But two enantiomers can have widely differing activities. Often, only one enantiomer has the desired activity. In the foods industry, the left-handed isomer of limonene smells of lemons, while its right-handed counterpart smells like oranges. And in medicines, one stereoisomer can have dramatically different effects to its mirror image. The S enantiomer of the non-steroidal anti-inflammatory drug naproxen is 28 times more effective than its right-handed isomer, which is extremely toxic to the liver.

Most drugs fit into an active site on a cell or an enzyme. One enantiomer fits into this receptor site while the other doesn’t, rather like trying to put a left hand into a right glove. In many cases, the undesired enantiomer merely behaves as ballast, and does nothing.

But sometimes, as with naproxen, the other enantiomer can produce side-effects. A local anaesthetic called bupivicaine, marketed as Marcain by AstraZeneca, has been in use for many years as an epidural during childbirth. Chiroscience, now part of Celltech, discovered that the left-handed enantiomer produces a much lower incidence of cardiotoxic side-effects than the right-handed isomer. Levobupivacaine is now marketed under the trade name Chirocaine by Abbott.

Before these differences became widely recognised, 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 a good reason why it cannot be made as a single isomer, such as a rapid interconversion 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.

In 2005 the top five global best selling drugs were chiral, according to data from IMS Health. Topping the list is Pfizer’s atorvastatin, sold as Lipitor. This cholesterol lowering drug has two chiral centres and global sales of USD 12.9bn (RMB 104bn) and brings in more than twice the revenue of the second biggest seller, clopidogrel, which is marketed by sanofi-aventis as Plavix and contains one chiral carbon. Next on the list is Nexium, with a chiral sulphur. The fluticasone component of GlaxoSmithKline’s combination asthma medication Seretide/Advair is a chiral steroid. Another statin, Merck’s Zocor, is the fifth best selling medicine in the world with a remarkable seven chiral centres.

As big-selling molecules such as these lose their patent protection and become open to generic competition, the market for chiral ingredients and intermediates to cater for generics producers will open up. Following a court case at the end of last year, the patents on atorvastatin remain intact and are due to last until 2011, while simvastatin’s patents expired in most European countries in 2003. In 2004 simvastatin became the world’s first statin available over the counter, available without prescription in the UK.

Larger amounts are likely to be prescribed as prices fall and healthcare systems look to save money, creating opportunities for generics producers and their suppliers. Typically, the price halves and volume doubles once generic competition arises.

For many older drugs, the chemistry required to manufacture intermediates and active pharmaceutical ingredients is relatively straightforward and the ingredients market has rapidly become commoditised. More complicated modern chiral drugs are typically much more difficult to make, providing a barrier to entry to those suppliers who are less technically competent. This is likely to prevent prices from plummeting quite as far and fast as they have after some patent expiries for medicines that are not chirally pure.

The importance of single enantiomers was not recognised by regulators until the early 1990s; the FDA’s first position paper on the subject was published in 1992. As a result, many of the chiral drugs that are due to come off patent in the coming couple of years are still racemic, such as the anticholesterol medicine fluvastatin, marketed by Novartis as Pravachol and the antidepressant venlafaxine, marketed by Wyeth as Effexor, both of whose UK patents are set to expire in 2008.

However, there is a steady growth in the number of big-selling single enantiomers that are becoming available for generic competition. Recent patent expiries include Pfizer’s Zoloft, generic name sertraline, and GSK’s Augmentin, a combination antibiotic consisting of amoxicillin and potassium clavulanate. Both of these medicinal products are chiral. To compete in the generic sector in the next few years, the ability to make single enantiomer drugs is going to become increasingly important as increasing numbers of drugs that were launched as single isomers reach the end of their patent life.

Around 80 per cent of all developmental drugs are now chirally pure, with most of the remainder being achiral. The importance of single isomer drugs over racemates cannot be underestimated. Global revenues of chiral compounds amounted to USD 7.7bn (RMB 61.71bn) in 2003 and this has been predicted to grow by 11 per cent a year between now and 2009. Market research company Frost & Sullivan estimates that by 2009 the global market will be worth USD 14.9bn (RMB 119bn).

In addition, it is estimated that around 15 per cent of all advanced intermediates, building blocks and auxiliaries have at least one chiral centre. These molecules are now a very important sector of the market for companies that make speciality chemicals, particularly those aimed at the pharmaceutical sector. As a result, a huge raft of processes designed to make chirally pure molecules have been developed and recently introduced.

There are, essentially, four ways of making chiral intermediates and ingredients. The simplest two are using a molecule from the chiral pool and by separating a racemic mixture into its component parts. In 2003 more than half, or 54 per cent, of commercial compounds came from one of these two sources. The chiral pool consists of naturally occuring chiral molecules, such as amino acids or sugars, which can be modified to make useful intermediates while keeping the chirality intact.

The logical place to start is the chiral pool. 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. S-hydroxy-gamma-butyrolactone, a key building block for Lipitor, is an important intermediate made in this way.

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.

Separations are generally carried out by some form of chromatography and various techniques have been developed in recent years that make the process simpler and quicker, such as simulated moving bed chromatography. Separation techniques will continue to be important in the future, not least because it is generally quicker to develop a synthetic route to a racemate than a single enantiomer and speed is of the essence in the early stages of drug development.

The alternative is to use a process that chemically introduces chirality into the molecule. If a manufacturing process can be identified that selectively makes just one enantiomer then this will almost certainly be cheaper and more effective in the long run. In 2003, 35 per cent of active pharmaceutical ingredients were made by chemocatalysis, using some form of chiral catalyst or auxiliary to force the reaction to make one enantiomer or the other. A further 11 per cent came from biocatalytic processes, which use enzymes to make chiral compounds.

In recent years, the growing importance of chiral molecules in the pharmaceutical marketplace has driven the development of a vast toolbox of chiral synthesis techniques that can be applied on a production scale. Perhaps the most widely used of these is asymmetric hydrogenation, using chiral metal catalysts. An enormous amount of effort has been put into the development of chiral ligands for hydrogenations and other reactions. Many of these, like the medicines themselves, have been patented and hence cannot be used in a commercial process without a licence. But many have already been licensed out on an exclusive basis.

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 biocatalytic methods has grown rapidly as techniques that make the reactions more reproducible and give better yields have been developed. Estimates from Frost & Sullivan indicate that biological methods will account for almost a third of the total market for chirals by 2009, reaching revenues of USD 3.3bn, having grown at 25 per cent a year.

Despite the growing importance of chemocatalytic and biocatalytic methods, Frost & Sullivan predicts that in the next few years the more traditional methods will continue to predominate in the manufacture of chirals because they remain easier and more reliable, even if they are often less efficient.

Many big European manufacturers of pharmaceutical ingredients and intermediates have been struggling in recent years, and have been placing an increasing focus on more specialised technologies such as chiral synthesis. As capacity in Europe reduces and manufacturers there put more focus on specialist skills, the ability of suppliers from outside the continent to make more complex active pharmaceutical ingredients and chirally pure intermediates will be vital to their future profitability.

Manufacturers in Asia currently have a big impact in the more commoditised European generics market where the chemistry is fairly straightforward. Suppliers with advanced manufacturing capabilities will be much more likely to win the confidence of big pharmaceutical companies, which commonly outsource the earlier stages of manufacturing patented medicines before completing the final stages in house. Manufacturers that can conduct chiral chemistry will be in great demand for the critical intermediate stages of producing patented medicines.