<p>This study aimed to investigate the dissolution profiles of ionizable drugs in biorelevant bicarbonate buffer (BCB) at the intermediate gastrointestinal pH level. For the pH maintenance tests, BCB was prepared by adjusting the pH and the ionic strength (<i>I</i>) of NaHCO₃/Na₂CO₃ solutions using HCl and NaCl (BCB: 5–20&#xa0;mM, pH 3.0–5.0, <i>I</i> = 0.14&#xa0;M). The floating lid method was used to prevent CO₂ loss. For the dissolution tests, febuxostat (FBX), dipyridamole (DPM), dantrolene Na (DNT Na), pioglitazone HCl (PIO HCl), and tosufloxacin tosylate monohydrate (TFLX TS) were employed. The dissolution profiles were measured at pH 4.5 (10&#xa0;mM BCB, <i>I</i> = 0.14&#xa0;M). Compendial citrate–phosphate buffer (CPB) and acetate buffer (ACB) were used for comparison. In the pH maintenance test, the pH change was ≤  + 0.11 for 2&#xa0;h in all conditions. The dissolution rates of FBX and DPM were slower in BCB than in CPB and ACB. DNT Na showed slightly less supersaturation in CPB than in BCB and ACB. In contrast, PIO HCl showed markedly higher supersaturation in BCB than in CPB and ACB. TFLX TS showed higher and lower supersaturation in the absence and presence of Cl⁻, respectively. The hemi-hydrochloride salt formed in the latter case. The dissolution profiles of ionizable drugs in BCB differed from those in CPB and ACB, especially in the case of the salt-form drugs with an acidic counterion. The floating lid method enables dissolution testing using BCB in the intermediate pH range.</p> Graphical Abstract <p></p>