The Use of Antibiotics as Chiral Selectors in Capillary Electrophoresis: A Review

Abstract

Chirality is becoming an essential issue in modern pharmaceutical research as regulatory agencies emphasize the safety and efficiency of enantiomers in drug development. The development of efficient and reliable chiral separation methods became a necessity in the last 30 years, and capillary electrophoresis (CE), due to its relatively low costs and "green" features, is attracting increased attention. Cyclodextrin (CD) and their derivatives are the most frequently used chiral selectors (CSs) in CE, however, the use of antibiotics as CSs represents an interesting alternative. Various classes of antibiotics (aminoglycosides, ansamycins, glycopeptides, lincosamides, macrolides, tetracyclines) have been used more or less successfully for the enantio-separation of pharmaceuticals. Antibiotics offer the possibility of a multitude of potential interactions (electrostatic, inclusion, hydrogen bonding, etc.) due to their chemical diversity, allowing the enantio-separation of analytes with a wide range of structural characteristics. This article aims to review the application of various classes of antibiotics in the CE enantio-separation of pharmaceuticals. Antibiotic physiochemical characteristics, variables impacting enantio-separation, advantages, and disadvantages when certain antibiotics are used as CSs in CE are also explored.

Keywords: antibiotics; capillary electrophoresis; chiral drugs; chiral selectors; chiral separation.

Figure 1

Chemical structure of Vancomycin.

Figure 2

Speculative diagram depicting the possible separation mechanism between vancomycin as CS and quinolone carboxylic acids. The figure is reproduced from Arai et al. [29] with permission from Elsevier.

Figure 3

Enantiomeric separation of carboxymethylcysteine and N-acetamido-carboxymethylcysteine (a) using 10 mM vancomycin as CS; (b) using 1 mM vancomycin as CS. The figure is reproduced from Fanali et al. [32] with permission from Wiley.

Figure 4

Comparison of the enantio-selectivity of balhimycin (b); and vancomycin (a) used as CS for the enantio-separation of dansylated α-amino acids (CS concentration 2 mM). The figure is reproduced from Kang et al. [35] with permission from ACS Publications.

Figure 5

Enantio-separation of enantio-enriched l-dansyl-methionine (A); and (S)-ketoprofen (B) by CE using balhimycin, bromobalhimycin, and dechlorobalhimycin as CS (CS concentration 2 mM). The figure is reproduced from Jiang et al. [45] with permission from Wiley.

Figure 6

Chemical structure of Erythromycin.

Figure 7

Enantio-separation of chlorpheniramine (A); and salsonilol (B) using β-CD, erythromycin (EM), and β-CD-derivatized erythromycin (β-CD-EM) (CS concentration 15 mM). The figure is reproduced from Dai et al. [57] with permission from Wiley.

Figure 8

Enatio-separation of nefopam in single and dual CS systems (CL—clarithromycin, Glu-β-CD—glucose-β-CD, HE-β-CD—hydroxyethyl-β-CD, Me-β-CD—methyl-β-cyclodextrin, HP-β-CD—hydroxypropyl-β-CD) (CL concentration 50 mM, Glu-β-CD concentration 40 mM, HE-β-CD concentration 20 mM, Me-β-CD concentration 20 mM, HP-β-CD concentration 15 mM). (A)CL + Glu-β-CD; (B) CL + HE-β-CD; (C) CL + Me-β-CD; (D) CL + HP-β-CD. The figure is reproduced from Yu et al. [60] with permission from Wiley.

Figure 9

Chemical structure of Clindamycin.

Figure 10

Enantio-separation of model basic drugs by MEKC using clindamycin phosphate as CS (Nefopam—NEF, PRO—propranolol, TRY—tryptophan, CHL—chlorphenamine, CIT—citalopram, MET—metoprolol, TME—tryptophan methyl ester, CET—cetirizine) (CS concentration 60 mM (NEF, PRO, CHL, TME, and CET) and 80 mM (TRY, CIT, MET). The figure is reproduced from Chen et al. [68] with permission from Elsevier.

Figure 11

Enantioseparation of model drugs using fusidic acid as CS (PCT—procaterol, PMQ—primaquine, CLQ—chloroquine, HCQ—hydroxychloroquine, ATE—atenolol, MET—metoprolol, ESM—esmolol, BIS—bisoprolol, PRO—propranolol), (CS concentration 60 mM), (the rigid planar structure (if any) of model drugs is drawn in grey). (A) Enantioseparation of PCT, PMQ, ClQ and HCQ; (B) Enantioseparation of ATE, MET, ESM, BIS, PRO. The figure is reproduced from Zhang et al. [77] with permission from Elsevier.