title: Is there any association between imidapril hydrochloride stability profile under dry air conditions and cancer initiation?
abstract: Stability study for imidapril hydrochloride (IMD) was performed under stress conditions of increased temperature (T=373 K) and decreased relative air humidity (RH=0%) in order to obtain and identify its degradation product. The degradation sample stored for 15 days under the above environmental conditions was analyzed by LC-MS technique and it was found that the only degradation impurity formed in the course of the investigated drug degradation was IMD diketopiperazine derivative (DKP) which was produced by dehydration and intramolecular cyclization. The kinetics of its formation was analyzed by a revalidated RP-HPLC method and the kinetic model of this reaction was established. It was concluded that the DKP formation follows Prout-Tompkins kinetics with the rate constant k±Δk=2.034±0.157×10(-6) [s(-1)]. The obtained degradation impurity was further assessed with respect to its mutagenic potential using commercial Ames MPF 98/100 microplate format mutagenicity assay kit equipped with Salmonella typhimurium strains TA 98 and TA 100. Both strains were exposed to six concentrations (in a range of 0.16-5.0mg/mL) of DKP in the presence and absence of metabolic activation system. No mutagenic effect was observed confirming that the presence of DKP in IMD final dosage form has no impact on cancer initiation.
authors.affiliation: Greater Poland Oncology Center, 15th Garbary Street, 61-866 Poznań, Poland; Poznan University of Medical Sciences, Department of Pharmaceutical Chemistry, 6th Grunwaldzka Street, 60-780 Poznan, Poland. Electronic address: katarzyna.regulska@wco.pl.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Regulska
authors.forename: Marek
authors.initials: M
authors.lastname: Murias
authors.forename: Beata
authors.initials: B
authors.lastname: Stanisz
authors.forename: Miłosz
authors.initials: M
authors.lastname: Regulski
mesh_terms: D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006813:Humidity / Q000517:prevention & control*; D048289:Imidazolidines / Q000009:adverse effects / Q000737:chemistry*; D009152:Mutagenicity Tests / Q000379:methods; D009369:Neoplasms / Q000139:chemically induced; D012486:Salmonella typhimurium / Q000187:drug effects / Q000502:physiology
chemical_list: D048289:Imidazolidines; C065166:imidapril
keywords: Bacterial reverse mutation assay; Degradation; Imidapril hydrochloride; Mutagenicity