Influence of peroxide impurities in povidone and crospovidone on the stability of raloxifene hydrochloride in tablets: identification and control of an oxidative degradation product.

The purpose of this study was to identify a degradation product in a tablet formulation of raloxifene hydrochloride (R-HCl), delineate the role of excipients in its formation, and develop a rational strategy for its control. The degradant was identified as an N-oxide derivative of the drug substance based upon spectroscopic characterization and chromatographic comparison to the synthetic N-oxide. To identify the factors contributing to the formation of N-oxide, binary mixtures of each excipient with R-HCl were exposed to 125 degrees C in open containers. Raloxifene hydrochloride underwent an order of magnitude increase in conversion to the N-oxide in the presence of two excipients, povidone and crospovidone, as compared with its conversion in the presence of other excipients. To confirm a hypothesis that peroxide impurities in these two excipients contributed to the oxidation of the drug substance, tablet lots were spiked with quantities of H2O2 equivalent to 200, 400, 600, and 800 ppm peroxide over the intrinsic levels present in povidone and crospovidone. A strong correlation was observed between the total peroxide level and the quantity of the N-oxide formed upon accelerated storage. From these experiments a rational limit test for peroxide content in povidone and crospovidone was adopted as part of a control strategy to limit formation of the degradation product.