Preclinical evaluation of modern solid oral dosage forms requires more advanced in vitro devices due to the trend of formulating low solubility, high permeability compounds for commercial therapeutics. Current compendial dissolution methodologies may not be suitable for such compounds due to high fluid shear rates, heterogeneity of shear rates, suboptimal fluid flow, unrealistic fluid volumes, and ultimately the lack of an experimental component that represents the absorption process. Here a dissolution apparatus is introduced that overcomes some limitations of the compendial apparatus using poly(dimethyl siloxane) (PDMS) as an in vitro biomimetic analogue that simulates the passive drug absorption process. PDMS is biomimetic because of similarities in small molecule transport such as mechanism, ionization selectivity, and lipophilicity. Nine molecular probes were used to evaluate the transport pathways and properties of PDMS to simulate human oral absorption rates. The transport pathways through PDMS are analogous to transcellular (TCDT) and paracellular (PCDT) drug transport pathways. PDMS PCDT was assessed using positronium annihilation life-time spectroscopy (PALS) and partition experiments; TCDT was assessed using diffusion and partition experiments. PALS determined that PDMS pores were uniform (diameter~0.85nm), isolated, and void volume was unaffected by drug accumulation. A strong linear correlation exists between predicted octanol-water partition coefficients and PDMS partition coefficients (LogPPDMS=0.736 x LogPO-W–0.971, R2=0.981). The characteristics of an ultra-thin large area PDMS membrane (UTLAM) dissolution/absorption system with respect to pH, partition coefficient (K), aqueous boundary layer (ABL), drug particle size, and administered dose were measured. A pH dependent solution diffusion model and a particle size-dose dependent particle dissolution-absorption model were derived. A 1.5” hydrofoil design was implemented to reduce particle coning, promote particle re-suspension, and control bulk fluid shear. PDMS membranes were successfully fabricated to thicknesses of 11.2 ± 0.5µm to 12.5± 0.2µm, and a UTLAM active surface area of 21.8-25.2cm2 (44.4cm2 total area) was achieved. Experiments between pH 1.9-12.5 were investigated using ibuprofen as a model weak acid drug. Partition coefficient (K) is the dominant factor determining absorption and the ABL played a significant role in absorption when the drug is mostly non-ionized. In aqueous and membrane limited diffusion absorption, there was a significant shift towards higher pH in the half of maximum absorption rate caused by K and ABL. Number and mass particle size distributions (PSD) measured and dissolution was studied. Particle dissolution was determined to occur in the ABL adjacent to the PDMS membrane and has a significant effect on flux of drug across the PDMS membrane. Suspension experiments conducted with ibuprofen particle size radii of 3.7µm, 18µm, 117µm at doses of 0.2, 1, 10, and 40mg/mL. Significant enhancements in flux were observed with increasing dose and decreasing particle size in accordance with theoretical predictions of particle dissolution within the ABL. In all PSD’s, an unaccounted increase in flux was observed at high doses and was attributed to particle settling on the horizontal PDMS membrane. In conclusion, the UTLAM PDMS diffusion cell exhibits improved hydrodynamics in the donor phase and the PDMS membrane mimics in vivo relevant passive absorption kinetics through PDMS membranes.PHDPharmaceutical SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/151729/1/sinkopd_1.pdfDescription of sinkopd_1.pdf : Restricted to UM users only
