AbstractThe bioavailability‐guided development of a fixed combination tablet formulation of glyburide and metformin hydrochloride, resulting in the identification of specific particle properties for the glyburide component that confer desirable in vivo performance, is described. Four separate pharmacokinetic studies were undertaken in healthy volunteers using fixed combination tablet formulations containing glyburide with differing particle properties. These studies directed first to the appropriate particle size in laboratory scale studies and subsequently confirmed the required, narrow particle size range in product made at commercial scale. Glyburide with particle size properties of 25% volume undersize of ≤6 µm, 50% volume undersize in the range 7–10 µm, and 75% volume undersize of ≤21 µm was identified for use in a fixed combination with metformin hydrochloride. The optimized combination provided for bioequivalence to single entity metformin and acceptable bioavailability, though not bioequivalence, to single entity glyburide whilst having unique and potentially clinically valuable pharmacokinetic properties. Drug Dev. Res. 66:25–35, 2006. © 2006 Wiley‐Liss, Inc.