Methods and approaches for determination and enantioseparation of (RS)-propranolol.

Propranolol, a β-adrenergic receptor antagonist, is a chiral compound that is marketed as a racemate, but only the (S)-(-)-enantiomer is responsible for the β-adrenoceptor blocking activity. Different chromatographic methods have been applied for separation and determination of enantiomers of (RS)-propranolol. In this article a review is presented on different liquid chromatographic methods used for enantioseparation of (RS)-propranolol, using both HPLC and TLC. In addition, some aspects of enantioseparation under achiral phases of liquid chromatography have been briefly mentioned.

Batra S ，Bhushan R 《-》

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

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.

Batra S ，Bhushan R 《-》

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

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.

Alwera S ，Bhushan R 《-》

Liquid chromatographic enantioseparation of (RS)-etodolac using (S)-levofloxacin and determination of absolute configuration of the diastereomeric derivatives.

(RS)-Etodolac was isolated from commercial tablets and was purified and characterized to be used as racemic standard. A pair of diastereomeric derivatives was synthesized using (S)-levofloxacin as a chiral derivatizing reagent. The derivatization reaction was carried out under conditions of stirring at room temperature (30°C for 1.5 h) as well as under microwave irradiation; the derivatives obtained by the two methods were compared. Reaction conditions for derivatization were optimized with respect to mole ratio of chiral derivatizing reagent and (RS)-etodolac. No racemization was observed throughout the study. Separation of diastereomeric derivatives was successful using C18 column and a binary mixture of methanol and triethyl ammonium phosphate buffer of pH 4.5 (80:20, v/v) as mobile phase at a flow rate of 1 mL min-1 and UV detection at 223 nm. An efficient approach for recognizing chirality and determining the absolute configuration of the diastereomeric derivatives of (RS)-etodolac is described, which in turn is a measure of the enantiomeric purity of (RS)-etodolac since the diastereomeric derivatives were separated and isolated using preparative thin-layer chromatography.

Singh M 《-》

Liquid chromatographic enantioseparation of three beta-adrenolytics using new derivatizing reagents synthesized from (S)-ketoprofen and confirmation of configuration of diastereomers.

Diastereomers of racemic β-adrenolytic drugs [namely (RS)-propranolol, (RS)-metoprolol and (RS)-atenolol] were synthesized under microwave irradiation with (S)-ketoprofen based chiral derivatization reagents (CDRs) newly synthesized for this purpose. (S)-Ketoprofen was chosen for its high molar absorptivity (εo  ~ 40,000) and its availability as a pure (S)-enantiomer. Its -COOH group was activated with N-hydroxysuccinimide and N-hydroxybenzotriazole; these were easily introduced and also acted as good leaving groups during nucleophilic substitution by the amino group of the racemic β-adrenolytics. The CDRs were characterized by UV, IR, 1 H-NMR, HRMS and CHNS. Separation of diastereomers was achieved by RP HPLC and open column chromatography. Absolute configuration of the diastereomers was established with the help of 1 HNMR supported by developing their optimized lowest energy structures using Gaussian 09 Rev. A.02 program and hybrid density functional B3LYP with 6-31G* basis set (based on density functional theory), and elution order was established. RP HPLC conditions for separation were optimized and the separation method was validated. The limit of detection values were 0.308 and 0.302 ng mL-1 . Copyright © 2016 John Wiley & Sons, Ltd.

Alwera S ，Bhushan R 《-》