Amit G. Nerkar et al. / Journal of Pharmacy Research 2011,4(4),1300-1303 Review Article Available online through ISSN: 0974-6943 http://jprsolutions.info Chiral switches: A Review Amit G. Nerkar*, Kedar S. Lade1, Nilam A. Gadhave2, Sanjay D. Sawant4 Asst. Professor (Pharmaceutical chemistry) Smt. Kashibai Navale College Of Pharmacy,Saswad Kondhwa Road, S. No 40/4, near Octroi post, Kondhawa (Bk),Pune 411048, Maharashtra, India. 1M.Pharm(Sem-III Student) Smt. Kashibai Navale College Of Pharmacy, Saswad Kondhwa Road, S. No 40/4, near Octroi post, Kondhawa (Bk), Pune 411048, Maharashtra, India. 3M.Pharm(Sem-III Student) Smt. Kashibai Navale College Of Pharmacy, Saswad Kondhwa Road, S. No 40/4, near Octroi post, Kondhawa (Bk), Pune 411048, Maharashtra, India. 4Professor & Principal Smt. Kashibai Navale College Of Pharmacy, Saswad Kondhwa Road, S. No 40/4, near Octroi post, Kondhawa (Bk), Pune 411048, Maharashtra, India. Received on: 05-12-2010; Revised on: 14-01-2011; Accepted on:09-03-2011 ABSTRACT Chiral drug are made up of molecule with the same chemical structure, but different three-dimensional arrangements. Modern manufacturing has enabled the development of products containing a single molecular arrangement. The development of these single enantiomers from is known as chiral switching. Enantiomers of the same drug can have different Pharmacodynamics and pharmacokinetic properties. This may translate into potential benefit, such as an improved safety margin, if one of the enantiomers has more favourable therapeutic and pharmacokinetic characteristics. However, some chiral switching has resulted in unpredicted toxicity and the withdrawal of the enantiomer from the marker or a half in its development. Drug companies are increasingly using chiral switching as a marketing strategy. But, before prescribers switch to single enantiomer drugs they should look for evidence from well-conducted clinical trials that show the chiral switch is cost-effective and improves the outcomes for patients rather than patents. Review describes the chiral switching of some compounds and their utility.

Key words:Enantiomer, racemates, pharmacokinetics, adverse effects.

