Chiral drugs enantiomeric purities

Dolezalova, M. and Tkaczykova, M., HPLC enantioselective separation of aromatic amino and hydrazino acids on a teicoplanin stationary phase and the enantiomeric purity determination of L-isomers used as drugs. Chirality, 11, 394, 1999. 

A high-sensitivity cell for the Agilent Capillary Electrophoresis System has recently been developed. The cell increases detection sensitivity by an order of magnitude compared to standard detection [61]. This new cell is expected to increase substantially the utility of CE/CEC for the detection of enantiomeric purity of chiral drugs and trace analysis in biological and environmental samples. 

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. 

In its broadest terms the discussion of HPLC detection for chiral species must include the analysis of mixtures with achiral substances as well as the quality testing of, for example, the enantiomeric purity of a chemically pure drug form. The distinction between the definitions of chemical purity versus optical purity can not be overemphasized. In an efficient chiral HPLC system the latter problem is trivial, and if retention times are significantly different then any conventional detector such as RI, electrochemical, absorption, etc., could be used. Co-elutions are a major experimental concern in separations of mixtures and at this juncture it is not only prudent but absolutely necessary to involve a chiroptical detector to preferentially identify the chiral analyte. 

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. 

Chirality plays a major role in biological processes and enantiomers of a particular molecule can often have different physiological properties. In some cases, enantiomers may have similar pharmacological properties with different potencies for example, one enantiomer may play a positive pharmacological role, while the other can be toxic. For this reason, advancements in asymmetric synthesis, especially in the pharmaceutical industry and life sciences, has led to the need to assess the enantiomeric purity of drugs. Chromatographic chiral separation plays an important role in this domain. Today, there are a large number of chiral stationary phases on the market that facilitate the assessment of enantiomeric purity. 

The demand for optically active compounds has spurred numerous research efforts in the areas of asymmetric synthesis and chiral separations. The impetus behind these chirotechnological activities often comes from regulatory authorities, e.g. the Food Drug Administration. Both preparative methods for large-scale purification of optically active compounds [4] as well as analytical methods for pharmacological studies and for assaying the enantiomeric purity of chiral precursors and final products of asymmetric syntheses are needed [5]. 

The enantiomeric purity or composition of drugs, synthetic intermediates, analogs, etc., in bulk samples can be determined via chiral derivatiza-tion in laboratory research, manufacturing processes, dosage forms, quality control, etc. In these applications, limitations on the amount of material available are usually nonexistent, allowing for convenient derivatization and ready detection. In such derivatizations, 0.1-1.0 mg is typically the amount of analyte derivatized. 

Development of enantiomeric assay —Synthesis/resolution of individual enantiomers —Safety evaluation of individual enantiomers —Pharmacokinetics of individual enantiomers —Bulk drug enantiomeric composition/purity —Chiral inversion... 

Qualitative analysis of chiral compounds, including drugs, pesticides, carbohydrates, amino acids, liquid crystals, and other biochemicals Determination of enantiomeric purity of chiral compounds... 

These results have led to an interesting industrial apphcation for the synthesis of the j5-blockers Metoprolol and Atenolol. Thus, epoxidation of the prochiral allyl ethers by several bacteria, including the P. oleovorans strain mentioned above, led to the corresponding (S)-epoxides which showed excellent enantiomeric purities (Fig. 3). Further on, these chirons (i.e. chiral building blocks) were transformed into the corresponding (S)-enantiomers of the drugs developed by the Shell and Gist-Brocades companies [44]. Refinement of this approach... 

The problem of chiral synthesis is critical in making pharmaceuticals. Researchers at GlaxoSmithKline, AstraZeneca and Pfizer have examined 128 syntheses from their own companies and found that as many as half of the drug compounds made by their process R D groups are not only chiral but also each contains an average of two chiral centers [ 15 2]. To meet regulatory requirements, enantiomeric purities of 99.5% were found to be necessary. Biocatalysis is thus an essential tool for pharmaceutical research, and contributes to the development of more sustainable processes. 

Many chiral drugs must be made with high enantiomeric purity due to potential side-effects of the other enantiomer. (The other enantiomer may also merely be inactive.)... 

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