and mixtures, with a special emphasis on molecular interactions, microscopic structures and internal dynamics. This analysis is then accompanied by a macroscopic image of the energetic compatibility and vitrification tendency of the mixtures in terms of their excess enthalpies and glass transition temperatures. Density-functional theory (DFT) and non-covalent interaction (NCI) analysis fortify our computational conclusions and enable us to map the intensities of particular NCI among the individual target materials and relevant molecular sites therein. Three archetypal polymer excipients and four API molecules are included in this study. The results of our computational analysis of molecular interactions in bulk systems agree with the experimentally observed trends of solubility of the given API in polymers. Our calculations confirm PVP as the most potent acceptor of hydrogen bonding among the three considered polymer excipients, whereas ibuprofen molecules are predicted to be the most efficient hydrogen bond donors among our four target APIs. Our simulations also suggest that carbamazepine does not exhibit particularly strong interactions with the considered polymer excipients. Although current MD cannot offer quantitative accuracy of many of the discussed descriptors, current computational models focusing on NCI of APIs with polymer excipients contribute to understanding of the behavior of these materials at the molecular level, and thus also to the rational design of novel efficient drug formulations.