Enantiomeric separation drugs

Mixing the additive in the eluent used as a mobile phase can also modify the chromatographic system (dynamic modification), but the use of modified adsorbents has led to an improvement of resolution. Example works include that by Armstrong and Zhou [11], who used a macrocyclic antibiotic as the chiral selector for enantiomeric separations of acids, racemic drugs, and dansyl amino acid on biphenyl-bonded silica. 

The preparation of enantiomerically pure drugs is one factor that makes enantioselective synthesis and the resolution of racemic drugs (separation into pure enantiomers) active areas of research today. 

Many stimulants, such as amphetamine, methamphetamine, and caffeine contain nitrogen atoms, which makes NPD analysis fairly straightforward (eg. Koide et al., 1998 Bach et al., 1999). Enantiomeric separation can be of particular importance for these drugs. A review by Liu and Liu (2002) provides extensive examples of methods for the determination of amphetamine and methamphetamine enantiomers and includes examples... 

Chiral separation of drng molecules and of their precursors, in the case of synthesis of enantiomerically pure drugs, is one of the important application areas of HPLC in pharmaceutical analysis. Besides HPLC, capillary electrophoresis (CE) is another technique of choice for chiral separations. Chapter 18 provides an overview of the different modes (e.g., direct and indirect ones) of obtaining 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 cnrrently the most frequently used techniques. These approaches require the use of the so-called chiral selectors to enable enantioselective recognition and enantiomeric separation. Many different molecnles have been nsed as chiral selectors, both in HPLC and CE. They can be classified into three different groups, based on their... 

As a typical example, the separation of the enantiomeric separation for an experimental drug R209130 (Figure 7), a compound with three chiral centers, resulting in eight... 

H Nishi, K Nakamura, H Nakai, T Sato. Enantiomeric separation of drugs by mucopolysaccharide-mediated electrokinetic chromatography. Anal Chem 67 2334-2341, 1995. 

XX Zhang, F Hong, WB Chang, YX Ci, YH Ye. Enantiomeric separation of promethazine and D,L-a-amino-/3-[4-(l,2-dihydro-2-oxo-quinoline)] propionic acid drugs by capillary zone electrophoresis using albumins as chiral selectors. Anal Chim Acta 392 175-181, 1999. 

An advanced type of column selectivity is chiral discrimination. Since enantiomers have identical physical properties they are not separable on conventional GC columns. However, if chiral analytes are allowed to interact with a chiral environment they will form transitory diastereomeric complexes which result in their being retained by the column to a different extent. As increasing numbers of enantiomerically pure drugs are synthesised in order to reduce side-effects, this type of separation will become increasingly important. 

Figure 25-8 Baseline separation of enantiomers of the drug Ritalin by HPLC with a chiral stationary phase. One enantiomer is pharmacologically active for treating attention deficit disorder and narcolepsy. The other enantiomer has little activity but could contribute to undesired side effects. Pharmaceutical companies are moving toward providing enantiomerically pure drugs, which could be safer than mixtures of optical isomers. [From R. Bakhtiar, L Ramos, and F. L. S. Tse, "Quantification of Methylphenidate in Plasma Using Chiral Uquid-Chromatography/Tandem Mass Spectrometry Application to Taxicokinetic Studies," Anal. Chim. Acta 2002, 469.261.]...

Enantiomeric separations are expected to continue to have a considerable economic impact on the development of new drugs and therapy in the biomedical field. 

Supercritical fluid chromatography Toribio et at. [132] used supercritical fluid chromatography for the enantiomeric separation of omeprazole. The drug was separated at semipreparative scale on a... 

Rojkovicova, T., Lehotay, J., and Cizmarik, J. (2001) Enantiomeric Separations of Drugs Using Macrocyclic Antibiotics, Ceska a Slovensko Farmacie 50, 166-172. 

A special case of host-guest inclusion is the resolution of a racemic mixture of chiral guests. This has important implications for the pharmaceutical industry, where the production of enantiomerically pure drugs has recently become increasingly important. A common method of chiral resolution is via the formation and separation of diastereomers. For example, a racemic acid AH may be treated with a chiral base B [21] ... 

Jung and Schurig [7] have investigated enantiomeric separations using capillary SFC and an immobilized cyclodextrin stationary phase of film thickness 0.25 /tm. The authors found no loss in selectivity and column performance after several months. Many NSAID enantiomers could be separated, but amine-containing drugs such as ephedrine or synephrine had to be derivatized with trifluoroacetic acid anhydride prior to assay (see Fig. 

TABLE 21-4. Summary of SMB Separations Reported in the Literature (Only Enantiomeric Separations on CSP and Purification of Intermediates and Drug Substance in Pharmaceutical Development)... 

Example 3. Enantiomeric Separation of DOLE. The interest in SMB for performing large-scale separations of enantiopure drugs has been recognized, and several pharmaceutical and fine chemical companies have already developed SMB processes. Whereas most of them have described in the past only applications obtained on pilot plant scale with columns up to 5-cm i.d. (Table 21-5) [128], meanwhile the first applications on production scale have been announced [129]. DAICEL has set up an SMB production plant with columns... 

Separation of enantiomers is a technique driven mainly by the needs of pharmaceutical industry to produce drugs with controlled enantiomeric purity. Enantiomeric separation involves more than knowledge of chromatography it requires an in-depth assessment of the stereochemistry of enantiomeric analytes and chiral stationary phase, as well as the interactions involved therein. In this situation, chromatography is just a tool that helps to separate enantiomers. That is why this chapter presents the main types of interactions occurring between the selectands and the selectors. Understanding these relationships, chiral separation becomes a logical process and trial and error is minimized. 

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