INTRODUCTION is a fundamental characteristic of nature and pervades the living world. logues. By providing a description of the increasing potency of the molecule as the We have been under its constant influence throughout evolution as a result of the affinity of the enantiomer with a receptor increases, a series of compounds can be asymmetrical nature of the environment and, while the origin of this phenom- analysed and information provided for molecular design. There can potentially be enon is a matter of speculation, the evidence surrounds us all. Most proteins, for more than one eudismic ratio for a racemate if the compound has more than one example, are formed of L-amino acids while carbohydrates are composed of pharmacological effect. natural sugars, all D-isomers. Biological receptor systems comprise a complex structural organization of helices and sheets and display ‘handedness’. This results Advantages of The Use of Single Enantiomer Instead of The Racemic in a profound effect on drug–receptor interactions. Mixtures · The main advantage of working with single enantiomers is the absence The subject has fascinated scientists since the middle of the 19th century, when of the distomer which has its own pharmacokinetic and pharmacody- Louis Pasteur first demonstrated the stereoisomeric forms of tartaric acid. Follow- namic profile. ing earlier work by de la Provostaye, he undertook crystallographic studies on · Single enantiomer has a much better solubility in aqueous solutions than tartaric acid and its salts, and demonstrated the presence of hemihedral facets. In the racemate so the intravenous dosage form only contains the former. some instances, these were orientated to the left and in others to the right. By · Economical advantages of developing the single enantiomer instead of handpicking the crystals, he divided them into two groups and found that the the racemate. solutions rotated light in equal but opposite directions. Pasteur recognized that the cause of this phenomenon lay in the molecular structure, and by extending these When A Single Enantiomer Not Better Than A ideas he evolved the theory of the asymmetrical carbon atom. Optical isomerism · The first reason for administration of racemic drugs can be that there is enables the existence of two non-superimposable mirror images or enantiomers no difference between the individual enantiomers in their pharmacody (Greek enantios=opposite, meros=part) that share identical physicochemical namic and pharmacokinetic profiles. properties but differ in their rotation of plane-polarized light. Importantly, they A second reason can be that the effect is Stereospecific, i.e. the effect is 100% can also differ in pharmacological profile, owing to highly stereospecific interac- related to the eutomer and the distomer shows no side effects.When enantiomeric tions at the receptor interface. A mixture of two enantiomers is called a ‘race- inversion occurs in the body. mate’, a term popularized by Beilstein. A racemate is designated by the prefix (±) or rac-, or by the symbol RS or SR, and has no optical activity. The use of the term RACEMIC SWITCH ‘racemic mixture’ is to be discouraged as it is synonymously used as a synonym for Over the last ten to fifteen years drug chirality, particularly the use of single both ‘racemate’ and ‘racemic conglomerate’. enantiomers versus racemic mixtures become an area of considerable interest. As a result of advances in the chemical technologies associated with the synthesis, STEREOSPECIFIC BIOLOGICAL INTERACTIONS separation and analysis of the individual enantiomers present in a racemate, Interaction of a drug with a biological system produces a cascade of events that together with regulatory requirements the number of chiral drugs presented for ultimately leads to a point at which some physiological response can be measured. approval to regulatory authorities as single enantiomers rather than racemates has The initial interaction is highly stereospecific and a hypothesis to explain this was increased. In addition to new chemical entities a number of “old“racemates have proposed by Easson and Stedman in 1933. When comparing affinities, the been reevaluated as potential single enantiomer products with the possibility for enantiomer with the highest affinity is termed the ‘eutomer’ and that with the an improved therapeutic profile. These so-called Chiral Switches have resulted lowest affinity the ‘distomer’. The pharmacological activity of the two enanti- in a number of agents being commercially available as both single enantiomer and omers can therefore be compared by calculation of the ‘eudismic ratio’. Eudismic racemic mixtures at the same time. However, not all these re-evaluations have analysis provides a powerful tool for drug design, by optimizing a series of enanti- resulted in the expected therapeutic benefits and unpredicted adverse reactions omer pairs by the comparison of the eutomers and distomers in a series of ana- have resulted. The issues, both economic and therapeutic, associated with the Chiral Switch processes are addressed here. *Corresponding author. Dr. Amit G. Nerkar In recent years there has been considerable interest in the biological activity, both Asst. Professor (Pharmaceutical chemistry) pharmacological and toxicological, of the enantiomers of chiral drugs. This inter- Smt. Kashibai Navale College Of Pharmacy, est in drug stereochemistry has resulted from the considerable advances in the Saswad Kondhwa Road, S. No 40/4, synthesis analysis and separation of chiral molecules, together with an increased near Octroi post, Kondhawa (Bk), Pune 411048, appreciation of the potential significance of the differential biological properties Maharashtra, India. of the enantiomers of chiral drugs administered as racemates. As a result of these

Journal of Pharmacy Research Vol.4.Issue 4. April 2011 1300-1303 Amit G. Nerkar et al. / Journal of Pharmacy Research 2011,4(4),1300-1303 advances in technology and the potential ben- efits of single enantiomer drugs, drug stereochem- istry became an issue for the pharmaceutical in- dustry and the regulatory authorities. A number of scientific meetings, involving academic, industrial and regulatory scientists, were held in the late 1980s – early 1990s with the specific objective of discussing the new technologies and the signifi- cance of chirality in pharmacology and therapeu- tics.

Example of Drugs Which Undergo Racemic Switch A racemic or chiral switch may be defined as the development of a single enantiomer from a previously marketed racemate. Frequently the marketed single enantiomers have the same, or very similar, therapeutic indications as the origi- nally marketed racemate but this may not always be the situation and novel indications for”old“compounds have been reported. The chiral switch process has resulted in a number of agents being re-marketed as single enantiomer products (Fig.1) and a summary of these agents, together with their reported therapeutic advantages, is pre- sented in Table 1

Table 1. Racemate To Single Enantiomer: The Chiral Switch Fig.1. Marketed single enantiomers of agents which have undergone the chiral switch. Sr.no Drug Action/Indication Comment

1 Dexketoprofen Non-steroidal anti-inflammatory drug Inhibition of cyclooxygenase activity resides in the S-enantiomer, unlike (R)-, (R)-ketoprofen undergoes minimal chiral inversion in humans (less than 10%). Reduced dose requirement in comparison to the racemate; formulation as the trometamol salt results in more rapid absorption and onset of action compared to the racemic free acid; reduced potential for gastric ulceration in animals.

