Insight into the\nStructure and Formation Mechanism\nof Esmolol Hydrochloride Polymorphs Based on Experiments and Molecular\nSimulations

Esmolol hydrochloride (EH) is a β-adrenergic receptor\nblocking\ndrug widely employed for atrial fibrillation and nodal tachycardia.\nHowever, to date, no systematic investigations into its polymorphism\nhave been conducted, posing a risk of polymorphic transformations\nduring storage or downstream processes. In this study, three solvent-free\nforms of EH (Form A, Form B, and Form C) were successfully obtained,\nwith Form B and Form C being reported for the first time. Single-crystal\nX-ray diffraction was employed to investigate the structure differences\namong the polymorphs, and a range of solid-state analytical techniques\nwas employed to evaluate the stability of the three polymorphs. Crystal\nstructure and Hirshfeld surface analyses revealed substantial differences\nin hydrogen-bonding interactions and molecular packing among the EH\npolymorphs. Furthermore, molecular electrostatic potential surface\nanalyses and dynamics simulations indicate that the hydrogen-bonding\nstrength between EH and solvent molecules increases in the order ethyl\nacetate < methyl acetate < water, influencing the ease of desolvation\nand consequently resulting in distinct polymorphs. The findings of\nthis study provide valuable insights into the polymorphs and quality\ncontrol of EH.