It was recognized some years ago that if a way could be found to control the direction of the spiral when synthesizing a coordinated polymer, it could, in theory, be used as a chiral sieve, for selecting in the "hand" of choice and excluding its mirror-image partner.
Approximately 80% of new medicines currently in development are chiral and can exist as mirror-image twins. As medicines, single enantiomers often exhibit greater potency and cause fewer side effects than do more conventional drug molecules, which may be chiral but are often racemic mixtures. Of late regulatory agencies, viz. US FDA and European Committee for Proprietary Medicinal Products, demand for enantiospecific pharmacokinetic, pharmacodynamic and toxicological data for racemic chiral pharmaceuticals to be presented for assessing their safety and efficacy. As a consequence pharmaceutical companies and research institutes have an inclination towards enantiopure medicines leading to the exponential explosion of chiral technology.
The main focus of chiral technology is the production of enantiopure chiral medicines and thus encompasses the range of techniques for producing and quantifying single-handed forms (enantiomers) of chiral compounds viz. chiral resolution for preparative purposes, chiral synthesis, chiral switch strategy and enantiomeric analysis respectively. Global revenues from chiral technology will raise from $75.0 billion in 2003 to $122.0 billion in 2008, according to Business Communications Company, Inc., USA. While forecasters say pharmaceutical markets will dominate chiral technology development for the foreseeable future, other promising outlets are on the horizon. One is optical communications. According to chiral and fine chemical consultant at Technology Catalysts International some advanced optical devices require single enantiomers of chiral inorganic crystals to propagate light waves.
Varieties of chiral technologies are available for the production of enantiopure medicines viz. separation (resolution), enantiospecific synthesis and chiral switch strategy.Separation dates back to discovery of chirality, when Louis Pasteur first isolated two isomers of tartaric acid by crystallization. Technology has advanced dramatically since then, and numerous modern chemical methods have been used to separate a racemate into its component enantiomers. These include crystallization, chromatography and resolution. In recent years, liquid chromatography has attracted increasing interest for chiral separation both on analytical and preparative scale.Today, very efficient and rugged chiral stationary phase's viz. polysaccharide based phases, protein based phases and Pirkle stationary phases are commercially available. The creation of cyclylodextrin phases and the introduction of the macrocyclic glycopeptide stationary phases by Daniel W Amstrong, Professor University of Texas at Arlington, has brought new incentives to the field of chiral separation.
More recently, capillary electrophoresis and electrochromatography have also proven useful for chiral separation in analytical scale. For large scale separations simulated moving bed (SMB) chromatography, though expensive, is an established technique. SMB has been employed to separate components from racemic mixtures, obtaining the two enantiomers of a chiral molecule with a high enough purity and in sufficient quantities to carry out clinical tests or even production stages. The variety of chiral selectors used as the stationary phase and the vast number of racemic mixtures produced by the pharmaceutical industry make this technique a powerful tool, and create a stimulating and challenging area of interest for both laboratory-scale studies and production plant design.
Synthetic routes to chiral pharmaceuticals have traditionally relied on chemical catalysts, and the most important reaction is enantioselective synthesis. According to analyst Frost & Sullivan (2003), chiral technologies are still mainly focused on traditional techniques, i.e. chiral pool synthesis and resolution (accounting for 55% of chiral technologies in 2002). In 2002, chiral synthesis based on chiral catalysts or biocatalysts accounted for 35% and 10% of the global market respectively. Biocatalyst is another area that has seen huge growth in recent years. Enzymes are nature's catalyst, and if the right enzyme for a specific reaction is spotted, then excellent yields of extremely chirally pure products are possible.
"Chiral switching" is a novel strategy for the production of enantiopure medicine. Chiral switches are chiral drugs that have been already claimed, approved and marketed as racemates or asa mixture of diastereomers, but have been redeveloped as single enantiomers.
The potential advantage of switching include less complex and improved pharamcodynamic profile; an improved therapeutic index through increase potency and selectivity and decreases side effects; an improved onset and duration of effect; a decreased incidence of drug-drug interactions and a less complex pharmacokinetic profile. Successful chiral switches include AstraZeneca's proton pump inhibitor, stomach acid remedy, Nexium (Omeprazole to Esomeprazole), Sepracor's anti-asthmatic agent Xopenex (Albuterol to Levalbuterol) and Lundbeck's antidepressant drug Cipralex (Citalopram to Escitalopram).
Experts see emerging chiral technologies viz. chiral sieve and hollow fiber membrane (HFM) technology being employed for chiral resolution in near future. It was recognized some years ago that if a way could be found to control the direction of the spiral when synthesizing a coordinated polymer, it could, in theory, be used as a chiral sieve, for selecting in the "hand" of choice and excluding its mirror-image partner. Following several years' of research, Matt Rosseinsky, Liverpool University's department of chemistry discovered that the direction of the helical spiral can be determined by the properties of the materials which bind to the metal ions in the co-coordinating polymer. i.e. by binding a chiral alcohol molecule to the metal ions, one can control the direction of the helical spiral. A left handed alcohol molecule produced a left-handed spiral and vice versa. In theory this forms the basis for chiral sieves. Matt Rosseinsky is already exploring the properties of coordination polymers he developed, with support from the UK's Engineering & Physical Sciences Research Council (EPSRC). He is currently focusing on the polymers' potential to perform separations (i.e., act as a sieve). Further research is in progress to investigate their potential to 'host' controlled chemical reactions within helical spaces.
Hollow fibre membrane technology is long narrow tubes whose walls contain microscopic channels.The goal is to immobilize chiral recognition agents in the channels. These agents being themselves chiral interact differently with the component enantiomers in a racemic mixture.Because of the enantioselective interaction the relative rate of transport of the enantiomers across the channel vary. This would result in one enantiomer being transported through the membrane wall faster than the other.Thus by just passing a racemic mixture through the centre of the HFM and collecting what is transported across the membrane, will result in a chiral separation. That is the kind of technology chiral chemists is working on.
Today, chiral capability has become an important portfolio in the drug discovery process. Kartheinz Drauz, vice president for technology and R&D management in the fine chemicals business unit of Degussa, Germany, believes that mastering as many chiral technologies as possible is essential to have a competitive edge and success in chiral research.
(The author is Reader (Quality Assurance Dept. of Pharmacy, Annamalai University, Tamil Nadu, India. He can be contacted at kvalliappan@gmail.com)