Propranolol, enantiomers

MIP films, applied to a QCM transducer, have been employed for chiral recognition of the R- and 5-propranolol enantiomers [107]. MIP films were prepared for that purpose by surface grafted photo-radical polymerization. First, a monolayer of 11-mercaptoundecanoic acid was self-assembled on a gold electrode of the quartz resonator. Then, a 2,2 -azobis(2-amidinopropane) hydrochloride initiator (AAPH), was attached to this monolayer. Subsequently, this surface-modified resonator was immersed in an ACN solution containing the MAA functional monomer, enantiomer template and trimethylolpropane trimethacrylate (TRIM) cross-linker. Next, the solution was irradiated with UV light for photopolymerization. The resulting MIP-coated resonator was used for enantioselective determination of the propranolol enantiomers under the batch [107] conditions and the FIA [107] conditions with an aqueous-ACN mixed solvent solution as the carrier. The MIP-QCM chemosensor was enantioselective to 5-propranolol at concentrations exceeding 0.38 mM [107]. 

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]...

Resolution was effected by changing the polarity of the mobile phases. It is very interesting to note that the change in resolution with respect to mobile phase compositions varied from compound to compound. Resolution on polysaccharide-based CSPs in the reversed-phase mode was improved by adding cations and anions. For propranolol enantiomers on Chiralcel OD-R with sodium perchlorate salt-acetonitrile (60 40, v/v) as the mobile phase, in the presence of cations, the order of retention was Na+ > Li+ > K+ > NH4+ > N(C2H5)4+, while in the presence of anions this order was C104 > SCN- > I- > N03 > Br > Cl > AcO [90],... 

FIGURE 5 Chromatograms of the chiral resolution of propranolol enantiomers on 3,5-dinitrobenzoyl-a-phenylglycine CSP using (a) n-dodecane and (b) -pentane as the major component of the mobile phases. (From Ref. 11.)... 

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). 

Besides the conventional factors causing peak broadening in LC. another source for lower efficiency in LC with chiral stationary phases may be the existence of at least two different adsorption sites (the stereoselective and non-stereoselective ones) that may considerably differ in their adsorption kinetics (heterogeneous mass transfer kinetics) and thus cause peak broadening and tailing. These factors have been investigated and modelled by Fomstedt et al.. e.g. for protein type CSPs [75,91-9.3] and their contribution was determined for different analytes and different type of CSPs (bovine serum albumin, cellobiohydrolase 1, tris(4-methylbenzoyl) cellulose) [94j. In a recent study, these authors reported on the adsorption isotherms as well as selective and nonselective contributions of propranolol enantiomers on a cellobiohydrolase 1 CSP in dependence of the mobile phase pH [95[. 

Peak tailing and/or relatively broad peaks are often observed and can be a considerable drawback. In analytical applications, e.g. in the determination of enantiomeric impurities in drugs with high ee, i.e. > 98%. The poor efficiency and tailing has been explained for propranolol enantiomers by Fomstedt et al. 93] on the basis of heterogeneous mass transfer kinetics on the chiral and non-chiral adsorption sites of a cellobiohydrolase-l-based CSP. 

Measurement of underivatized propranolol enantiomers in serum using a celluIose-tris(3,5-dimethylphenylcarbamate) high performance liquid chromatographic (HPLC) chiral stationary phase" (54). A method for the direct measurement of the enantiomers of propranolol in human serum was developed using the OD CSP and a mobile phase composed of hexane 2-propranol W,W-dimethyloctylamine (92 8 0.01, v/v/ v). The assay was validated for use in pharmacokinetic and metabolic studies and was subsequently used in the investigation of the effect of cimetidine on the metallism and clearance of propranolol enantiomers (60). 

Table 2 Pharmacokinetic Parameters for Propranolol Enantiomers in Dog and Man after i.v. Administration of a Deuterium-Labeled Pseudoracemate and Their Bioavailability and Urinary Excretion upon Oral Administration...

E Albani, R. Riva, M. Contin, and A. Baruzzi, Stereoselective binding of propranolol enantiomers to human ot, acid glycoprotein and human plasma, Br. /. Clin. Pharmacol., 18 244 (1984). 

J. Oravcova, S. Bystricky, and X Irnovec, Different binding of propranolol enantiomers to human alpha-l-acid glycoprotein, Biochem. PharmacrA., 38 ... 

H. Takahashi, H. Ogata, S. Kanno, and H. Takeuchi, Plasma protein binding of propranolol enantiomers as a major determinant of their stereoselective tissue distribution in rats, J. Pharmacd. Exp. Then, 252 272 (1990). 

