Bicarbonate media are reflective of the ionic composition and buffer capacity of small intestinal luminal fluids. Here we investigate methods to stabilise bicarbonate buffers which can be readily applied to USP-II dissolution apparatus. The in vitro drug release behaviour of three enteric coated mesalazine (mesalamine) products is investigated. Asacol® 400 mg and Asacol® 800 mg (Asacol® HD) and the new generation, high dose (1200 mg) delayed and sustained release formulation, Mezavant® (Lialda®), are compared in pH 7.4 Krebs bicarbonate and phosphate buffers. Bicarbonate stabilisation was achieved by: continuous sparging of the medium with 5% CO2(g), application of a layer of liquid paraffin above the medium, or a specially designed in-house seal device that prevents CO2(g) loss. Each of the products displayed a delayed onset of drug release in physiological bicarbonate media compared to phosphate buffer. Moreover, Mezavant® displayed a zero-order, sustained release profile in phosphate buffer; in bicarbonate media, however, this slow drug release was no longer apparent and a profile similar to that of Asacol® 400 mg was observed. These similar release patterns of Asacol® 400 mg and Mezavant® displayed in bicarbonate media are in agreement with their pharmacokinetic profiles in humans. Bicarbonate media provide a better prediction of the in vivo behaviour of the mesalazine preparations investigated.