Insight into the Structure and Formation Mechanism of Esmolol Hydrochloride Polymorphs Based on Experiments and Molecular Simulations

Esmolol hydrochloride (EH) is a β-adrenergic receptor blocking drug widely employed for atrial fibrillation and nodal tachycardia. However, to date, no systematic investigations into its polymorphism have been conducted, posing a risk of polymorphic transformations during storage or downstream processes. In this study, three solvent-free forms of EH (Form A, Form B, and Form C) were successfully obtained, with Form B and Form C being reported for the first time. Single-crystal X-ray diffraction was employed to investigate the structure differences among the polymorphs, and a range of solid-state analytical techniques was employed to evaluate the stability of the three polymorphs. Crystal structure and Hirshfeld surface analyses revealed substantial differences in hydrogen-bonding interactions and molecular packing among the EH polymorphs. Furthermore, molecular electrostatic potential surface analyses and dynamics simulations indicate that the hydrogen-bonding strength between EH and solvent molecules increases in the order ethyl acetate < methyl acetate < water, influencing the ease of desolvation and consequently resulting in distinct polymorphs. The findings of this study provide valuable insights into the polymorphs and quality control of EH.