LAUSR

Abstract The dissolution profile of a drug product in the stomach has been assessed by an in vitro dissolution test using a single acidic pH condition (typically pH 1.2). However, there are inter- and intra-individual variations in gastric pH. The purpose of the present study was to investigate the effect of small pH differences on the dissolution equivalence of branded and generic drug products containing an acidic drug salt. Diclofenac sodium was used as a model drug. The dissolution profiles of Voltaren® (VOL) and two generic products (GE A and GE B) were evaluated by a compendial dissolution test at pH 1.2, 1.6, and 2.0. In addition, pH shift dissolution tests were also performed (from acidic pH to pH 6.5). Since clinical BE studies have not been performed for GE A and GE B, plasma concentration (Cp) -time profiles were predicted based on the pH shift dissolution test. In the compendial dissolution test, at pH 1.2, no supersaturation was observed in the dissolution profiles of VOL, GE A, and GE B. In contrast, at pH 1.6, supersaturation was observed for GE B, but not for VOL and GE A. At pH 2.0, significant supersaturation was observed for all drug products, but the dissolution profiles showed marked differences among the drug products. In the pH shift dissolution test, the drug products also showed significant differences in their dissolution profiles depending on the initial pH condition. The drug concentrations dissolved from the drug products were of opposite order in the single pH and pH shift tests, the latter being consistent with the in vivo Cmax in dogs reported in the literature. The clinical Cp - time profile of VOL was appropriately predicted based on the pH-shift dissolution data. GE A and B were predicted to be BE except when the initial pH was 2.0. In conclusion, a small difference in pH (only 0.4 pH unit) can markedly affect dissolution equivalence between the drug products of an acidic drug salt. Multiple acidic pH conditions should be used to ensure dissolution equivalence.