Racemate refers to a mixture of two chemical substances that differ only in their three-dimensional structure. These behave to each other like image and mirror image and can each have very different pharmacological effects on the human body.
What is a racemate?
The pain reliever ibuprofen is usually present as a racemate. A racemate (also racemic mixture) refers to a mixture of two chemical substances that are present in the same quantitative ratio to each other. They differ in their three-dimensional structure, which results from the respective arrangement of the atoms. If an atom has four bonds to four other different atoms or groups of atoms, this atom is called chiral. If a chemical compound has at least one chiral atom, the four bonding partners can adopt two different arrangements around the chiral atom. This results in two substances, so-called enantiomers, which behave to each other in their spatial structure like image and mirror image or like left and right gloves: Although they contain exactly the same atoms or groups of atoms, they cannot be made to coincide and are thus clearly distinguishable from one another. They are usually referred to as (R)- and (S)-enantiomers.
Pharmacological action
The enantiomers of a substance differ in their physical properties only with respect to their optical activity. A substance is optically active if it measurably changes a certain property of light as it passes through it. This is one of the ways in which the respective enantiomers can be distinguished and represents an essential criterion in the purity testing of a potentially racemic mixture. Enantiomers often differ considerably in their physiological properties, making their distinction or the purity of a racemate of great importance in pharmaceutics. Every drug has a site of action in the human body, a so-called target, at which it is recognized by the body’s own structures. These structures are usually themselves chiral and usually recognize only a particular enantiomer of a substance. It is therefore extremely important in the manufacture of drugs that only the active enantiomer is contained in the product. Otherwise, serious side effects can occur, as the (often less effective) mirror-image enantiomer can, for example, bind to a completely different site in the body and trigger an unwanted reaction. It is also possible that the wrong enantiomer is degraded by an enzyme in the body before it even reaches its target. Or it may bind to a transport protein and reach an undesired location in the body. The possibilities for interaction are extremely diverse, which is why side effects are hard to predict when a racemate or non-enantiomerically pure mixture is present in the product. A less serious but more practical example is aroma compounds. The olfactory receptors in our nose also possess chirality and are tailored to recognize specific substances. Thus, an enantiomer of the natural substance carvone smells like caraway, but the corresponding mirror image enantiomer smells like mint.
Medicinal application and use
Many of the organic compounds used as active ingredients in drugs have chiral atoms and thus different enantiomers. Therefore, care must already be taken during the synthesis of these substances to obtain a product that is as enantiomerically pure as possible. Subsequent separation is technically very complex, which is why side effects are tolerated in some cases and a racemate is approved as a drug. Since the related enantiomers often have different potencies, the final drug product in this case must be dosed higher to achieve the same efficacy as that of an enantiomerically pure drug. For example, the anesthetic drug ketamine has an (S)-enantiomer, which has better analgesic and anesthetic effects as well as lower psychotropic side effects than the corresponding (R)-enantiomer. In this case, it is advantageous for the patient if the (S)-enantiomerically pure drug is used. Another example is the analgesic ibuprofen, which is usually present as a racemate. Only the (S)-enantiomer has an analgesic effect, while the (R)-enantiomer is virtually ineffective.However, a certain proportion of the latter is converted into the active (S) form in the organism by an endogenous enzyme. Therefore, no complex synthesis or subsequent separation of the enantiomers is required.
Risks and side effects
Inefficacy of an enantiomer is a comparatively harmless side effect of using a racemic mixture as a drug. A tragic example of very serious side effects is the sleeping pill thalidomide, which contains the active ingredient thalidomide. Thalidomide was advertised in the 1950s as a non-lethal sleep aid and was popular with pregnant women because it additionally reduced morning sickness. Animal studies conducted up to that time showed hardly any side effects. However, after its market launch, more malformations occurred in newborns and the drug was withdrawn from the German market after four years. Many studies then investigated the mode of action of thalidomide and were able to show that the molecule binds to a growth factor in the unborn child and thus disrupts embryonic development. So far, this teratogenic effect could not be definitively attributed to either enantiomer, especially since the two enantiomers convert into each other in the body. However, similar studies suggest that the (S)-enantiomer of thalidomide may have a stronger damaging effect. In the case of the local anesthetic bupivacaine, a significant hazard comes from accidental entry into the bloodstream. Here, the (R)-enantiomer triggers a greater drop in heart rate than the corresponding (S)-enantiomer. However, both show a comparable anesthetic effect. If an (S)-enantiomer-pure agent is used here, these serious side effects for patients can be reduced.
