Chiral separation of drugs

The chiral separation of drug molecules and of their precursors, in the case of the synthesis of enantiomerically pure drugs, is one of the important application areas of HPLC in pharmaceutical analysis. Besides HPLC, capillary electrophoresis is another technique of choice for chiral separations. In this chapter we give an overview of the different modes (e.g., direct and indirect ones) by which it is possible to obtain a chiral separation in HPLC and CE. The direct approaches, i.e., those where the compound of interest is not derivatized prior to separation, are discussed in more detail since they are the most frequently used... 

TABLE 9 Examples of the Chiral Separation of Drugs Using Proteins as Chiral Selectors... 

TABLE 10 Examples of Chiral Separations of Drugs Using Chiral MIPs as Stationary Phase... 

Ding, GS. et ah. Chiral separation of racemates of drugs and amino acid derivatives by high-performance liquid chromatography on a norvancomycin-bonded chiral stationary phase, Chromatographia, 59, 443, 2004. 

Aumatell, A., Guttman, A. Ultra-fast chiral separation of basic drugs by capillary electrophoresis. J. Chromatogr. A 1995, 717, 229-234. 

Zhu, X., Lin, B., Jakob, A., Wuerthner, S., Koppenhoefer, B. Separation of drugs by capillary electrophoresis, part 10. Permethyl-alpha-cyclodextrin as chiral solvating agent. Electrophoresis 1999, 20,1878-1889. 

Maftouh, M., Granier-Loyaux, C., Chavana, E., Marini, J., Pradines, A., Vander Heyden, Y., Picard, C. Screening approach for chiral separation of pharmaceuticals Part in. Supercritical fluid chromatography for analysis and purification in drug discovery. J. Chromatogr. A 2005, 1088, 67-81. 

CE has been established as a very efficient technique for the separation of drug enantiomers. Chiral separations in CE are also based on the formation of diastereomeric complexes between the enantiomers and a chiral selector. The main advantages of the technique are its high efficiency, short analysis times, versatility due to the great variety of chiral selectors that can be added to the BGE, short equilibration times required when changing the chiral selector and low consumption of selector. °... 

The main limitation of these CSPs is their limited pressure stability, which makes them not very suitable for HPLC application. However, they have proved to be an excellent tool for the preparative separation of drugs by low-pressure HPLC. To make these CSPs accessible to HPLC, silica gel-based phases were developed. " This type of phase is available from Merck (Darmstadt, Germany) under the name Chiraspher. Polymer phases of different types have been developed by Okamoto s group. > They are prepared by the asymmetric polymerization of triphenylmethyl-methacrylate monomers. The original character of these polymers is that they do not possess any chiral centre and therefore their chirality is only due to their helicity. However, clear mechanisms have not been proposed... 

H Nishi, T Fukuyama, M Matsuo. Chiral separation of optical isomeric drugs using micellar electrokinetic chromatography and bile salt. J Microcolumn (Sep 1) 234—242, 1989. 

Lelievre and Gareil (31) studied chiral separations of nonsteroidal anti-inflammatory drugs (carprofen, flurbiprofen, indoprofen, ketoprofen, naproxen, propafenone, and suprofen) and determined the acidity and inclusion complex formation constants of these chiral compounds with different neutral CDs (/3-CD, HP-/3-CD, DM-/3-CD, TM-/3-CD, and HP-y-CD). In... 

J Haginaka. Enantiomer separation of drugs by capillary electrophoresis using proteins as chiral selectors. J Chromatogr A 875 235-254, 2000. 

J Haginaka, N Kanasugi. Separation of drug enantiomers by capillary zone electrophoresis using ovoglycoprotein as a chiral selector. J Chromatogr A 782 281-288, 1997. 

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. 

Resolution is optimized by adjusting the buffer pH and the amount of organic modifiers. The most commonly used buffers are perchlorate, acetate, and phosphate. The protocol of the selection and optimization of the mobile phase for the enantiomeric resolution of drugs on polysaccharide-based CSPs in reversed-phase mode is presented in Scheme 2. Table 4 correlates the effects of separation conditions for neutral, acidic, and basic drugs on polysaccharide-based CSPs. From Table 4, it may be concluded that a simple mixture of water and an organic modifier will produce chiral separation of a neutral molecule because there is no... 

Figure 9.5 Electropherogram of chiral separation of three basic drugs [25].

Dungelova, J., Lehotay, J., Rojkovicova, T., and Cizmarik, J. (2003) Chiral Separations of Some Drugs on the Basis of Macrocyclic Antibiotics in HPLC, SFC and CEC, Ceska a Slovensko Farmacie 52, 119-125. 

Fast chiral separations were carried out in a quartz chip using a linear imaging UV detector. Figure 6.11 shows the chiral separation of a tocainide derivative (an antiarrhythmic drug). UV imaging with a diode-array detector located along the 25-mm-long separation channel reveals the separation between the two enantiomers. Another chiral separation of pseudoephedrine was achieved in 13 s. The... 

Apart from being able to distinguish between diastereomers the analytes must also be separated from all other potentially chiral interferences that either are endogenous to the mixture or are likely to be produced in the derivatization reaction. Accordingly interest has been directed towards the separation of drug enantiomers by high performance liquid chromatography (HPLC). The technique can provide a quick, reliable and sensitive method for chiral resolution and for the determination of the enantiomeric purity. 

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