(533f) Mechanistic Mass Transport Modeling of Ionizable Drug Dissolution Under In Vivo-Relevant Buffer and Hydrodynamical Conditions

There is a need to develop a biorelevant, predictive dissolution method that can be applied by pharmaceutical industry to facilitate marketing access for generic and novel drug products. In a recent clinical and computational study, the critical factors deriving the dissolution and absorption in the human GI tract have been more accurately determined. The primary goal of this study is understanding the rate-determining factors for ionizable drug dissolution from intubation studies, real-time magnetic resonance imaging (MRI) manometry, and computational fluid dynamic simulations (CFD), taking advantage of mechanistic mass transport modeling to quantify the GI tract hydrodynamical and environmental parameters, and finally incorporating the in vivo knowledge to an in vitro dissolution apparatus that can simulate the in vivo drug dissolution rate in the GI tract.

A mathematical mass-transport model was developed for ionizable drug dissolution in bicarbonate using the rules of conservation of mass and electric charge in addition to accounting for the diffusional times and reaction rate constants of the CO₂-H2CO₃ interconversion. The predictions made by the aforementioned model were compared to the experimental data generated by an intrinsic dissolution setup for three ionizable drugs: indomethacin, ibuprofen and haloperidol. A CFD approach was used to quantify the hydrodynamical conditions in commonly used USP II type in vitro dissolution device. Moreover, dissolution testing for suspended ibuprofen particles was performed under different hydrodynamical conditions in bicarbonate and phosphate buffers in a USP II type dissolution device. The particle-size distribution of ibuprofen particles was characterized using a laser diffraction particle size analyzer.

An agreement between the simulated and experimental dissolution rates obtained by intrinsic dissolution experiments lends credibility to use this model for a range of drugs. The sensitivity analysis with respect to the hydrodynamical conditions indicates that at high shear rates where the diffusion layer next to the solid-liquid interface is thin the interfacial pH is low. The low interfacial pH causes a lower dynamic solubility of acidic drugs at the solid-liquid interface and this led to a decrease in the dissolution flux. For ionizable particle dissolution in bicarbonate, comparing small particles with thinner diffusion layer to the large particles with thicker boundary layer, the flux is lower than that of the large particles. This is because the effective pKa governing the buffering action of bicarbonate in the boundary layer decreases as this layer gets thinner. This is due to the interconversion between H₂CO₃ and CO₂ not being fast enough to achieve equilibrium within the timeframes allowed by the diffusional processes in the boundary layer.

The mechanistic mass transport model for in vitro drug dissolution under different buffer and hydrodynamical conditions highlights the implications of using surrogate buffers such as phosphate for quality control tests. The gain in dissolution rate of ionizable drug that is obtained by the drug particles micronization in phosphate buffer is higher than in the in vivo-relevant bicarbonate buffer. The hydrodynamical conditions could potentially change the boundary layer thickness of particles and consequently the dissolution rate. Furthermore, in order to design an in vivo-relevant dissolution test both hydrodynamical and buffer conditions should match with the in vivo conditions to achieve better in vivo-in vitro correlation (IVIVC).