2 Non-steroidal anti-inflammatory drug Main activity, inhibition of cyclooxygenase, resides predominantly in the S-enantiomer. Following administration of the racemate (R)-ibuprofen undergoes partial chiral inversion (approximately 60%) to the active S-enantiomer. A statistical evaluation of six clinical trials involving a variety of conditions, including backpain, joint pain, rheumatoid arthritis and ankylosing spondylitis, indicated that treatment with the single enantiomer (1200 mg daily) to be equivalent to, or better than, the racemate (2400 mg daily) . The mean daily dose of dexibuprofen in patients with rheumatoid arthritis was reduced by approximately one third compared to the racemate. A post marketing surveillance study in 1400 patients has indicated that dexibuprofen is a highly effective NSAID with a low adverse effect profile.Single enantiomer preparations are available in Austria and Switzerland. S-Enantiomer of omeprazole; lower first pass metabolism, slower plasma clearance and increased systemic availability compared 3 Proton pump inhibitor to the R- enantiomer. Clinical evidence that the single enantiomer maintains intragastric pH above 4 in patients with gastro- oesophageal reflux disease significantly longer, with a 24 median intragastric pH greater than an equal dose of the racemate. Reduction in interpatient variability in response.

Quinolone derivative the activity of which resides in the S-enantiomer modest differences in enantiomeric disposition favour the 4 Antimicrobial single enantiomers. 5 Levobupivacaine Local anaesthetic Enantiomers of bupivacaine exhibit stereoselectivity with respect to blockade of sodium and potassium ion channels, the R-enan- tiomer being more potent. The cardiotoxicity of the drug appears to be predominantly associated with the Renantiomer, in vitro investigations have indicated smaller conduction changes following treatment with the S-enantiomer in comparion to either (R) - - bupivacaine or the racemate . Following intravenous infusion of the racemate or S enantiomer to healthy volunteers a significantly reduced negative ionotropiceffect (approximately half) was observed with the single enantiomer compared to his mixture. Clinical studies have indicated that sensory block and the clinical profile following the single enantiomer are essentially the same as the racemate. Thus, the single enantiomer results in a similar clinical profile with a reduction in cardiotoxicity.

6. Selective serotonin reuptake inhibitor S-Enantiomer of citalopram a potent selective Serotonin reuptake inhibitor which in in vitro test systems is between 130 and 160 fold more potent than the R-enantiomer. Clinical studies in depressed patients have indicated as much improvement with 10 mg daily of the single enantiomer as achieved following 40 mg daily of the racemate (similar trends were observed with 20mg daily of the single enantiomer), together with a faster onset of action, reduction in side effects and improved tolerability profile. The single enantiomer is available in the UK and USA. 7 (S)-Ketamine Anaesthetic (S)-Ketamine has a greater analgesic and anaesthetic potency than the R-enantiomer in both animals and man; post anaesthetic emergence reactions (hallucinations and agitation) are predominantly associated with the R-enantiomer. The single S-enantiomer is available in Germany. 8. Levocetirizine H1-Antihistamine R-Enantiomer of cetirizine; Ki values against H1-receptors 3.2 and 6.3 nM for the R-enantiomer and racemate respectively. Clinical studies have indicated the equivalence of a 2.5 mg dose of the single enantiomer compared to 5 mg of the racemate, the S-enantiomer being essentially inactive. 9. Cisatracurium Neuromuscular blocker Developed from atracurium, a compound containing four chiral centres in its structure due to its symmetrical nature exists as a mixture of ten stereoisomeric forms ;cisatracurium, the 1R,2R,1’R,2’R-stereoisomer comprises approximately 15 % of the mixture . The single stereoisomer is approximately three fold more potent than the mixture, with a slightly slower onset of action and reduced histamine releasing properties. As a result of the lower dose requirement of the single stereoisomer the formation of laudanosine a metabolite reported to induce seizures in animals is reduced compared to atracurium. 10. (R)-Salbutamol [levalbuterol] ß -agonist Racemic and (S)-salbutamol induce airway hyperresponsiveness in sensitised animals; use of the racemate is associated with some 2 loss of bronchodilator potency, decreased protection against bronchoprovocation and increased sensitivity to allergen challenge and bronchoconstrictor stimuli . Studies in humans have indicated that inhalation of (R)-salbutamol produces significantly greater bronchodilatation than the equivalent dose of the racemate. The single enantiomer is available in USA. 11. (R,R)-Methylphenidate Attention-deficit hyperactivity disorder The R, R-enantiomer is approximately ten fold more potent than (S,S)-methylphenidate in the inhibition of dopamine and noradrena- line into striatal and hypothalamic synaptosomes respectively. The drug undergoes enantioselective disposition, due to presystemic metabolism, the absolute bioavailability being 0.23 and 0.05 for the R, R- and S, S-enantiomers respectively. Reported to be equally effective as the racemate at half-the-dose with the advantages of a more rapidonset of action and possible improved side effect profile. Available in USA.

