Separation of metoprolol

The efficiency of many CSPs increases dramatically when liquid eluents are replaced with sub- or supercritical fluids. During a comparison of LC and SFC performed with a Chiralcel OD CSP, Lynam and Nicolas reported that the number of theoretical plates obtained was three to five times higher in SFC than in LC [26]. The separation of metoprolol enantiomers by LC and SFC on a Chiralcel OD CSP is illustrated in Fig. 12-2. Although impressive selectivity is achieved by both techniques, resolution is higher in SFC (R = 12.7) than in LC (R = 4.8), and the higher flowrate in SFC reduces the analysis time. The increased efficiency of SFC also improves peak symmetry. 

Fig. 12-2. Separation of metoprolol enantiomers by LC and SFC on a Chiralcel OD CSP. Chromatographic conditions for LC 20% 2-propanol in hexane, with 0.1 % diethylamine, 0.5 mL min f Chromatographic conditions for SFC 20 % methanol with 0.5 % isopropylamine in carbon dioxide, 2.0 mL min 15 MPa, 30 °C.

Mistry, B., Leslie, J.L., Eddington, N.D. Enantiomeric separation of metoprolol and a-hydroxymetoprolol by liquid chromatography and fluorescence detection using a chiral stationary phase. J. Chromatogr. B 758, 153-161 (2001)... 

Leloux, M.S. Rapid chiral separation of metoprolol in plasma—appUcation to the pharmacokinet-ics/pharmacodynamics of metoprolol enantiomers in the conscious goat. Biomed.Chromatogr., 1992, 6, 99-105... 

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. 

The most important characteristic of the chiral recognition is that the chiral selector, either present in mobile phase or impregnated in the stationary phase, has to be compatible in size and structure with the racemic species to be resolved. This approach has been used by LuCid et al. [20] who developed a method for the separation of ( )-metoprolol tartrate. In order to approach the separation, the... 

Nasa SL, Yadav S. Microencapsulation of metoprolol tartrate using phase separation coacervation techniques. East Pharm 1989 32 133-134. 

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-... 

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. 

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... 

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. 

Lanchote, V.L., Bonato, P.S., Cerqueira, P.M., Pereira, V.A., Cesarino, E.J. Enantioselective analysis of metoprolol in plasma using highperformance liquid chromatographic direct and indirect separations applications in pharmacokinetics. J. Chromatogr. B 738, 27-37 (2000)... 

A. Karlsson, M. Berglin, and C. Charron, Robustness of the chromatographic separation of alprenolol and related substances using a silica-based stationary phase and selective retention of metoprolol and related substances on a porous graphitic carbon stationary phase, J. Chromatogr. A 797 (1998), 75-82. 

The separation of the metoprolol enantiomers was performed on a i-acid-glycoprotein column (100 mm x 4 mm ID) (ChromTech AB, Stockholm, Sweden) with a mobile phase of 0.25% 2-propanol in 20 mmol/1 phosphate buffer (pH=7) at a flow-rate of 0.8 ml/min. 

Schill, G. Wainer, I.W. Barkan, S.A. Chiral separation of cationic drugs on an al-acid glycoprotein bonded stationary phase. J.Liq.Chromatogr, 1986, 9, 641-666 [chiral also bromdiphenhydramine, brompheniramine, bupivacaine, butorphanol, carbinoxamine, chlorpheniramine, clidinium, cocaine, cyclopentolate, dimethindene, diperidone, disopyramide, doxylamine, ephedrine, homatropine, labe-talol B, labetalol, labetalol A, mepensolate, mepivacaine, methadone, methorphan, methylatropine, methylhomatropine, methylphenidate, metoprolol, nadolol, nadolol A, nadolol B, oxprenolol, oxy-phencyclimine, phenmetrazine, phenoxybenzamine, promethazine, pronethalol, propoxyphene, propranolol, pseudoephedrine, terbutaline, tocainide, tridihexethyl]... 

Balmer, K. Persson, A. Lagerstrom, P.-O. Persson, B.-A. Schill, G. Liquid chromatographic separation of the enantiomers of metoprolol and its alpha-hydroxy metabolite on Chiralcel OD for determination in plasma and urine. J.Chromatogr., 1991, 553, 391-397 [plasma urine human dog extracted metabolites fluorescence detection chiral column temp 35 column temp 25 LOD 10 nM]... 

Figure 1. Separation of the enantiomers of p-receptor blockers as oxazolidin-2-one derivatives. Column 18-m glass capillary column with XE-60-L-valine-R- phenylethylamide. Peaks 1, dechlorobupranolol 2, toliprolol 3, demethylbupranolol 4, alprenolol 5, bupranolol 6, 2-chlorbupranolol 7, isopropylbu-pranolol 8, oxprenolol 9, penbutolol 10, metoprolol [92].

Bauer LA, Horn JR, Maxon MS, Easterling TR, Shen DD, Slrandness DE. Effect of metoprolol and verapamil administered separately and concurrently after single doses on liver blood flow and drug disposition. J Clin Pharmacol (2000) 40,533 3. 

Three other studies confirmed that cimetidine increased metoprolol serum levels after single or multiple doses, but none of the studies found that this interaction resulted in an increase the effect of metoprolol on the heart rate during exercise. " An isolated case describes one patient who complained of a very irregular heart beat while taking both drugs, which was much less marked when he took the two drugs separated by as much time as possible. In contrast, two other studies found that cimetidine did not affect the serum levels of a single 100-mg dose of metoprolol. ... 

The Separation of Derivatized Metoprolol and Atenolol at High Sensitivity... 

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