Separation of terbutaline enantiomers in capillary electrophoresis with neutral cyclodextrin‐type chiral selectors and investigation of the structure of selector‐selectand complexes using nuclear magnetic resonance spectroscopy

Abstract

The major goal of this study was to determine the affinity pattern of the terbutaline (TB) enantiomers toward α‐, β‐, γ‐, and heptakis(2,3‐di‐O‐acetyl)‐β‐cyclodextrins and using NMR spectroscopy for the understanding of the fine mechanisms of interaction between the cyclodextrins (CD) and TB enantiomers. It was shown once again that CE in combination with NMR spectroscopy represents a sensitive tool to study the affinity patterns and structure of CD complexes with chiral guests. Opposite affinity patterns of TB enantiomers toward native α‐ and β‐CDs were associated with significant differences between the structure of the related complexes in solution. In particular, the complex between TB enantiomers and α‐CD was of the external type, whereas an inclusion complex was formed between TB enantiomers and β‐CD. One of the possible structures of the complex between TB and heptakis(2,3‐di‐O‐acetyl)‐β‐CD (HDA‐β‐CD) was quite similar to that of TB and β‐CD, although the chiral recognition pattern and enantioselectivity of TB complexation with these two CDs were very different.

Advances of capillary electrophoresis enantioseparations in pharmaceutical analysis (2017–2020)

“…The authors concluded that it may be difficult to draw conclusions on the complex structures by NMR in some cases. Even the simultaneous presence of both complexes (1) and (2) in solution could not be ruled out [77]. Interestingly, formation of a complex between TER and 2,3-DM-β-CD could not be derived by NMR spectroscopy explaining the lack of resolution observed in CE experiments, while TER formed an inclusion complex with 2,6-DM-β-CD (Figure 1) [79].…”

“…Interestingly, application of α‐CD and HMDS‐β‐CD, which resulted in the migration order S > R, did not result in the formation of inclusion complexes. Instead, external complexes were concluded from ROESY data indicating spatial proximity of the phenyl ring to the secondary wider rim of α‐CD [77]. In case of HMDS‐β‐CD, nuclear Overhauser effects (NOEs) were observed between the methyl protons of the TER tert ‐butyl moiety and a methylene group of the side chain [76].…”

“…It may be hypothesized, that this complex is stabilized by an ionic interaction between the 3‐sulfo group and the protonated nitrogen of the TER side chain. As to γ‐CD, TER seemed to form only a weak complex with the drug located “on top” of the wider rim of the torus as concluded from weak NOEs observed in 1D ROESY experiments [77]. Nonetheless, efficient enantioseparations were observed with the CDs despite the fact that high concentrations of 100 mg/mL were required in the case of α‐CD and γ‐CD.…”

“…The authors concluded that it may be difficult to draw conclusions on the complex structures by NMR in some cases. Even the simultaneous presence of both complexes (1) and (2) in solution could not be ruled out [77].…”

Chiral Separations by Capillary Electrophoresis and related Techniques with Different Chiral Selectors: A Review

“…The use of different substituents alters the enantioselectivity of the modified β-CDs. Modified β-CDs can be created in neutral [141,143], cationic [144][145][146] and anionic forms [147,148]. Cyclodextrin (CD) and its derivatives are among the most preferred chiral selectors in CE due to their chemical resistance, conveniences related to their structural properties and low UV absorptions [149][150][151].…”