Propranolol, enantiomer separation

Fig. 15 Separation of ropivacaine and propranolol enantiomers using an MIP plug composed of (S)-ropivacaine MIP and (S)-propranolol MIP. The capillary was 100 cm in total length and 91.5 cm in effective length. The electrolyte contained acetonitrile/2 mol L-1 acetic acid adjusted to pH 3 by the addition of triethanolamine (90/10, v/v). The separation voltage was 15 kV, and the capillary column was thermostated to 60 °C. The MIPs were injected hydrodynamically at 50 mbar for 6 s each, and the sample was composed of 50 pmol L 1 rac-propranolol (first eluting) and rac-ropivacaine injected electrokinetically at 16 kV for 3 s. Detection was performed at 214 (top) and 195 nm (bottom) [42]...

A. M. Dyas, M. L. Robinson, and A. G. Fell, An evaluation of the structural requirements for the separation of propranolol enantiomers on Pirkle phases following achiral derivatisation, Chromatographia, 30 13 (1990). 

MIPs used as chiral stationary phases in o-CEC, p-CEC as well as in rod-CEC have shown high selectivity but relatively low efficiency. Most of the reported enantiomer separations on these phases were performed without pressurization of the flow system. Only Schweitz et al. described on the enantiomer separation of propranolol and metoprolol (print molecule R-propranolol or S-metoprolol) [57] and ropivacaine, mepivacaine and bupivacaine (print molecule S-ropivacaine) [58] by... 

Pure enantiomer imprinting of L-phenylalanine anilide, (/ )-propranolol, S)-metoprolol and (50-ropivacaine has been undertaken and these MIP capillaries have been used in the CEC mode for enantiomer separations [39-41,60-62,70,71] (Table 16.1). Baseline separations for the enantiomers of phenylalanine (Fig. 16.7) and for propranolol and metoprolol could be carried out in less than 2 min. (Fig. 16.5). A propranolol column was shown to be able to resolve several other j8-blockers, including prenalterol, atenolol, pindolol, etc. (Fig. 16.8) [41] and the ropi-... 

Fig. 16.8. Enantiomer separations of (A) rac-prenalterol, (B) rac-atenolol and (C) rac-pin-dolol on a capillary column containing imprints of (7 )-propranolol. This demonstrates the ability of a MIP to recognise structural analogues of the template molecule used for the imprint preparation. Reprinted from [41] Copyright (1997), with permission from Wiley-VCH.

Fornstedt, T, Sajonz, P., Guiochon, G. Thermodynamic Study of an Unusual Chiral Separation. Propranolol Enantiomers on an Immobilized Cellulase,... 

Figure 22.4 for the successful separation of the propranolol enantiomers on a chiral stationary phase the molecule should have a rigid structure. This was obtained by a precolumn derivatization with phosgene. This reagent gives an oxazolidone ring from the alcohol and secondary amino groups. The reaction is fast at 0°C. 

Tamai, G. Edani, M. Imai, H. Chiral separation and determination of propranolol enantiomers in rat or mouse blood and tissue by column switching high performance liquid chromatography with ovomucoid bonded stationary phase. Biomed. Chromatogr. 1990, 4, 157-160. 

Morante-zarcero, S., Sierra, 1. (2012). Comparative HPLC methods for yS-blockers separation using different types of chiral stationary phases in normal phase and polar organic phase elution modes. Analysis of propranolol enantiomers in natural waters, Biomed.Anal. 62, 33-41. 

A graph relating the resolution of the enantiomers and the acid ase composition is shown in figure 8.11. It is seen from figure 8.11 that the acid ase concentration is quite critical. If this type of mobile phase is applicable, there are several advantages. The system offers simplicity and versatility and, in addition, it uses a relatively inexpensive, non-toxic, solvents. An example of the system in the separation of the Propranolol enantiomers is shown in figure 8.12. 

Schweitz, L. Spegel, P. Nilsson, S. Molecularly imprinted microparticles for capillary electrochromatographic enantiomer separation of propranolol. Analyst 2000, 125, 1899-1901. 

Matrix matched calibrators were prepared in blank rat plasma for each enantiomer separately and also for racemic propranolol. Prior to online extraction-analysis each 25p,L plasma sample was spiked with an equal volume of a solution (250ng.mL ) of the internal standard (d7-propranolol) in 20% methanol 80% 0.5 M formic acid in water, so the internal standard concenh ation in all anal54ical samples was 125ng.mL. To monitor the accuracy and precision of the assay, fom different sets... 

Servais A-C, Rousseau A, Fillet M, Lomsadze K, Salgado A, Crommen J, Chankvetadze B (2010) Separation of propranolol enantiomers by capillary electrophoresis using sulfated P-cyclodextrin derivatives in aqueous and nonaqueous electrolytes comparative CE and NMR studies. Electrophoresis 31 1467-1474... 

