The solid-state structure of the β-blocker metoprolol: a combined experimental and in silico investigation

摘要

Metoprolol {systematic name: (RS)-1-iso­propyl­amino-3-[4-(2-meth­oxy­eth­yl)phen­oxy]propan-2-ol}, C15H25NO3, is a cardioselective β1-adrenergic blocking agent that shares part of its mol­ecular skeleton with a large number of other β-blockers. Results from its solid-state characterization by single-crystal and variable-temperature powder X-ray diffraction and differential scanning calorimetry are presented. Its mol­ecular and crystal arrangements have been further investigated by mol­ecular modelling, by a Cambridge Structural Database (CSD) survey and by Hirshfeld surface analysis. In the crystal, the side arm bearing the isopropyl group, which is common to other β-blockers, adopts an all-trans conformation, which is the most stable arrangement from modelling data. The crystal packing of metoprolol is dominated by an O—H⋯N/N⋯H—O pair of hydrogen bonds (as also confirmed by a Hirshfeld surface analysis), which gives rise to chains containing alternating R and S metoprolol mol­ecules extending along the b axis, supplemented by a weaker O⋯H—N/N—H⋯O pair of inter­actions. In addition, within the same stack of mol­ecules, a C—H⋯O contact, partially oriented along the b and c axes, links homochiral mol­ecules. Amongst the solid-state structures of mol­ecules structurally related to metoprolol deposited in the CSD, the β-blocker drug betaxolol shows the closest analogy in terms of three-dimensional arrangement and inter­actions. Notwithstanding their close similarity, the crystal lattices of the two drugs respond differently on increasing temperature: metoprolol expands anisotropically, while for betaxolol, an isotropic thermal expansion is observed.