Influence of dose and the USP basket and flow-through cell dissolution apparatuses in the release kinetics of metronidazole immediate-release products

Abstract

Metronidazole has been classified as a drug with high solubility/high permeability and for this compound a biowaiver monograph has been published however, no significant in vitro-in vivo correlation was found using the current pharmacopeial conditions. On the other hand, ineffectiveness due to low drug plasma levels in patients as well as differences in dissolution performance from commercial products even between batches of the same product, have been found. The objective of this study was to evaluate the dissolution performance of two metronidazole generic products and the reference product Flagyl® at two doses (250- and 500-mg) under the hydrodynamic environment generated by the flow-through cell (USP Apparatus 4) and to compare it with the results obtained with the USP official basket method. USP Apparatus 4 with laminar flow at 24 ml/min and 0.1 N hydrochloric acid solution as dissolution medium was used. In USP Apparatus 1, 250-mg products were classified as very rap- id dissolution products (> 85% dissolved in 15 min), whereas the 500-mg products were classified as rapid dissolution (> 85% in 30 min). With the USP Apparatus 4, 250-mg products were considered rapid dissolution products (> 85% dissolved in 30 min) and 500-mg products were not considered rapid dissolution products due to not reaching 85% dissolution in 30 min. Under this system, that best simulates the gastrointestinal flow, only the 500-mg reference product achieved 100% release up to 52 min. Dissolution profiles were compared using model-dependent and -independent methods and with both approaches significant differences were found (p < 0.05). Metronidazole is considered an ideal drug for waiver of bioequivalence studies but their dissolution equivalence is not as obvious when doses or system are changed, which impacts on request biowaiver.