Enantioseparation of Mirabegron Using Cyclodextrin‐based Chiral Columns: High‐performance Liquid Chromatography and Molecular Modeling Study

Mhammad, Ali and Dombi, Gergely and Dobó, Máté and Szabó, Zoltán‐István and Fiser, Béla and Tóth, Gergő (2025) Enantioseparation of Mirabegron Using Cyclodextrin‐based Chiral Columns: High‐performance Liquid Chromatography and Molecular Modeling Study. Journal of Separation Science, 48 (4). No.-e70132. ISSN 1615-9306

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Abstract

A novel high-performance liquid chromatography method for the enantioseparation of mirabegron (R-mirabegron), a selectiveβ-3 adrenergic receptor agonist, using cyclodextrin (CD)-based chiral stationary phases (CSPs) was developed. Seven differentCSPs containing β-, γ-, hydroxypropyl-β-, sulfobutyl-β-, carboxymethyl-β-, permethyl-β-, and phenylcarbamate-β-cyclodextrinwere evaluated under both polar organic and reversed-phase conditions. Only the phenylcarbamate-β-cyclodextrin containingthe Chiral CD-Ph column displayed enantiorecognition. Optimization of conditions using a full factorial design led to thedetermination of the most suitable conditions: a mobile phase composition of 90:10:0.1 methanol:water:diethylamine, a flow rateof 0.8 mL/min, and a column temperature of 40◦C with enantiomeric elution order, where the impurity S-mirabegron elutesfirst. Using the optimized conditions, enantioseparation with Rs = 1.9 was achieved within 10 min. The developed method wasvalidated according to current guidelines and successfully applied for the determination of S-mirabegron, as a chiral impurity inpharmaceutical formulations. The enantiorecognition mechanism was investigated by molecular docking and thermodynamicanalysis. Using molecular modeling, the interactions between CDs and the analyte were analyzed at the molecular level, revealingthat mirabegron interacts primarily with the phenylcarbamate groups on the outer surface of the structure. Enthalpy-controlled enantioseparation was consistently observed across all eluent compositions, regardless of the conditions. The developed and validated method is highly suitable for routine determination of the enantiomeric purity of mirabegron, offering a reliable tool for regulatory compliance.T

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