Determination of quinacrine dihydrochloride dihydrate stability and characterization of its degradants

Although quinacrine dihydrochloride dihydrate is a widely used drug substance, a comprehensive determination of its stability profile is lacking. In this work, an integrative approach is implemented to determine the drug stability both in the solid state and aqueous solutions, identify the impurities that can be found in the active pharmaceutical ingredient, and evaluate the associated toxicity risks. Thermal analyses pointed out a two‐step dehydration of the solid state. This phenomenon seems to be consistent with the organization of the water molecules in the crystal structure and results in the destruction of the lattice. Seven related compounds of quinacrine have been identified by liquid chromatography-ion trap mass spectrometry. The main thermal degradant both in the solid state and the solution corresponds to the N‐deethyl compound, whereas quinacrine tertiary amine oxyde appears to be a signal impurity of oxidative stress in solution. Moreover, two photolytic impurities can be formed in solution either by aromatic amine cleavage or via O‐demethylation. Additionally, using computational approaches, the analysis of the potential toxicity of the impurities compared with the parent compound one shows that ketone and O‐demethyl derivatives may exhibit specific toxicity profiles. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3223-3232, 2011