Chiral Technologies

The niche field of chiral technologies has hugely impacted routes to discovery and means of production of pharmaceuticals and other chemical compounds. It is concerned with the stereoselective production and analysis of specific chiral isomers.

1. Traditional Methods

The implementation of traditional technologies is a $5 billion market and represents 55 percent of the total chiral revenues. These techniques are used to simultaneously produce both enantiomers (to develop chiral intermediates) or to generate only one enantiomer (to develop end-use chemicals).

  • Diastereomeric Crystallization: This method chemically separates enantiomers from racemic mixture by producing a salt. This is done by adding an enantiopure acid or base to the mixture so that the resulting salts are not mirror images of each other. Instead they are diastereomers with different chemical and physical properties that allow their separation. Note that not all compounds will form complexes and therefore crystallize, but because of its easy adoption for manufacturing purposes, most companies first try this method and use the other methods only if this method does not work. Today 65% of chiral products are made using this technique.

  • Chromatographic Resolution: This includes the use of gas chromatography (GC), supercritical fluid chromatography (SFC), capillary electrophoresis (CE) and high performance liquid chromatography (HPLC). A pair of enantiomers is considered to be resolvable if alpha > 1.1. Here one enantiomer is retarded in its passage through the column because of its preferential binding to the chiral stationary phase. Because of this, the two enantiomers of a racemate emerge from the column at different times and with different volume fractions of eluent. Unfortunately, most chiral resolutions involve only small difference in eluent fractions.

  • Chiral pool: These compounds are found in large quantities and already possess their intrinsic chirality assigned by nature. Raw material is largely incorporated into the product. However this process needs special precautions and carefully chosen conditions and is prone to inconsistent results.

2. Asymmetric

The implementation of asymmetric technologies is more than $3 billion market, representing 35 percent of the total chiral revenues. The main driver for this method is the volume and waste reduction. However, the techniques for chiral synthesis have been highly complex, sophisticated and specialized; and the technology platforms developed for the purpose need to be adapted for each product. This makes the adoption of the technique for manufacturing purposes very expensive and difficult.

  • Asymmetric synthesis: which involves the introduction of chirality through selective chemical transformation such as hydrogenation, oxidation, etc., has the advantage that the conversions can result in better yields with little loss of material, since the unwanted isomer is not involved. But the number of steps involved and tedious nature of those steps makes this solution very costly.

  • Asymmetric Catalysis: This technique uses the metals known for their catalytic activities and includes the transition metals like titanium, or noble metals such as osmium, palladium, rhodium. The organic component is an enantiomeric compound, known as chiral ligand. It allows a stereospecific reaction to take place and therefore avoids formation of racemates. However, the efficiency and availability of the catalyst, the cost of the starting material and the reaction condition requirements such as very low temperature or high pressure can make this an impractical choice. Other factors to consider are the volumetric productivity and the ease of removing the catalyst.

3. Biological

Implementation of biological technologies is about $1 billion market and accounts for 10 percent of total chiral revenues. The main growth is fuelled by the high versatility, selectivity and performance of biological material alongside rapid advances in manufacture and supply. Due to the chemo-, regio- and stereo-selective nature of the biological process, the reaction products are usually formed without the need for massive experimental optimization, However because of its need for specialized conditions and challenges in process technology development, adapting it for industrial scale-up operation has been very difficult.

  • Kinetic Resolution: In this method, one enantiomer of a racemic substrate mixture derivatizes preferentially in the presence of the other racemate. The 'correct' enantiomer can interact with the enzyme to produce the required synthesis, leaving behind the 'wrong' isomer unreacted.

  • Biocatalysis: This method involves the chemical dramatization of either aprochiral substrate or one enantiomer in a racemate. This can be achieved through interaction between the molecule and the enzyme, giving rise to a synthesis that has been directed through levels of chemo-, regio- and stereo selectivity