Journal of Pharmacy Research Vol.4.Issue 4. April 2011 1300-1303 Amit G. Nerkar et al. / Journal of Pharmacy Research 2011,4(4),1300-1303 PHARMACODYNAMIC DIFFERENCES BETWEEN ENANTIOMERS Dopa: L-dopa decarboxylated to yield dopamine; side effects: nausea, vomiting, The interaction in the body between a drug and the proteins which elicit therapeu- anorexia, mental effects,involuntary movements, granulocytopenia tic or adverse effect and eliminate the drug require a specific three-dimensional Norgestrel: progestogen; oral Norgestrel. contraception. configuration of drug and protein. Since enantiomers have different three-dimen- Table 2- Racemate To Enantiomer: Approved Status sional configuration, the pharmacodynamics and pharmacokinetics of the two enantiomers which make up a racemic drug can be quite different. The differences Drug Name Class Appoval Status often depend on whether the center of asymmetry of the drug is in close proxim- 1. Dexfenfluramine Anoretic Withdrawn ity to the points of attachment to the protein. For example: 2 .Levofloxacin Antimicrobial Japan, UK, USA 3. Dilevalol b-blocker Development stopped Ibuprofen is a racemic mixture of two non-superimposable mirror image enanti- 4. Dexibuprofen NSAID Austria (1994), Switzerland, EU (2005 omers, (+)-(S)-ibuprofen and (-)-(R) - ibuprofen.The majority of the effects of 5 .Dexketoprofen NSAID Spain, UK racemic ibuprofen are elicited by (+)-(S)-ibuprofen. 6 .Levobupivacaine Local anesthetic UK 7. (S)-Ketamine Anesthetic Germany · (S)-ibuprofen is over 100=fold more potent an inhibitor of cyclo- 8. Esomeprazole H+-pump inhibitor UK, USA

oxygenase I than (R) - ibuprofen. 9. (R)-Salbutamol b2-agonist USA · citalopram methadone has a 20-fold higher affinity for the µ opoid 10. (R)-Fluoxetine Antidepressant Development stopped 11. Cisatracurium Neuromuscular blockade UK, USA receptor than (S)-methadone. 12. Levocetirizine Antihistamine UK, · (S)-citalopram is over 100-fold more potent an inhibitor of the seroto- 13.(R,R)-Methylphenidate ADHD USA 14 .Escitalopram Antidepressant UK, USA nin reuptake transport than (R) - citalopram. 15. (S)-Amlodipine Dihydropyridine India The so-called inactive enantiomer is not necessarily an inert substance with no 16 Eszopiclone Insomnia USA (April 2005) 17 Arformoterol b -agonist USA (April 2007) effects in vivo. For example, the cardiotoxicity of bupivacaine is mainly associ- 2 18 Armodafinil Antinarcoleptic USA (Approvable letter, April 2007) ated with the (R)-enantiomer, the psychomimetic effects of ketamine are more associated with the (R)-enantiomer,and (S)-beclofen antagonizes the effects of (R)- beclofen. The beneficial effects of a drug can therefore reside in one enanti- CHIRAL SWITCH: COMMERCIAL ASPECTS omer, with its paired enantiomer having: Advantage over de novo drug design; chance of success that much greater; costs · No activity. lower. · Some activity. · Antagonist activity against the enentiomer. Omeprazole / Esomeprazole: (R,S) sales 2001, $5.6 billion; combined sales · Completely seprate beneficial or adverse activity from the active (R,S) & (S) 2002 $6.6 billion.“Patents for Nexium give AZ more than 20 years enantiomer. of protection on the same molecule, omeprazole.”

