IntroductionRacemization has long been an ignored risk in drug development, probably because of a lack of convenient access to good tools for its detection and an absence of methods to predict racemization risk. As a result, the potential effects of racemization have been systematically underestimated. Areas coveredHerein, the potential effects of racemization are discussed through a review of drugs for which activity and side effects for both enantiomers are known. Subsequently, drugs known to racemize are discussed and we review methods to predict racemization risk.Application of a method quantitatively predicting racemization risk to databases of compounds from the medicinal chemistry literature shows that success in clinical trials is negatively correlated with racemization risk. Expert opinionIt is envisioned that a quantitative method of predicting racemization risk will remove a blind spot from the drug development pipeline. Removal of the blind spot will make drug development more efficient and result in less late-stage attrition of the drug pipeline. KeywordsRacemization; quantitative prediction; stability; enantiomers; risk; Adrenaline, 10, can be used to induce vasoconstriction at the site of injection of local anaesthetics and the L-form is 10 times more effective than the D-form.[18] Certain aromatase inhibitors, such as fadrozole, 11, have significantly different activities for each of the two enantiomers; S-fadrozole is most active for instance. [19] Other studies have investigated the pharmacokinetic properties of enantiomers.Ketoprofen, 12, is a non-steroidal anti-inflammatory and its delivery via a trans-dermal route has been considered.[20] When used orally, it is delivered as a racemate but stereoselective skin permeation might favour its use as a single enantiomer for this alternative delivery route. Studies showed the racemate to be higher melting than the individual enantiomers and x-ray diffraction patterns support the racemate having a different solid form than the individual enantiomers suggesting that the two enantiomers co-crystallize and are both present in the unit cell. When 0.05 M solutions of each of the enantiomers was applied to mouse skin, no difference in permeation was detected between enantiomers or racemate.Further studies supported no stereoselectivity for skin permeability for ketoprofen.Ketorolac, 13, was investigated in a pharmacokinetic study in healthy volunteers. [21] Following intravenous injection, the concentration of the two enantiomers was monitored separately. This showed that S-ketorolac is cleared more rapidly than the R enantiomer leading to higher exposure to R-ketorolac. Surveys* N ALK ALK * OH * H * NH 2 FDA statement on the development of new stereoisomeric drugs. * 12. Eriksson T, Bjorkman S, Roth B, Fyge A, Hoglund P. Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide. Chirality 1995;7:44-52. This paper provides rare, and therefore very valuable, kinetic data for racemization in huma...

Racemization has alarge impact upon the biological properties of molecules but the chemical scope of compounds with knownr ate constants for racemization in aqueous conditions was hitherto limited. To address this remarkable blind spot, we have measured the kinetics for racemization of 28 compounds using circular dichroism and 1 HNMR spectroscopy. We show that rate constants for racemization (measured by ourselves and others) correlate well with deprotonation energies from quantum mechanical (QM) and group contribution calculations.Such calculations thus provide predictions of the second-order rate constants for general-basecatalyzedr acemization that are usefully accurate.W hen applied to recent publications describing the stereoselective synthesis of compounds of purported biological value,t he calculations reveal that racemization would be sufficiently fast to render these expensive syntheses pointless.Thalidomide racemizes in am atter of hours and yet it remains ap oster child for enantioselective synthesis which would not have saved its victims.[1] Thes tatus quo in enantioselective synthesis thus ignores the cruel blind spot that we address in this paper:racemization.Although necessary in dynamic kinetic resolution protocols, [2,3] racemization and epimerization can caus es afe compounds to become toxic or lose efficacy, [4][5][6][7][8][9][10][11] lead to misidentification of chiral compounds extracted from natural sources, [12] etc.I gnoring racemization thus leads to wasted material and human resources.Racemization is ap articular problem because its detection requires chiral analytical methods. [13,14] Hence,f ew reports disclose rate constants for racemization under aqueous conditions. [1,[15][16][17][18][19][20] Chiral centers with certain combinations of substituents have been posited to be prone to general-basecatalyzed racemization although with little supporting data. [21][22][23] We therefore classified stereogenic carbon atoms according to their attached substituents.E ach substituent is identified as one of sixty types, [24] which encompass more than 99.95 %ofall such substituents in the GOSTAR database. [25] Thet en most frequently occurring substituents are listed in Figure 1; the Hr equired for general-base-catalyzed racemization is prominent.[24] Groups labelled *w ere selected for experimental study.Based on prevalence,e arlier work, [21][22][23] and chemical intuition, several compounds were selected for detailed kinetic studies. [26][27][28] Ther ate constants for general-basecatalyzed racemization were derived for ar ange of 11 arylglycine derivatives (1, 2 and 3), 12 hydantoins (4, 5 and 6)a nd 5t hiohydantoins (7 and 8). Briefly,a ts everal buffer concentrations,c ircular dichroism spectroscopy (CD) followed the decrease in ellipticity and/or 1 HNMR spectroscopy the incorporation of Dfrom deuterated buffers.T he pseudo- first-order rate constants for these processes were corrected for hydrolysis side reactions if required. [24] Plotting the firstorder rate constants for ...

Racemization has a large impact upon the biological properties of molecules but the chemical scope of compounds with known rate constants for racemization in aqueous conditions was hitherto limited. To address this remarkable blind spot, we have measured the kinetics for racemization of 28 compounds using circular dichroism and 1H NMR spectroscopy. We show that rate constants for racemization (measured by ourselves and others) correlate well with deprotonation energies from quantum mechanical (QM) and group contribution calculations. Such calculations thus provide predictions of the second‐order rate constants for general‐base‐catalyzed racemization that are usefully accurate. When applied to recent publications describing the stereoselective synthesis of compounds of purported biological value, the calculations reveal that racemization would be sufficiently fast to render these expensive syntheses pointless.