(600a) Thinking Outside the Box: Innovative Methods and Applications of Solid-State Modeling in Drug Discovery and Development.

Solid-state modeling is widely applied in industrial drug discovery and development programs because of its unique ability to support and complement experimental work. Many solid-state modeling techniques, including dispersion-corrected density functional theory (DFT-D) based crystal structure prediction and the calculation of enthalpies of mixing, are now mostly mature and are routinely applied by specialists for tasks such as drug product de-risking and virtual cocrystal screens. However, the methodologies themselves are known to show weaknesses for many applications; furthermore, there are several fields in which solid-state modeling is not routinely applied but could provide meaningful help and insight. In this presentation we discuss the background of solid-state modeling, which areas would benefit from improvement of the methodologies, which fields of research would be amenable to the application of computational methods, and some of the ways these changes could be brought upon. In particular, we show some examples of innovative methods and applications of solid-state modeling in drug discovery and development projects, including finding ways to estimate the kinetic accessibility of predicted crystal structures, the estimation of the relative solubility of several compounds in drug discovery, a workflow to propose crystallization counterions for large molecules, and the improvement of relative polymorph stability by pushing CSP beyond DFT-D.