Insights from molecular dynamics simulations for the design of lyophilized protein formulations

A large fraction of therapeutic proteins is lyophilized to increase the shelf life and allow long-term storage. Despite being a mild process, lyophilization may nevertheless result in loss of protein activity; addition of suitable formulation components is necessary to maximize the recovery of therapeutic potency. The formulation components stabilize proteins by a complex interplay of thermodynamic and kinetic mechanisms, whose strength and relative importance strongly depend on the molecular properties of the system under consideration. Molecular simulations, including molecular dynamics (MD), offer the possibility to characterize these phenomena at an incomparable level of detail. In this chapter, we briefly review the challenges of formulation development and highlight the fundamental role that the MD approach may have in this context. The peculiarities of molecular simulations for formulation development are discussed and compared to other emerging technologies. We briefly describe the main MD techniques currently available and offer some practical examples of observables that can be extracted from MD trajectories and that could help the selection of excipients for lyophilized formulations.