Citalopram / Escitalopram: (R,S) sales 2002, $1.1 billion; (S) last three PHARMACOKINETIC DIFFERENCES BETWEEN ENANTIOMERS months of 2002, $81 million. FDA: does not consider single enantiomers of As the distribution and elimination of drugs from the body also involved their approved drugs as NCE and marketing exclusivity for (S) 3 years. interaction with proteins, then the pharmacokinetics of enantiomers can also be different. For example; Chiral Switch: Problems · The bioavailability of (R) - verapamil is is more than double that of (S)- Labetalol: combined a- and ß-adrenoceptor antagonist; mixture of four verapamil due to reduced hepatic first-pass metabolism. stereoisomers, two pairs of enantiomers; a- and ß-activity resides in the S, R- · The volume of distribution of (R) - methadone is double that of (S) - and R, R-stereoisomers respectively. methadone due to lower plasma binding and increased tissue binding. · The clearance of (R)-fluoxetine is about four times greater then (S) - Dilevalol: (R, R)-labetalol; development stopped due to hepatotoxicity in a pindolol due to reduced renal tubular secretion. These differences in small number of patients.Cost Schering $100 million (Scrip 1543). clearances and volume of distribution translate into differences in half- life. For example the half-life of (S)-fluoxetine is one quarter that of (R)-fluoxetine .in addition these pharmacokinetic properties can be Sotalol: racemic, nonselective ß-adrenoceptor antagonist with Class III modified in a stereoselective manner by disease, genetics, ethnicity, age antiarrhythmic activity. (-)- Enantiomer 14 to 50 fold more potent as a ß- and other drugs. Finally, the enantiomers of some drugs such as warfarin blocker; equipotent as antiarrhythmic.SWORD trial (Survival with Oral d- can be metabolized by different enzymes. Sotalol); evaluated in patients with depressed ventricular function following myocardial infraction.Study terminated following recruitment of less than 50% RATIONALE FOR MARKETING CHIRAL SPECIFIC DRUGS of the intended 6,400 patients due to increased mortality in tratment group There are several possible health benefits to chiral switching they include: (5%) compared with placebo control group (3.1%) [Lancet 1996]. · An improved safety margin (therapeutic index) through increased recep- tor selectivity and potency, and reduced adverse effects. (R)-Fluoxetine : development as single isomer; Sepracor Licensing agreement · A longer or shorter duration of action due to pharmacokinetic consid- with Lilly. More predictable pharmacology, shorter washout period; reduction in erations (e.g.half-life) resulting in a more appropriate dosing frequency. accumulation; increased flexibility of treatment.But at the highest dose level · Decreased interindividual variability in response commonly due to examined small but significant increase in QT interval; development stopped. polymorphic metabolism. c Sepracor received $23 million of what was to have been a $90 million deal; · Decreased potential for drug-drug interactions. Sepracor stock value fell by 28% (Chem Eng News 2000). As some racemic drugs were patented without separate patents for each enantiomer, some companies have seized the opportunity to develop and market or licence single enantiomers of marketed chiral drugs.(for Dexfenfluramine / Fenfluramine: anoretic agent; racemic drug had been example an American company now marketed (R) – salbutamol). An- available for 25 years.Association with valvular heart disease initially reported other commercially driven reason for chiral switches is the impending for the combined use of fenfluramine-phentermine (fen-phen combination) in expiry of the patents of some “blockbuster” racemic drugs. The manu- the USA. Also, rare but serious risk of pulmonary hypertension. Both single facturers have developed and marketed the patent franchise and pro- enantiomer and racemate voluntarily . tecting themselves from competitors who produce generic copies of the racemate. Methadone: It is used as maintenance therapy in the management of opioid Obtaining marketing approval for a chiral switch usually requires rela- dependence. R-enantiomer 50 fold more potent analgesic compared to (S)- tively few new studies to be conducted if the racemate is already mar- methadone. Racemate used in the majority of countries but R-enantiomer used keted. The single enantiomer can be ready for launch before the patent in Germany. Decrease costs, replaced by a double dose of the racemate. Result: for the racemate expire and before the marketing of any generics. decrease in the serum concentration/dose ratio for the active enantiomer; some patients experienced withdrawal symptoms, required dose adjustment. Penicillamine: It is used in treatment of Wilson’s disease; animal toxicity: weight loss, intermittent fits, death in rats; L >> D; mutagenicity L > D; Optic SINGLE ENANTIOMERS DOMINATE neuritis with racemate in man, drug withdrawn (USA). Sales growth in several key therapeutic categories has been very robust. Al-

