The first-principles approach presented in this work combines surface kinetics and convective diffusion modeling applied to compounds with pH-dependent solubility and in different dissolution media. This analysis is based on experimental data available for approximately 100 compounds of pharmaceutical interest. Overall, there is a linear relationship between the drug solubility and intrinsic dissolution rate expressed through the total kinetic coefficient of dissolution and dimensionless numbers defining the mass transfer regime. The contribution of surface kinetics appears to be significant constituting on average ∼20% resistance to the dissolution flux in the compendial rotating disk apparatus at 100 rpm. The surface kinetics contribution becomes more dominant under conditions of fast laminar or turbulent flows or in cases when the surface kinetic coefficient may decrease as a function of solution composition or pH. Limitations of the well-known convective diffusion equation for rotating disk by Levich are examined using direct computational modeling with simultaneous dissociation and acid-base reactions in which intrinsic dissolution rate is strongly dependent on pH profile and solution ionic strength. It is shown that concept of diffusion boundary layer does not strictly apply for reacting/interacting species and that thin-film diffusion models cannot be used quantitatively in general case.

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