Dissolution

The Johnson dissolution model is widely recognized as the most accurate method for predicting dissolution and its effect on drug absorption. While it is theoretically possible to track the dissolution of each and every drug particle, the model groups particles of similar size into a limited number of particle size fractions, much like particle sizing instruments would. Dissolution is occurring at a rate determined by the time-dependent surface area for all particle size fractions and the single concentration gradient determined from the dissolution of all particle size fractions. This time-dependent concentration gradient is updated at each step of the numerical method, typically every second. As such, the model provides a mechanistically based simulation of polydisperse powders under any conditions: sink or non-sink.

The best independent verification of the Johnson dissolution model was published by Jun-ichi Jinno, Naoki Kamada, Masateru Miyake, Keigo Yamada, Tadashi Mukai, Masaaki Odomi, Hajime Toguchi, Gary G. Liversidge, Kazutaka Higaki, and Toshikiro Kimura, “Effect of particle size reduction on dissolution and oral absorption of a poorly water-soluble drug, cilostazol, in beagle dogs,” Journal of Controlled Release (2006) 111:56-64. In this paper, the authors reproduced the Johnson dissolution model, and used it to predict the dissolution of cilostazol for three different particle size distributions. The original data, the code for the Johnson dissolution model, and a detailed explanation appears in the book Computer Simulation For Pharmaceutical Scientists by Kevin C. Johnson.

With a mechanistic model in hand, Johnson used a time-dependent diffusion layer thickness equal to the particle radius to simulate the dissolution of polydisperse powders. This led to increased research into the nature of the diffusion layer thickness. Johnson’s assumptions have withstood the test of time and found to be consistent with existing hydrodynamic theory. In Computer Simulation For Pharmaceutical Scientists, drug particle radius is calculated explicitly, allowing a more refined calculation of the diffusion layer thickness. However, the impact of the differences in the diffusion layer thickness discussed in the literature is minor compared to the impact of surface area on dissolution rate.