Computational approach to elucidate the formation and stabilization mechanism of amorphous formulation using molecular dynamics simulation and fragment molecular orbital calculation.

α-Glycosyl rutin (Rutin-G) consists of a flavonol skeleton and sugar groups and is a promising additive for amorphous formulations. In our previous study, experimental approaches suggested an interaction between the model drug carbamazepine (CBZ) and flavonol skeleton of Rutin-G that stabilizes amorphous formulations. In the present study, the formation and stabilization mechanisms of CBZ/Rutin-G amorphous formulation were investigated using a computational approach. The CBZ/Rutin-G amorphous formulation was obtained via molecular dynamics (MD) simulation, which mimicked the melt-quenching method. Root mean square deviation analysis revealed that the translational motion of CBZ during the cooling process was suppressed by adding Rutin-G. Monitoring the atomic distance during the cooling process revealed that hydrogen bonds via carboxamide oxygen of CBZ with hydroxyl hydrogen of Rutin-G were preferentially formed with flavonol skeletons than sugar groups. The simulated amorphous formulation was then calculated using fragment molecular orbital (FMO) method. The quantitative evaluation of multiple interactions revealed that the hydrogen bond energy was higher in CBZ-sugar groups than in CBZ-flavonol skeleton, while the π-type of interaction energy was higher in CBZ-flavonol skeleton than in CBZ-sugar groups. The computational approach combining MD simulation and FMO calculation provides information on various interactions that are difficult to detect using experimental approaches, which helps understand the formation and stabilization mechanism of amorphous formulations.