Evaluation of a diltiazem cream preparation for estimation of degradation behavior

Abstract

Diltiazem cream, which is used in chronic anal fissure (CAF) treatment, is known to be susceptible to hydrolysis and degradation in aqueous solutions. The major pathway of degradation is o-deacetylation which leads to formation of 'desacetyl diltiazem' and this study focuses on this degradation mechanism. In this study, degradation of diltiazem incorporated into an oil-in-water cream base was investigated. It was especially aimed to show the effect of the formulation preparation procedure on impurity formation during the diltiazem cream formulation. In this regard, preliminary studies were performed to optimize the formulation parameters for stability. The outcome of these studies was applied to the preparation procedure; the compositions of excipients were kept constant while the order of addition of excipients to the aqueous phase and the mixing time were varied. To our knowledge, there is no study published regarding the relation between this degradation and the formulation process. Formulations were characterized in terms of formation of the desacetyl diltiazem impurity with a validated stability indicating HPLC method. The cream formulation with the highest stability was obtained through mixing propylene glycol and water first and adding diltiazem active substance in the final step of formation of aqueous phase with a shortened stirring time. This preparation procedure exhibited reduced desacetyl diltiazem impurity formation.