Evaluation of hydrolytic stability of drugs using theoretical calculations and kinetics simulations

Abstract

It is useful to obtain theoretical prediction data for decomposition reactions in the stability test of drugs. In this study, theoretical analyses and reaction kinetics simulations using free energy were performed for the hydrolysis reaction of aspirin. Reaction analysis of B3LYP/6-311+G(d,p)//B3LYP/6- 31G(d) level of theory estimated ΔG‡=27.2 kcal/mol for decomposition of aspirin with two water molecules transferring protons. Kinetics simulations using this result computed a calculated value of 0.091% which agreed with an experimental value of 0.083% of the decomposition rate in 6 months under the condition of 37 degrees Celsius temperature and 42% humidity. We also conducted a wide range of simulations at a humidity of 30 to 100% and obtained very good agreement with experimental values even under conditions of 60 degrees Celsius temperature and 30% humidity.