Raloxifene HCl (RHCl) is known to be susceptible to oxidation and forms the corresponding N-oxide derivative as the primary degradation product. The purpose of this study was to evaluate the role of excipients on the generation of the N-oxide derivative from the corresponding RHCl–excipient binary mixtures. Binary mixtures of RHCl with crospovidone, povidone, magnesium stearate, Tween 80 and anhydrous lactose in drug: excipients ratio of 1 : 1 (crospovidone and povidone); 10 : 1 (Tween 80 and magnesium stearate) and 1 : 5 (anhydrous lactose) were prepared by both dry blending (trituration) and wet blending (to improve contact between drug and excipients). The prepared binary mixtures were then stored at 25, 40, 75 and 125 °C and generation of the N-oxide derivative was monitored over six months using a validated HPLC method. Pure drug and excipients stored similarly acted as controls. Further, all the individual excipients (used as control) were monitored for peroxide impurity generation using an in-house colorimetric method. The results showed that N-oxide generation was observed from all binary mixtures and the amount of N-oxide derivative formed were always higher from the mixtures prepared by wet blending and the amount of N-oxide derivative formed was dependent on storage temperature. This study thus shows that the presence of peroxide in the excipient and its role in oxidative degradation of drug substance calls for monitoring of the peroxide impurity present in the excipients used for formulating of drug sensitive to oxidation as used herein.
2009 The Pharmaceutical Society of Japan