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

Abstract

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.

Last ten years (2008–2018) of chiral ligand‐exchange chromatography in HPLC: An updated review

“…This non‐conventional way to exploit the CLEC concept was later pursued by Singh and Bhushan . This time, Cu(II) binary complexes of ( S )‐proline, ( S )‐histidine, ( S )‐phenylalanine, and ( S )‐tryptophan were added to the racemic mixtures to be enantioseparated, i.e., ( R , S )‐bupropion, ( R , S )‐baclofen, and ( R , S )‐etodolac, before running the chromatographic analysis.…”

Enantioresolution of (RS)‐baclofen by liquid chromatography: A review

“…With the concept of ligand exchange enantioseparation, as mentioned above, separation of ( RS )‐Bac has been achieved by modifying the conventional ligand exchange approach (Singh & Bhushan, ). The Cu(II) complexes were first prepared with a few l ‐amino acids, namely, l ‐Pro, l ‐His, l ‐Phe and l ‐Trp, and to these was introduced a mixture of enantiomer pair ( RS )‐Bac.…”

Enantioseparation of basic drugs by reverse phase high‐performance liquid chromatography system using carboxymethyl‐β‐cyclodextrin as chiral mobile phase additive

“…11,12 On the other hand, the method of utilizing the CMPA has been widely used in exploratory research as a versatile and flexible method to demonstrate greater potential in chiral separation. 13,14 So far, a wide range of chiral selectors, including cyclodextrins (CDs), [14][15][16][17][18] chiral ion-pair inclusions, 19,20 and chiral ligand-exchange inclusions, [21][22][23] have been explored in CMPA techniques.…”