For example, best results were obtained for norephedrine enantiomers on plates imprinted with (—)-norephedrine, using ITA as functional monomer and eluting with acetic acid (1M) in methanol. Later, Suedee et al. [50] extended their research to MIPS prepared with (7 )-(- -)-propranolol, which separated (/ ,5)-propranolol giving rise to very tailing spots (a = 7.11 and Rs = 1.0) (see Table 4.12) and to MIPS imprinted with (5)-(- -)-naproxen that resolved racemic (/ ,5)-ketoprofen. 

The enantiomers of propranolol were separated on molecularly imprinted polymer of / -(+)-propranolol, but tailing spots were obtained [21],... 

With regard to the resolution of enantiomers, some applications can be found with modified silica gel supports. Thus, a Pirkle-type CSP was used for the separation of 200 mg of a racemic benzodiazepinone [75]. Also tris-(3,5-dimethylphenyl)carba-mate of cellulose coated on silica [91, 92] was applied successfully to the resolution of the enantiomers of 2-phenoxypropionic acid and to oxprenolol, alprenolol, propranolol among other basic drugs. However, the low efficiency of this technique and the relative high price of the CSPs limits its use to the resolution of milligram range of sample. 

Most of the chiral membrane-assisted applications can be considered as a modality of liquid-liquid extraction, and will be discussed in the next section. However, it is worth mentioning here a device developed by Keurentjes et al., in which two miscible chiral liquids with opposing enantiomers of the chiral selector flow counter-currently through a column, separated by a nonmiscible liquid membrane [179]. In this case the selector molecules are located out of the liquid membrane and both enantiomers are needed. The system allows recovery of the two enantiomers of the racemic mixture to be separated. Thus, using dihexyltartrate and poly(lactic acid), the authors described the resolution of different drugs, such as norephedrine, salbu-tamol, terbutaline, ibuprofen or propranolol. 

Fig. 21. Molecular imprinting of (R)-propranolol using methacrylic acid (MAA) as the functional monomer and trimethylolpropane trimethacrylate (TRIM) as the crosslinking monomer. (Reprinted with permission from [126], Copyright 1998 Elsevier). The enantiose-lectivity of a given polymer is predetermined by the configuration of the ligand, R-propranolol present during its preparation. Since the imprinted enantiomer possesses a higher affinity for the polymer, the separation is obtained with a predictable elution order of the enantiomers...

Capillaries coated with MIP have also been used successfully for chiral separation [34]. Schweitz et al. also synthesized highly porous, monolithic Ml-poly-mers inside such capillaries for the separation of S- and R-propranolol [38,90]. Figure 8 A shows a baseline separation of S-propranolol from the R-enantiomer in such capillaries, the latter of which was used as template. The difference in retention times for the two enantiomers was verified by analyzing the two chiral compounds also individually see Fig. 8B, C. 

Wren et al. (24) determined the binding constants of the enantiomers of propranolol and atenolol with DM-/3-CD. The results explained well the experimental observations on the separation of the enantiomers of these compounds in CE. In particular, the enantiomers of propranolol, for which the binding constants and the binding selectivities (KR/KS) were higher, were resolved better and at lower DM-/3-CD concentration than were the enantiomers of atenolol. 

HSA and BSA were used as chiral selectors to separate ofloxazin, propranolol, and verapamil enantiomers. With ketoprofen and warfarin as displacers, preferred binding sites at both proteins were discussed. 

It also presents the application of a mixture of two MIPs for the simultaneous chiral separation of two different drugs, propranolol and ropivacaine. Last but not least, the authors have prepared an MIP with incorporation of two different templates, 5-propranolol and 5-ropivacaine. This multiply templated MIP was also used in the partial filling CEC technique and sufficiently separated the enantiomers of both compounds in a single run. 

Steuer et al. demonstrated the use of supercritical fluid chromatography in the separation of enantiomers of 1,2 amino alcohols, namely pindolol, metoprolol, oxprenolol, propranolol, and DPT 201-106 using ionpairing modifiers [21]. The mobile phase consisted of carbon dioxide mixed with acetonitrile containing triethylamine as a counterion and /V-benzo-xycarbonylglycyl-L-proline as a chiral counterion. They found that the ca-... 

Pirkle CSPs have been used for LC separations of the enantiomers of alcohols, sulfoxides, bi-(3-naphthols, (3-hydroxysulfides, heterocycles such as hydantoins, succinimides, and agents related to propranolol. These phases have also been used in SFC for the separation of phosphine oxide enantiomers.40... 

Chiral resolution was also achieved by means of CE chromatographic techniques, with an enantioselective stationary phase, as reported by Li and Lloyd (1993), who used a,-acid glycoprotein as stationary phase packed in fused silica capillaries of 50 mm i.d. These authors reported the optimization (by varying pH, electrolyte, and organic modifier concentration in the mobile phase) of the separation of the enantiomers of hexobarbital, pentobarbital, isofosfamide, cyclophosphamide, diisopyramide, metoprolol, oxprenolol, al-prenolol, and propranolol. 

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