Preformulation characteristics of the opioid growth factor antagonist-naltrexone hydrochloride: stability and lipophilicity studies

Recent reports on naltrexone hydrochloride (NTX), an opioid growth factor antagonist, have highlighted its role in the treatment of diabetic keratopathy by topical application onto the eye surface. This study aims at establishing key preformulation parameters in order to develop a stable ocular formulation. These include HPLC method development and validation, forced degradation studies, Arrhenius degradation behavior in an aqueous solution and partition coefficient determination (P). Oxidation was deemed to be the main degradation pathway for NTX as indicated by the S-shaped pH-degradation-rate profile and discoloration of the degraded solutions. The main degradation products were identified using mass spectroscopy. NTX degradation followed first-order kinetics and the reaction rate constants were found to be 0.001 and 0.008 day(-1) at 4 and 25 degrees C using the Arrhenius equation. The log P values were determined as 1.54 and 1.76 at 20 and 37 degrees C. The developed HPLC method was rapid (retention time at 4.16 min), precise, sensitive and stability indicating. The determined preformulation parameters are critical to tailor an ocular formulation for NTX.