Particle Size, Dose, and Confinement Affect Passive Diffusion Flux through the Membrane Concentration Boundary Layer.

The authors present a steady-state-, particle-size-, and dose-dependent dissolution-permeation model that describes particle dissolution within the concentration boundary layer (CBL) adjacent to a semipermeable surface. It is critical to understand how particle size and dose affect the behavior of dissolving particles in the presence of a CBL adjacent to a semipermeable surface both in vivo and in vitro . Control of particle size is ubiquitous in the pharmaceutical industry; however, traditional pharmaceutical assumptions of particle dissolution typically ignore particle dissolution within the length scale of the CBL. The CBL does not physically prevent particles from traveling to the semipermeable surface (mucus, epithelial barrier, synthetic membrane, etc.), and particle dissolution can occur within the CBL thickness (δ C ) if the particle is sufficiently small (∼ d particle ≤ δ C ). The total flux (the time rate transport of molecules across the membrane surface per unit area) was chosen as a surrogate parameter for measuring the additional mass generated by particles dissolving within the donor CBL. Mass transfer experiments aimed to measure the total flux of drug using an ultrathin large-area membrane diffusion cell described by Sinko et al. with a silicone-based membrane ( Mol. Pharmaceutics 2020, 17, (7) 2319-2328, DOI: 10.1021/acs.molpharmaceut.0c00040). Suspensions of ibuprofen, a model weak-acid drug, with three different particle-size distributions with average particle diameters of 6.6, 37.4, and 240 μm at multiple doses corresponding to a range of suspension concentrations with dimensionless dose numbers of 2.94, 14.7, 147, and 588 were used to test the model. Experimentally measured total flux across the semipermeable membrane/CBL region agreed with the predictions from the proposed model, and at a range of relatively low suspension concentrations, dependent on the average particle size, there was a measurable effect on the flux due to the difference in δ C that formed at the membrane surface. Additionally, the dose-dependent total flux across the membrane was up to 10% higher than the flux predicted by the standard Higuchi-Hiestand dissolution model where the effects of confinement were ignored as described by Wang et al. ( Mol. Pharmaceutics 2012, 9 (5), 1052-1066, DOI: 10.1021/mp2002818).