Gradient high-performance liquid chromatography (HPLC) and gas chromatography were applied as screening methods for determination of impurities in fluoxetine hydrochloride drug substances and formulated products from multiple sources. Nuclear magnetic resonance spectroscopy was also used for identification of excipients and some residual solvents. Thirty potential impurities and excipients were investigated. Several impurities were observed in generic products using gradient HPLC that were not detected with isocratic pharmacopeial methods for fluoxetine hydrochloride. Analysis of drug substance samples and capsule formulations from many different suppliers showed a wide variation in quality which, in many cases, would go undetected using isocratic methods. The quality of the innovator's product and some generic samples was high, but many generic samples contained high levels of impurities. A new impurity, N-benzyl fluoxetine, was observed in some generic samples at levels as high as 0.9 %. The gradient HPLC method was also used for stability studies and established that generic capsules formulated with lactose were less stable under accelerated conditions than those formulated without lactose.

The stability of cefaclor monohydrate drug substance and formulated products was studied under accelerated conditions in order to provide a rapid indication of differences that might result from a change in manufacturing process or source of the sample. The USP stability-indicating related substances assay was used to assess the extent of sample degradation. An Arrhenius study of drug substance stability from 45 to 70 degrees C predicted a degradation rate consistent with that observed in room-temperature studies. Qualitative degradation profiles of samples held at 65 degrees C for 2 weeks were also very similar to those of samples held at room temperature for 2 years. Based on these results, additional studies were conducted at 65 degrees C for 2 weeks on drug substance and formulated product samples. Stability differences were observed among some capsule formulations that had also exhibited real time differences. In some studies, rapid degradation after 5 days was observed at 65 degrees C followed by a slower rate from 5 to 15 days. Similar behavior was observed for cefaclor monohydrate containing high amounts of amorphous cefaclor, suggesting that differences in amorphous content could be an explanation for stability differences observed in various samples. The accelerated conditions were shown to differentiate samples and can provide a rapid indication of relative stability.