Acyclovir chemical kinetics with the discovery and identification of newly reported degradants and degradation pathways involving formaldehyde as a degradant and reactant intermediate

Publication date: 15 January 2018 Source:International Journal of Pharmaceutics, Volume 535, Issues 1–2 Author(s): Bhanu C. Bejgum, Paul R. Johnson, William C. Stagner The purpose of this research was to determine acyclovir (ACV) acidic degradation kinetics which is relevant to gastric retentive device product design. A stability-indicating method revealed two unknown degradation products which have been identified by mass spectrometry as ACV and guanine formaldehyde adducts. In addition to the formation of these adducts, a proposed degradation scheme identifies the formation of methyl acetal ethylene glycol, formaldehyde, ethylene glycol, and guanine as additional ACV degradation products. pH-rate profiles were explained by using a rate law which assumed acid-catalyzed hydrolysis of protonated and unprotonated ACV. The predicted and observed rate constants were in good agreement. Data-driven excipient selection recommendations were based on the chemical kinetic study results, degradation scheme, and pH-rate profiles. The average activation energy for the degradation reaction was determined to be 31.3±1.6kcal/mol. The predicted ACV t90% at 37°C and pH 1.2 was calculated to be 7.2days. As a first approximation, this suggests that ACV gastric retentive devices designed to deliver drug for 7days should have acceptable drug product stability in the stomach. Graphical abstract
Source: International Journal of Pharmaceutics - Category: Drugs & Pharmacology Source Type: research