Prediction of Passive Membrane Permeability by Semi‐Empirical Method Considering Viscous and Inertial Resistances and Different Rates of Conformational Change and Diffusion

Membrane permeability is an important property of drugs in adsorption. Many prediction methods work well for small molecules, but the prediction of middle-molecule permeability is still difficult. In the present study, we modified a classical permeability model based on Fick's law to study passive membrane permeability. The model consisted of the distribution of solute from water to membrane and the diffusion of solute in each solvent. The diffusion coefficient is the inverse of the resistance, and we examined the inertial resistance in addition to the viscous resistance, the latter of which has been widely used in permeability prediction. Also, we examined three models changing the balance between the diffusion of solute in membrane and the conformational change of solute. The inertial resistance improved the prediction results in addition to the viscous resistance. The models worked well not only for small molecules but also for middle molecules, whose structures have more conformational freedom.