Fornstedt,T, Goetmar, G., Andersson, M., Guiochon, G. Dependence on the Mobile-Phase pH of the Adsorption Behavior of Propranolol Enantiomers on a Cellulase Protein Used as the Chiral Selector, /. Am. Chem. Soc., 1999,121, 1164-1174. 

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

Kim, H., Jeong, K., Lee Sangsan, Jung S., Molecular Modeling of the Chiral Recognition of Propranolol Enantiomers by 3-Cyclodextrin, Bull. Korean Chem. Soc. 2003, 24(1) 95-98. 

Lindner, W., Rath, M., Stochitzky, K., Semmelrock, H. J. Pharmacokinetic data of propranolol enantiomers in a comparative human study with (S)- and (R,S)-propranolol. Chirality 1989, 7, 10-13. 

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. 

Figure 9 Permeation profiles for propranolol enantiomers in the absence of CDMPC across excised human skin from phosphate buffer pH 7.4 (w = 6 + SE). (From Ref. 45.)... 

The stereoselective release behaviors of low-swelling molecularly imprinted polymer bead matrices in pressed-coat tablets were studied using either R- or S-propranolol selective MIPs. The in vitro release profiles of the low-swelling matrices showed a difference in the release of enantiomers, in that the nontemplate isomer was released faster than the template isomer. However, in the last phase of dissolution this difference was reduced and later reversed [64]. Stereoselectivity of release profiles for propranolol enantiomers were identified in MIP synthetic membranes from tablet formulations with significant differences between enantiomers [65]. Release of the enantiomer used as the print was always faster than the... 

Heard, C.M. Suedee, R. Tereoselective adsorption and trans-membrane transfer of propranolol enantiomers using cellulose derivatives. Int. J. Pharm. 1996, 139 (1-2), 15-23. 

Suedee, R. Brain, K.R. Heard, C.M. Differential permeation of propranolol enantiomers across human skin in vitro from formulations containing an enantioselective excipient. Chirality 1999, 11 (9), 680-683. 

Stereoselective retardants have been used by some researchers in the donor vehicles as a means of blocking one enantiomer and thereby facilitating the permeation of the other enantiomer [19,40]. Stereoselective retardants such as cellulose tris (3,5-dimethyl phenyl carbamate), which are known for their ability to resolve enantiomers when used as chromatographic stationary phases, were examined. When pure propranolol enantiomers were used, the steady-state flux ratio of R/S was 1.70 across silastic membrane. No such differences in the permeation were observed in the absence of retardants. 

Figure 18 Permeation profiles of caproyl propranolol enantiomers across fullthickness skin and DFP-treated skin. Circles and triangles represent intact prodrug and converted propranolol, respectively. Open and closed symbols represent (R) and (S) isomers, respectively. (Adapted from Ref. 54.)...

Age and gender do not appear to play a substantial role in the plasma protein binding of propranolol enantiomers (Table 2). A modestly lower unbound fraction of (-)-propranolol in females (10.9%, Table 2) compared with males (12.8%, Table 2) reported in one study [21] was not observed in a subsequent study [22] which reported an unbound fraction of 9.1 and 9.2 in men and women, respectively (Table 2). 

The effect of age on the stereoselective pharmacokinetics of propranolol has been the subject of several studies [21,46- 8], with conflicting results. For instance, while Colangelo et al. [48] and Lalonde et al. [46] reported no significant changes in the oral clearances of the propranolol enantiomers with advancing age, others [21,47] have reported a significant decline in the clearance of both enantiomers in the elderly. Additionally, in contrast to... 

Table 6 Oral Clearance and Plasma Half-Lives of Propranolol Enantiomers After Oral Administration of the Racemate (80 mg) to Volunteers with Different Phenotypes of Debrisoquine and Mephenytoin Hydroxylation... 

In contrast to the Chinese, the black population responds less to the same dose of propranolol, than the white population. Sowinski et al. [45] showed that both the systemic and oral clearances of both enantiomers of propranolol are substantially higher in blacks than in whites. This difference was mostly attributed to a higher intrinsic clearance of propranolol enantiomers, in association with a slightly lower (9%) hepatic blood flow in blacks. The limited available information on the effects of ethnicity on the pharmacokinetics of propranolol suggest that the racial differences in the effects of this drug cannot be attributed to the stereoselectivity in the pharmacokinetics of the drug. Rather, these differences may be due to pharmacodynamic differences among ethnic populations. 

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. 

Takahashi, H. Ogata, El. Plasma protein binding and blood cell distribution of propranolol enantiomers in rats. Biochem. Pharmacol. 1990, 39, 1495-1498. 

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