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Mitosis inhibitor (R)-litronesib (LY2523355) is a 1,3,4-thiadiazoline-bearing phenyl and N-(2-ethylamino)ethanesulfonamido-methyl substituents on tetrahedral C5. Chiral instability has been observed at pH 6 and above with the rate of racemization increasing with pH. A positively charged trigonal intermediate is inferred from the fact that p-methoxy substituent on the phenyl accelerated racemization, whereas a p-trifluoromethyl substituent had the opposite effect. Racemization is proposed to occur through a relay mechanism involving intramolecular deprotonation of the sulfonamide by the side chain amino group and attack of the sulfonamide anion on C5, cleaving the C5S bond, to form an aziridine; heterolytic dissociation of the aziridine yields an ylide. This pathway is supported by (1) a crystal structure providing evidence for a hydrogen bond between the sulfonamide NH and the amino group, (2) effects of substituents on the rate of racemization, and (3) computational studies. This racemization mechanism results from neighboring group effects in this densely functionalized molecule. Of particular novelty is the involvement of the side-chain secondary amino group, which overcomes the weak acidity of the sulfonamide by anchimeric assistance., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

The delamination of glass contact surfaces because of hydrolytic instability has been well documented. However, the lack of glass surface integrity can also lead to other undesirable outcomes prior to visible glass delamination. This work shows how the early stages of delamination, namely, glass corrosion, can influence the chemical stability of active pharmaceutical ingredient (API) solutions contained within a glass container, even prior to the observation of visible delamination. Multiple containers, all constructed of glass classified as USP Type I, were evaluated for hydrolytic stability and how they influence the chemical stability of the API in question. The glass composition of these analytical consumables, the vendor source, and presumably manufacturing process were examined. The implications of glass container durability on product development decisions, the influence on analytical results, and the practice of like-for-like glass container interchangeability are considered., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Oxidative susceptibility testing was performed on a drug substance containing a methoxy-naphthalene moiety. 2,2'-azobisisobutyronitrile (AIBN) was employed to initiate peroxy radical oxidation to mimic autoxidation processes. In acetonitrile (ACN)-water solvents, three major degradation products are formed. However, addition of small amounts of methanol to the solvent system completely eliminated the observed degradation products. To understand this effect, the structures of the three degradants have been elucidated using nuclear magnetic resonance, liquid chromatography-tandem mass spectrometry, and accurate mass Fourier transform ion cyclotron resonance mass spectrometry. One degradant structure definitively proves the degradation resulted from alkoxy radicals (2-cyano-2 propoxy radical) arising from the disproportionation of the tertiary AIBN-derived peroxy radicals, rather than from the intended action of the AIBN peroxy radicals themselves. The reaction occurs over a wide range of AIBN and drug substance concentrations. This "protective effect" of several percent methanol by volume is rationalized by known methanol H atom donation rates to similar tert-butoxy and cumyloxy radicals (ca. 10 M(-1) s(-1) ) and the high methanol concentration relative to the dilute substrate being investigated. This work confirms recent proposals for addition of at least about 10% methanol to the standard ACN-water AIBN stress testing diluent to insure that only the desired peroxy radical activity is present during the oxidative stress test., (Copyright © 2013 Wiley Periodicals, Inc.)