Presently, almost 20 million chemical compounds are known and a number of them are isomers. Isomers are compounds with identical molecular formulas. But they differ in the nature of the sequence of the bonding of their atoms in space. There are two main kinds of isomers. They are:
■ Constitutional - Constitutional isomers have the same number and kinds of atoms, but differ in terms of the arrangement of atoms in the molecules Eg: Propanol 1, Propanol2, Methyl, Ethyl and ether.
■ Stereo chemical -These are compounds that have the same molecular formula and functional groups bonded in the same fashion, but differ in the three-dimensional (3D) arrangement of their atoms or groups. The condition for the creation of stereoisomer is the presence of at least one asymmetric carbon atom (or other four-binding atom) in the molecule.
The symmetry of a molecule determines whether it is chiral. Chiral molecules lack symmetry and therefore cannot be superimposed on their mirror images. The two mirror images of such a molecule are referred to as enantiomers. Almost all of their physical properties are identical, including melting and boiling points and the results of spectroscopic analysis.
Superficially, the only difference is the direction in which they rotate plane polarized light, a unidirectional light source. But two enantiomers can have widely differing activities. Often, only one enantiomer has the desired activity. While nature usually only creates one chiral form of a molecule, man-made chemical compounds are almost always either achiral (lacking chirality), or they contain equal quantities of both mirror-image forms. Such mixtures are known racemic mixtures or compounds considered to contain 50 per cent impurity.
Chirality is critical in the biochemistry of natural products and drugs. Most bimolecular - proteins, hormones, nutrients, sugars, fats, and many others - are chiral. In nature, a molecules' chirality is often as important as its chemical makeup. Our body recognizes chirality. For instance, thalidomide, a drug used during the 1950s as a sleeping pill and to relieve morning sickness in pregnant women. Thalidomide is chiral and both chiral forms were present in the manufactured drug. One chiral form of thalidomide was responsible for its beneficial therapeutic effect, while the other caused severe birth defects. Hence, the challenge lies in developing a cost-effective manufacturing process for single isomer chiral molecules.
Chiral synthesis technologies
There are, essentially, four ways of making chiral intermediates and ingredients. The simplest two are using a molecule from the chiral pool and by chiral resolution.
Chiral pool technology: The chiral pool consists of naturally occurring chiral molecules, such as amino acids or sugars, which can be modified to make useful intermediates, while keeping the chirality intact. If a suitable starting material can be pinpointed, this is generally the cheapest way to go about creating a chiral intermediate or active pharmaceutical ingredient. For example, S-hydroxy-gamma-butyrolactone, a key building block for Lipitor, is an important intermediate made in this way.
Chiral resolution: The other traditional method is to take a racemate and then separate the two enantiomers. Although racemic mixtures are generally much easier to make than single enantiomers, this method has one big disadvantage - the maximum yield is 50 per cent, as half of the product is the wrong one. It can be possible to recycle the unwanted isomer into the desired one by a dynamic resolution technique, often involving enzyme catalysis, which increases the yield.
Asymmetric hydrogenation: This process involves use of chemical catalysts to synthesize desired isomers directly from starting materials. This method leads to no wastage of products and probably is the most widely used chiral technique.
Biological Technology: The fourth method for making chiral molecules involves using enzymes as biological catalysts. Nature is very good at making single enantiomer molecules. So if processes can be designed that use enzymes as catalysts, they will by default make just one isomer. In the past few years, the number of processes that use biocatalyst methods has grown rapidly as these techniques make the reactions more reproducible and give better yields. Despite the growing importance of chemo catalytic and biocatalyst methods, traditional methods continue to predominate in the manufacture of chirals because they remain easier and more reliable, even if they are often less efficient.
Pharmacological activity
A large proportion of pharmacologically active compounds possesses a chiral centre and therefore exists in at least two stereo isomeric forms. As discussed, only one stereoisomer of a drug molecule may fit perfectly in a chiral protein receptor, while the other may exhibit much less activity because of its inability to fit in that receptor. But sometimes, as with thalidomide, the other enantiomer can produce side effects.
In connection with the pharmacological activities of enantiomers, two new terms have been recently used - eutomer and distomer. The eutomer is the enantiomer in which the desired effects are concentrated. The distomer is the enantiomer, which is inactive or in which toxicity is concentrated.
Before these differences became widely recognized, companies would routinely launch racemic versions of their medicines. These racemates, which contain the two enantiomers in equal numbers, tend to be cheaper and simpler to make.
Nowadays, the regulators want drugs that are submitted for approval to be single enantiomers, if it is at all possible. For a racemate to be approved there has to be good reasons why it cannot be made as a single isomer, such as a rapid inter conversion between the two forms. Furthermore, in the late 1990s, a number of single enantiomer drugs were developed and launched, based on big-selling racemic drugs, largely as a patent extension strategy. AstraZeneca developed a single enantiomer version of its bestseller Losec, or omeprazole, to produce Nexium, or esomeprazole, currently the third biggest selling medicine in the world.
Thus, the focus of a large number of pharmaceutical companies is aimed at producing optically pure molecules, including active pharmaceutical ingredients (APIs) and intermediates, which are used as the framework for single enantiomer drugs.
Chiral molecules as drug - Individual Isomers as well as racemic mixture
Chiral blockbusters: As per IMS Health data 2005, in 7 of the top 10 drugs the active ingredients are chiral.
Racemic switches
A number of single enantiomer drugs were developed and launched based on big-selling racemic drugs, largely as a patent extension strategy. When patents of racemates expire, the patent company can undercut generic competition by launching the single enantiomer, thereby increasing patent life.
Examples:
■ AstraZeneca developed a single enantiomer version of its bestseller Losec, or omeprazole, to produce Nexium, or esomeprazole, currently the third biggest selling medicine in the world.
■ Ibuprofen: Reaches therapeutic concentrations in blood in 12 minutes versus 30 minutes for racemic mixture
■ Ketoprofen: non-steroidal anti-inflammatory drug
■ Albuterol: Antiasthmatic inhalant. (D)-Albuterol may provoke airway constriction Levalbuterol ((L)-Albuterol) avoids these side effects.
■ Allegra - Isomer from a metabolite of Seldane that avoids the life-threatening heart rhythm disorders of Seldane
■ Desloratadine - An allergy medication, which is a pure isomer from a metabolite of Claritin.
(--Chemicals, Materials and Food, Frost & Sullivan)