Metoprolol chiral resolution

Biermanns et al. reported the chiral resolution of /3-blockers, including propranolol, metoprolol, and atenolol using packed-column supercritical fluid chromatography [38]. A Chiracel OD column with a mobile phase of 30% methanol with 0.5% isopropylamine in carbon dioxide was used for the separation. A baseline separation of isomers was obtained in less than 5 min at a mobile-phase flow rate of 2 ml/min. While keeping the column outlet pressure constant, the flow rate was increased to 4 ml/min and it was noted that, although the retention was reduced, the resolution remained the same. Both R- and S-propranolol gave linear responses from 0.25-2500 ppm with a correlation coefficient of >0.9999. The detection limit was approximately 250 ppb for a S/N ratio of 3. The reproducibility for both R- and S-propranolol was less than 1.5%. It was also noted that 0.09% R-propranolol can be quantitated in the presence of 2500 ppm of S-Propranolol. 

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. 

Armstrong, D.W. Chen, S. Chang, C. Chang, S. A new approach for the direct resolution of racemic beta adrenergic blocking agents by HPLC. J.Liq.Chromatogr., 1992, 15, 545-556 [chiral also alprenolol, carteolol, labetolol, metoprolol, nadolol, oxprenolol, pindolol, propranolol, timolol]... 

Hermansson, J. Grahn, A. Resolution of racemic drugs on a new chiral column based on silica-immobilized cellobiohydrolase. Characterization of the basic properties of the column. J. Chromatogr., 1994, 687, 45-59 [chiral also acebutolol, atenolol, hetaxolol, bisoprolol, carbuterol, cathinone, dobutamine, dopropizine, epanolol, epinephrine, laudanosine, metanephrine, metoprolol, moprolol, norepinephrine, normetanephrine, octopamine, oxybutynine, pamatolol, practolol, prilocaine, propafenone, prox-yphylline, sotalol, talinolol, tetrahydropapaveroline, tetramisole, timolol, tolamolol, toliprolol]... 

Bhushan, R. and Arora, M., Direct enantiomeric resolution of (-l-)-atenolol, (-l-)-metoprolol and (-P)-propranolol by impregnated TLC using L-aspartic acid as chiral selector, Biomed. Chmmatogr., 17, 226-230, 2003. 

Also, D-(—)-tartaric acid has been used as a CMPA for the separation of ( )-metoprolol tartarate on silica gel plates preimpregnated with the mobile phase (ethanobwater, 70 30, v/v) containing D-(-)-tartaric acid as a chiral selector. The results of experiments performed with different concentrations of D-(-)-tartaric acid (5.8,11.6, and 23 mmol/1) revealed that the best resolution of the metoprolol tartarate enantiomers was achieved with 11.6 mmol/1 d-(-(-tartaric acid in both the mobile phase and the impregnation solution at 25 2" C. It has been assumed that tartaric acid (p Tai 2.93) dissolved in excess of ethanol could react with ethanol forming monoethyltartrate, which might play a role of a real chiral selector in this separation system [43]. The structures of CSA, ZGP, and monoethyltartrate as counterions are presented in Figure 6.3. 

Chiral separations of different /3-blockers have been performed using direct and indirect modes. Direct separation of propranolol, pindolol, nadolol, oxpren-olol, atenolol, timolol, and bupranolol has been performed using tailor-made and native chiral stationary phases. Direct resolution of propranolol, atenolol, and metoprolol has been achieved using impregnation of stationary phases with optically pure compounds such as A -(3,5-dinitrobenzoyl)-/ -(—)-a-phenylglycine and Al-(3,5-dinitrobenzoyl)-L-leucine, L-aspartic acid, L-arginine, L-lysine, and D(—) tartaric acid. 

The mobile phases consisting of acetonitrile/methanol [16] or acetoni-trile/methanol/water [18] in different ratios with a few drops of ammonia solution were found to discriminate between two enantiomers of these three -blockers in one-dimensional (ID) ascending development mode. The mobile phase composition and values of chiral separation factor a are listed in Table 11.3. The zones of separated antipodes were detected using iodine vapor and the detection limit of both alprenolol and propranolol racemates was 2.6 ng, while that of metoprolol was 0.26 /rg [16]. The effects of temperature on the separation of these three jS-blockers were also investigated [16]. It was observed that no resolution of atenolol racemate was achieved at the temperatures higher than 15" C, as well as below 8°C. The best resolution of propranolol and metoprolol racemates was achieved at 22°C. Increase of the temperature above 22°C led to the tailing, while a decrease up to 6°C had little or no effect on the quality of resolution. 

The effects of different temperatures on the separation of all three j8-blockers using L-aspartic acid as a chiral selector were also investigated. It has been found that 17°C was the most suitable temperature for the resolution of the examined jS-blockers, providing desired mobility to the diastereomeric ion pair formed anionic species of L-aspartic acid and protonated cations of amino moieties of the corresponding )3-blockers. The presence of chiral selector in situ was established by treating the developed chromatograms with ninhydrin that produced a characteristic color with aspartic acid in both spots of the resolved enantiomers [18]. This method was very sensitive, enabling detection of 0.26 fig atenolol and 0.23 tig of each metoprolol and propranolol. 

Enantiomers of metoprolol were det mined employing d-(—)-tartaric acid as chiral selector added to the mobile phase [14]. The results of experiments revealed that good resolution of enantiomers was achieved with 11.6 mmol/1 d-(—)-tartaric acid in the mobile phase and in the impregnation solution at 25 2°C [17]. 

The resolution of ( )-metoprolol into their enantiomers was achieved by TLC on silica gel plates impregnated with optically pure L-lysine (0.5%) and L-arginine (0.5%) as the chiral selectors. Different combinations of acetonitrile and methanol were used as the mobile phase. Spots were detected using iodine vapor. The detection limit for metoprolol was 0.26 /xg [19]. 

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