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.

Enantioseparation of a few commonly administered racemic β-adrenolytics (namely, carvedilol, betaxolol, salbutamol and bisoprolol) has been achieved using a water micellar mobile phase containing surfactants (sodium dodecyl sulphate and Brij-35) without organic solvents as a new approach in RP-HPLC. Two chiral derivatizing reagents based on enantiomerically pure (S)-(-)-levofloxacin were synthesized using N-hydroxysuccinimide and N-hydroxybenzotriazole as the activation auxiliaries. Diastereomeric derivatives of the chosen β-adrenolytics were synthesized under microwave irradiation in a very short reaction time. The (S)-(-)-levofloxacin moiety enhanced molar absorbance of the diastereomeric derivatives resulting in very low limit of detection (1.618 and 4.902 ng/mL, respectively, for diastereomeric derivatives of (RS)-betaxolol and better resolution with lower retention times (for all the analytes), in comparison to literature reports. There was 15-20 times less consumption of mobile phase because of lower retention time.

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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 (ε ~ 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, 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 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 . Copyright © 2016 John Wiley & Sons, Ltd.

Developing surfactant-based aqueous solvents as alternatives to organic solvents for chromatographic enantioseparation is highly desired. Surfactants are inexpensive, nontoxic, environmental friendly, and increase the solubility of organic compounds in aqueous solutions. In this work, the impact of surfactant-based aqueous solvents on RP-HPLC enantioseparation of (RS)-mexiletine is studied. The in situ derivatization of (RS)-mexiletine with chirally pure moieties [(S)-levofloxacin, (S)-ketoprofen, (S)-ibuprofen)] was carried out/performed to reduce consumption of organic solvents and side wastes, and to maintain a green approach. We report the impact of increasing concentration of surfactants on separation of diastereomeric derivatives of (RS)-mexiletine on a C18 column of HPLC. Surfactant in water increased the solubility of a diastereomeric derivative, provided the lowest elution time (t R between 2.152 and 10.87 min), and minimized the consumption of solvent. The use of surfactant-containing aqueous mobile phases in chromatographic separations is a good alternative for replacement of organic solvents. The hydrolysis of the synthesized diastereomeric derivatives was carried out, and native enantiomers of mexiletine were isolated and characterized. In addition, the lowest-energy optimized structures were developed using the Gaussian 09 Rev. A.02 program for determination of elution order, and the method was validated for linearity, accuracy, limit of detection (LOD), and limit of quantitation (LOQ).