Indirect chiral ligand exchange chromatography for enantioseparation: a modification of conventional techniques

2017

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Atenolol, a β-adrenergic receptor antagonist, is a chiral compound used for the treatment of cardiovascular diseases and to treat hypertension, coronary heart disease, arrhythmias, sinus tachycardia and myocardial infarction, where it acts preferentially upon the β-adrenergic receptors in the heart. It is marketed as a racemate, but only the (S)-enantiomer of (RS)-atenolol is responsible for the β-adrenoceptor blocking activity. Different chromatographic methods have been applied for the separation and determination of enantiomers. In this article a review is presented on liquid chromatographic methods for enantioseparation of (RS)-atenolol by both direct and indirect approaches involving practical applications of several chiral stationary phases, chiral derivatization reagents and ligand exchange and impregnation methods. These include methods using both HPLC and TLC for separation, determination and bioassay of enantiomers of atenolol. In addition, some aspects of enantioseparation under achiral phases of liquid chromatography have been briefly mentioned as applicable to (RS)-atenolol. This review provides current available enantioseparation choices not only for (RS)-atenolol but also for other applicable racemic drugs.

Section: Enantioresolution Using Achiral Phasesmentioning

confidence: 99%

Bioassay, determination and separation of enantiomers of atenolol by direct and indirect approaches using liquid chromatography: A review

Batra

2017

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“…In addition, there have been a few reports from this laboratory on successful enantioseparation of certain β-blockers using ligand exchange chromatography (Kumar and Bhushan, 2014) and CDRs based on difluorodinitrobenzene (Bhushan and Tanwar, 2009;Bhushan and Nagar, 2014a), cyanuric chloride (Bhushan and Dixit, 2012) and (S)-naproxen (Singh and Bhushan, 2015). For 1,5-Difluoro-2,4-dinitrobenzene (DFDNB)-based derivatives a photochemical decomposition occurs if the solutions are not protected from light and many of the other reagents lead to formation of unstable derivatives, or lack of quantitative yield or poor detection.…”

Section: (Rs)-propranololmentioning

confidence: 99%

(RS)‐Propranolol: enantioseparation by HPLC using newly synthesized (S)‐levofloxacin‐based reagent, absolute configuration of diastereomers and recovery of native enantiomers by detagging

Alwera

2016

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Diastereomers of (RS)-propranolol were synthesized using (S)-levofloxacin-based new chiral derivatizing reagents (CDRs). Levofloxacin was chosen as the pure (S)-enantiomer for its high molar absorptivity (εo ∼ 24000) and availability at a low price. Its -COOH group had N-hydroxysuccinimide and N-hydroxybenzotriazole, which acted as good leaving groups during nucleophilic substitution by the amino group of the racemic (RS)-propranolol; the CDRs were characterized by UV, IR, (1) H-NMR, high resolution mass spectrometry (HRMS) and carbon, hydrogen, nitrogen, and sulphur fundamental elemental components analyser (CHNS). Diastereomers were separated quantitatively using open column chromatography; absolute configuration of the diastereomers was established and the reagent moiety was detagged under microwave-assisted acidic conditions. (S)- and (R)-propranolol as pure enantiomers and (S)-levofloxacin were separated, isolated and characterized. Optimized lowest-energy structures of the diastereomers were developed using Gaussian 09 Rev. A.02 program and hybrid density functional B3LYP with 6-31G* basis set (based on density functional theory) for explanation of elution order and configuration. In addition, RP HPLC conditions for separation of diastereomers were optimized with respect to pH, concentration of buffer, flow rate of mobile phase and nature of organic modifier. HPLC separation method was validated as per International Conference on Harmonization guidelines. With the systematic application of various analytical techniques, absolute configuration of the diastereomers (and the native enantiomers) of (RS)-propranolol was established. Copyright © 2016 John Wiley & Sons, Ltd.

“…The principle and application of chiral ligand exchange chromatography have been well documented in the literature (Davankov and Rogozhin, ; Sanaie and Haynes, 2006 , ; Natalini et al ., ) and the technique has been found to be successful for direct enantiomeric (HPLC) resolution of amino acids, β‐blockers and hydroxy acids by HPLC (Yamazaki et al ., ; Bazylak, ; Katoh et al ., ; Nikolic et al ., ; Koidl et al ., ; Sun et al ., ; Sotgia et al ., ; Kumar and Bhushan, ).…”

Section: Resultsmentioning

confidence: 99%

“…In all there were 12 pairs of diastereomeric ligand exchanged complexes; their UV spectra were recorded to verify the formation of such diastereomeric complexes prior to HPLC analysis. The principle and application of chiral ligand exchange chromatography have been well documented in the literature (Davankov and Rogozhin, 1971;Sanaie and Haynes, 20062006a, 2006bNatalini et al, 2008Natalini et al, , 2010 and the technique has been found to be successful for direct enantiomeric (HPLC) resolution of amino acids, β-blockers and hydroxy acids by HPLC (Yamazaki et al, 1994;Bazylak, 1994;Katoh et al, 1989;Nikolic et al, 2003;Koidl et al, 2008;Sun et al, 2006;Sotgia et al, 2008;Kumar and Bhushan, 2014).…”

Section: Formation Of Diastereomeric Chiral Ligand Exchange Complexesmentioning

confidence: 99%

HPLC enantioseparation of racemic bupropion, baclofen and etodolac: modification of conventional ligand exchange approach by pre‐column formation of chiral ligand exchange complexes

Singh

2016

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Separation of racemic mixture of (RS)-bupropion, (RS)-baclofen and (RS)-etodolac, commonly marketed racemic drugs, has been achieved by modifying the conventional ligand exchange approach. The Cu(II) complexes were first prepared with a few l-amino acids, namely, l-proline, l-histidine, l-phenylalanine and l-tryptophan, and to these was introduced a mixture of the enantiomer pair of (RS)-bupropion, or (RS)-baclofen or (RS)-etodolac. As a result, formation of a pair of diastereomeric complexes occurred by 'chiral ligand exchange' via the competition between the chelating l-amino acid and each of the two enantiomers from a given pair. The diastereomeric mixture formed in the pre-column process was loaded onto HPLC column. Thus, both the phases during chromatographic separation process were achiral (i.e. neither the stationary phase had any chiral structural feature of its own nor did the mobile phase have any chiral additive). Separation of diastereomers was successful using a C column and a binary mixture of MeCN and TEAP buffer of pH 4.0 (60:40, v/v) as mobile phase at a flow rate of 1 mL/min and UV detection at 230 nm for (RS)-Bup, 220 nm for (RS)-Bac and 223 nm for (RS)-Etd. Baseline separation of the two enantiomers was obtained with a resolution of 6.63 in <15 min. Copyright © 2016 John Wiley & Sons, Ltd.