Toward an In Vitro Bioequivalence Test.

Oral absorption of Biopharmaceutics Classification System (BCS) II drugs is limited by in vivo dissolution. The current pharmacopeial in vitro dissolution methodologies are designed for quality control, and do not reflect in vivo performance criteria. This project is an investigation into the key in vitro dissolution parameters: hydrodynamics, pH, surfactants/bile salts, and buffer species that are important to in vivo dissolution. Hydrodynamics, i.e., the convective contributor to dissolution, was examined through the stagnant diffusional layer thickness, happ, of fenofibrate in a USP dissolution apparatus II. These results demonstrate that happ has different functional dependences on particle sizes and the paddle speed. At 50 rpm, happ is linear with square root of particle size within the range of 6.8-106 μm. In contrast, at 100 rpm a transitional particle radius exists at 23.7 μm, above which the relationship becomes constant. Further, the effect of particle size and paddle speed on happ can be combined using dimensional analysis. In addition, key components of GI fluids such as pH, bile salts and buffer species were also investigated. The effects of pH and surfactants on ketoprofen were investigated. The dramatic enhancement of in vitro solubility/dissolution attributable to an increase of pH and presence of SLS mimics the in vivo solubilization/dissolution behavior of ketoprofen, when the pH increases from 1 to 2 in the stomach to 5 to 6 in the duodenum. Further, even at the same pH and buffer concentration, the importance of buffer species was demonstrated by a) 50-200% faster intrinsic dissolution rates of ketoprofen and indomethacin in USP SIF, FaSSIF phosphates than in various concentrations of bicarbonates more reflective of in vivo; and b) the dependence of buffer differential on biopharmaceutical properties, e.g., drug pKa, solubility and diffusivity. Finally, simple phosphate buffers are recommended: at pH 6.5, ketoprofen and indomethacin require 13-14 mM and 3-4 mM phosphate buffer to match 85% and 108% of the dissolution rates in 15 mM bicarbonate buffer, respectively. In summary, this research demonstrates that to establish a meaningful in vitro bioequivalence method, both the hydrodynamics and the GI fluids composition should be carefully considered.PhDPharmaceutical SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/57668/2/jsheng_1.pd