title: Preformulation stability study of the EGFR inhibitor HKI-272 (Neratinib) and mechanism of degradation.
abstract: The stability in solution of HKI-272 (Neratinib) was studied as a function of pH. The drug is most stable from pH 3 to 4, and degradation rate increases rapidly around pH 6 and appears to approach a maximum asymptotic limit in the range of pH 812. Pseudo first-order reaction kinetics was observed at all pH values. The structure of the major degradation product indicates that it is formed by a cascade of reactions within the dimethylamino crotonamide group of HKI-272. It is assumed that the rate-determining step is the initial isomerization from allyl amine to enamine functionality, followed by hydrolysis and subsequent cyclization to a stable lactam. The maximum change in degradation rate as a function of pH occurs at about pH 6, which corresponds closely to the theoretical pKa value of the dimethylamino group of HKI-272 when accounting for solvent/temperature effects. The observed relationship between pH and degradation rate is discussed, and a self-catalyzed mechanism for the allylamine-enamine isomerization reaction is proposed. The relevance of these findings to other allylamine drugs is discussed in terms of the relative stability of the allylic anion intermediate through which, the isomerization occurs.
authors.affiliation: Wyeth Research, Pharmaceutical Development, Pearl River, New York, USA. Qinghong_lu@yahoo.com
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Lu
authors.forename: Mannching Sherry
authors.initials: MS
authors.lastname: Ku
mesh_terms: D000499:Allylamine / Q000737:chemistry; D004355:Drug Stability; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D008962:Models, Theoretical; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology; D012996:Solutions
chemical_list: D011804:Quinolines; D012996:Solutions; D000499:Allylamine; D066246:ErbB Receptors; C487932:neratinib