Isomeric ballast

In the case of chiral molecules that are biologically active the desired activity almost always resides in only one of the enantiomers. The other enantiomer constitutes isomeric ballast that does not contribute towards the desired activity and may even exhibit unwanted side effects. Hence, there is a marked trend in pharmaceuticals, agrochemicals and flavours and fragrances towards the marketing of products as enantiomerically pure compounds. This, in turn, has generated a demand for economical methods for the synthesis of pure enantiomers (Sheldon, 1993a). 

When Professor Ariens shook up the scientific community in 1984 by using such terms as "isomeric ballast" and "sophisticated nonsense in pharmacokinetics and clinical pharmacology" to describe the neglect of stereochemical factors for chiral compounds (3), this stimulated an explosive revival in the state of the science. The long-known basic scientific principles began to be applied to drug development, and today the pharmaceutical industry is very cognizant of the relevant issues (4-6), some of which are listed in Table 1. 

Stereoisomerism arises from the occurrence within drug molecules of chiral centres. The number of possible stereoisomers is 2", where n is the number (usually unity) of chiral centres. A substantial proportion of the commonly used synthetic drugs contain one or more chiral centres and are commercially available as preparations (dosage forms) containing racemates. Drug preparations containing racemic mixtures have been described as combinations of active drug plus isomeric ballast when one enantiomer produces little or no therapeutic effect (Ariens, 1986). The eudismic or potency ratio is defined as the ratio of the doses (in vivo studies) or the concentrations (in vitro studies)... 

The examples cited above indicate that the removal of isomeric ballast from a mixture may have considerable financial consequences. For example, it has been estimated that the research and development costs of dilevalol represented an investment of 100 million [176]. In some instances, it could be argued that the development of single-enantiomer products from previously marketed racemates does not provide a genuine therapeutic benefit [177]. However, a number of commercially successful drugs are marketed as racemates, and the potential economic significance of singleenantiomer forms of these agents is obvious. 

Geisslinger, G. Menzel-Soglowek, S. Beck, W.S. Brune, K.A. R-flurbipro-fen isomeric ballast or active entity of the racemic compound Agents Actions Suppl. 1993, 44, 31-36. 

An important factor in the resolution methods is the need to introduce the resolution step much earlier in the synthetic scheme to avoid carrying the isomeric ballast through a number of steps. Figure 9.3 for the synthesis of captopril illustrates the obvious difference between late and early introductions of the resolution step. 

This ensures optimum economics since unwanted isomeric ballast is not carried through the process, and everything else being equal, halves the waste. Furthermore, at least in the case of agrochemicals, the environment is loaded with only half the amount of substance, i.e. the part which is bioactive. 

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