title: Degradation of NSC-281612 (4-[bis[2-[(methylsulfonyl)oxy]ethyl]amino]-2-methyl-benzaldehyde), an experimental antineoplastic agent: effects of pH, solvent composition, (SBE)7m-beta-CD, and HP-beta-CD on stability.
abstract: NSC-281612 (4-[bis[2-[(methylsulfonyl)oxy]ethyl]amino]-2-methyl-benzaldehyde, 1), is a chemically unstable, poorly water soluble, experimental antineoplastic agent. The saturated solubility in water at 25 degrees C was determined as approximately 30 microg/mL. In the pH range 2-11, 1 displayed pH-independent stability (t(50) was around 24 hr). However, an increase in the degradation rate was observed at pH 12. The hydrolysis of the methane sulfonate groups to the corresponding hydroxyl groups was the major degradation pathway in water in the absence of buffers and added halide ions. In phosphate buffer solutions without sodium chloride, phosphate degradants appear to be formed in addition to the mono- and dihydroxy degradants. Additional degradants, the mono- and dichloro degradation products, were formed when the ionic strength of the solution was adjusted with sodium chloride. When bromide and iodide ions were added, the corresponding mono- and dihalides were formed. The chloro compounds subsequently underwent further degradation to the hydroxy products. A deuterium kinetic solvent isotope effect study showed that water was minimally involved in the rate-determining step. The addition of either (SBE)(7m)-beta-cyclodextrin (CD) or HP-beta-CD resulted in a significant enhancement in drug solubility and stability. The apparent binding constants for HP-beta-CD and (SBE)(7m)-beta-CD were 1,486 and 2,740 M(-1), respectively. The stability of 1 in the presence of 0.1 M HP-beta-CD and (SBE)(7m)-beta-CD was enhanced 9- and 15-fold, respectively. Thus, (SBE)(7m)-beta-CD displayed better solubilization and stabilization efficacy than HP-beta-CD.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kansas, 2095 Constant Avenue, Lawrence, KS 66047, USA.
authors.forename: M
authors.initials: M
authors.lastname: Jumaa
authors.forename: L
authors.initials: L
authors.lastname: Chimilio
authors.forename: S
authors.initials: S
authors.lastname: Chinnaswamy
authors.forename: S
authors.initials: S
authors.lastname: Silchenko
authors.forename: V J
authors.initials: VJ
authors.lastname: Stella
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D001547:Benzaldehydes / Q000737:chemistry / Q000378:metabolism*; D001711:Biotransformation; D003505:Cyclodextrins / Q000737:chemistry / Q000378:metabolism*; D004355:Drug Stability; D015507:Drugs, Investigational / Q000737:chemistry / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D012995:Solubility; D012997:Solvents / Q000737:chemistry / Q000378:metabolism; D047392:beta-Cyclodextrins
chemical_list: D000970:Antineoplastic Agents; D001547:Benzaldehydes; D003505:Cyclodextrins; D015507:Drugs, Investigational; C492379:NSC281612; C103513:SBE7-beta-cyclodextrin; D012997:Solvents; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin