Hydrodynamic Enhancements of Dissolution from Drug Particles: \textit{In vivo} vs. \textit{In vitro}

Absorption of drug molecules into the blood stream is generally limited by dissolution-rate in the intestines. Dissolution occurs via diffusion enhanced by a response to the hydrodynamic flow environment, a process that is very different in the human intestine than in a USP-II dissolution apparatus, commonly used by drug companies to validate new drug formulations. Whereas \textit{in vivo} hydrodynamics are driven by the motility of intestinal wall muscles, the USP-II apparatus is a rotating paddle to mix drug particles during dissolution testing. These differences are of current interest to agencies that regulate drug product development. Through lattice-Boltzmann-based computer simulation of point particles transported through human intestine, we analyze the hydrodynamic parameters associated with convection that quantify the extent to which \textit{in vitro} dissolution tests are or are not relevant to \textit{in vivo} hydrodynamics. . We show that for drug particles less that $\sim$100-200 microns, effects of convection are negligible in the intestines. However, we discover a previously unappreciated phenomenon that significantly enhances dissolution-rate and that distinguishes \textit{in vitro} from \textit{in vivo} dissolution: the fluid shear rate at the particle. \textit{Supported by NSF and AstraZeneca}.