Non-isothermal stability by linear heating: a fast method for preformulation stability screening of drugs at the discovery and development interface

Abstract

The non-isothermal method for prediction of chemical stability of pharmaceuticals has been discussed in the literature for almost half a century but it has not yet been systematically evaluated. The purpose of this study was to carry out a comprehensive experimental evaluation of the non-isothermal method against the conventional isothermal method for a fast preformulation stability screening. The chemical stabilities of 20 pharmaceutical compounds in aqueous based solution were investigated. Degradation rate constants (k), activation energies (E a ), t 90% and t 98% (times for 10 and 2% loss of potency, respectively) were determined by applying the Arrhenius equation to stability data generated by both non-isothermal and isothermal methods. A comparison of the results indicated that the '1 week' non-isothermal experiment is as accurate as the '8 weeks' isothermal experiment for placing compounds (15 out of 16 cases) into the same binning categories based on t 90% and t 98% values. The absolute values of k, t 90% and t 98% at 25°C determined by the non-isothermal method for compounds with first order (or pseudo-first order) degradation kinetics were within a factor of two compared to those determined by the isothermal method. The non-isothermal method proved to be not applicable for accurate prediction of the shelf-lives of pharmaceuticals, however, when used to bin discovery compounds based on likely issues related to chemical instability, the non-isothermal method can be carefully implemented as a cost effective, fast, and relatively 'high-throughput' method to support drug stability screening at the discovery and development interface.