Journal of Pharmacy Research Vol.4.Issue 4. April 2011 1300-1303 Amit G. Nerkar et al. / Journal of Pharmacy Research 2011,4(4),1300-1303 though part of this increase, particularly in cancer therapy, has been from cally active form are not all that uncommon. Considering the potential for increased approvals for biologics, small-molecule single enantiomers also have developing new and improved products from existing drugs at much lower costs, played a significant role. The future growth of single-enantiomer products is compared to discovery and development of new molecular entities, development expected to be strong based on the following key market drivers: of chiral molecules is an attractive proposition for Indian companies. The strat- 1. increased evidence and awareness of improved therapeutic profiles; egies that need to be evolved include identification of the right candidate drug for 2. published policies and guidelines of regulatory agencies; evaluation of its optically pure enantiomer, adequate technology strengths in 3. advances in chiral technologies; synthesis, optical resolutions, separation techniques, biological evaluation meth- 4. racemic switches as a generic defense strategy; odologies, clinical trials and drug approvals by regulatory agencies, in a time frame much shorter and at much lower costs than what will be required for new drug 5. Need for new and better anticancer and antiviral drugs. discovery and development. Whether, following the U.S. model, specialised com- panies to develop chiral products would be relevant to India is to be evaluated. ECONOMIC CONSIDERATION The global market for pharmaceuticals is enormous, estimated to be worth ap- CONCLUSION proximately $ 300 billion US in 1997. However, over the next five years the The pharmaceutical industry is currently very interested in the so-called “racemic patents on a number of drugs, the market worth of which is quoted as $ 40 billion, switch.” Many drugs exist as asymmetric three-dimensional (chiral) molecules and are due to expire . There is also evidence that the rate of development of new will therefore have several stereoisomers. There are often pharmacodynamic, agents is declining, for example the US FDA approved only 28 new chemical pharmacokinetic and/or toxicological differences between enantiomers. The choice entities in 2001 which is reported to be the lowest number for 30 years. between developing a racemate or single enantiomers depends on therapeutic advances and developmental costs involved. Regarding the target environment The situation is compounded by the fact that research and development costs are for drug intervention, even if natural physiological mediators are achiral, their increasing, having doubled over the last fifteen years, and were estimated to be receptors may demonstrate a preference for the (-)- or (+)-enantiomer of ago- between $ 300 and 400 million in 1997. The current cost estimates of bringing a nists or antagonists. It is also obvious that the majority of enzymes and channels drug to market are of the order of $ 600 million and may be as high as $ 800 are stereospecific, at least to a variable extent. From a pharmacokinetics point of million. Additionally, drug development time is now so long that the average view, chirality can have an influence on drug absorption, distribution, metabolism effective patent life of a “new”agent is only 10-12 years. As a number of commer- and elimination. With a few exceptions, toxicological differences between iso- cially highly successful drugs are chiral the economic significance of stereochem- mers of known drugs are less dramatic than thought to be and only seldom istry to the pharmaceutical industry is obvious. The chiral switch process provides substantiate the necessity of a racemic switch. a strategy to extend the profitable life of a pharmaceutical “bestseller”, and may result in extended patent protection and provide an advantage against generic REFERENCES: competition. In some instances it could be argued that the development of a single stereoisomer from a racemate would not result in a significant therapeutic 1. Caner H, Groner E, Levy L.Trends, in the development of chiral drugs. Drug discovery; 2004; advantage. In the case of omeprazole, the biggest selling drug worldwide in 1997, 9(3); 105-110. sales the USA alone being greater than $ 5 billion, there is some controversy 2. Szelenyi I,Geisslinger G, Paul W, Brune J,The real Gordian knot:racemic mixture versus pure enantiomers. Drug news and perspectives; 1998; 11(3); 139. regarding the relative merits of the single enantiomer. 3. Hutt A, Valentova J,The development of single enantiomer drugs from racemates.Acta facilitates pharmaceutical universitutis comenianae; 2003; 12(3); 205. INDIAN OPPORTUNITIES 4. Vangrnum P,Single enantiomer drugs drive advances in asymmetric synthesis. Pharmaceutical technology; 2006; 15(3); 201. It is difficult to predict whether a single enantiomer of a marketed drug will offer 5. Agranet I, Caner H, Caldwell S,Putting chirality to works; the strategy of chiral switches: drug any advantages in terms of improvement in efficacy or reduction in side effects discovery; 2002; 753-768. over the corresponding racemate. It is possible that once a pure chiral form is 6. www.beckman coulter.com/ literature/biosearch. 7. www.science.widener.edu. available, it may have a totally different pharmacological and therapeutic profile. 8. www.student.ccbsmd.edu Examples, such as that of the highly toxic, banned drug, Thalidomide, which led to 9. www.uric.ca/notes. several thousand mal-formed babies, resurging as an anti-cancer drug in its opti- 10. www.sciencedirect.com

Source of support: Nil, Conflict of interest: None Declared

Journal of Pharmacy Research Vol.4.Issue 4. April 2011 1300-1303