A preformulation evaluation of a photosensitive surface active compound, explaining concentration dependent degradation

Abstract

A candidate drug within the cardiovascular area was identified during early research and evaluated for further development. The aim was to understand and explain the degradation mechanisms for the present compound. The stability of the active pharmaceutical ingredient (API) in solution and solid state was studied during different conditions. The bulk compound was exposed to elevated temperatures, increased relative humidity and stressed light conditions. Degradation of the drug in solutions was followed in the presence versus absence of ethylenediaminetetraacetic acid (EDTA), during aerobic versus anaerobic conditions, stored protected from light versus exposed to light and as a function of pH and concentration. It was possible to improve the stability by adding EDTA and completely abolish degradation by storing dissolved compound at anaerobic conditions. Solutions of API were stable between pH3 and 7, with some degradation at pH1, when stored protected from light and at 22°C, but degrade rapidly when exposed to ambient light conditions. The degradation products were identified by mass spectroscopy. Degradation schemes were drawn. There was concentration dependence in the degradation of dissolved drug when exposed to light, showing a titration behavior that concurred with the measured critical micelle/aggregation concentration (CMC/CAC) of the compound. The compound was stable in solution during the investigated time period, at concentrations above CMC/CAC, where the molecule was protected from photodegradation when the compound aggregated. Below CMC/CAC, a significant degradation of the API occurred. This may be a potential explanation why other surface active compounds show concentration dependent degradation. The photosensitivity was also observed for the neutral compound in crystalline and amorphous form, as well as for the crystalline chloride salt of the drug. However, the degradation of amorphous form was faster compared to crystalline material. No difference was observed in the degradation pattern between the neutral form of the compound and the salt form of the drug.