Dissolution of weak acids under laminar flow and rotating disk hydrodynamic conditions: application of a comprehensive convection-diffusion-migration-reaction transport model.

A steady-state mass transfer model that incorporates convection, diffusion, ionic migration, and ionization reaction processes was extended to describe the dissolution of weak acids under laminar flow and a rotating disk hydrodynamics. The model accurately predicted the experimental dissolution rates of benzoic acid, 2-naphthoic acid, and naproxen in unbuffered and monoprotic buffers within the physiological pH range for both hydrodynamic systems. Simulations at various flow rates indicated a cube root dependency of dissolution rate on the flow rate for a given bulk pH value for the laminar hydrodynamic system, as proposed earlier by Shah and Nelson (1975. J Pharm Sci 64(9):1518-1520) for neutral compounds. The model has limitations in its ability to accurately predict the dissolution of weak acids under certain conditions that imposed steep concentration gradients, such as high pH values, and for polyprotic buffer systems that caused the numerical solution to be unstable, suggesting that alternative numerical techniques may be required to obtain a stable numerical solution at all conditions. The model presents many advantages, most notably the ability to successfully predict the complex process under physiological conditions without simplifying assumptions, and therefore accurately representing the system in a comprehensive manner.

Low-affinity uptake of the fluorescent organic cation 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (4-Di-1-ASP) in BeWo cells.

Understanding the mechanisms of transport processes in the placenta can improve the safety and efficacy of drug delivery during pregnancy. Functional studies of organic cation transporters (OCTs) are usually carried out using radioactivity, and a fluorescent marker would add flexibility to experimental methods. As a published substrate for OCT1 and OCT2, the fluorescent compound 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (4-Di-1-ASP) was chosen as a candidate for studying placental OCT function in BeWo cells. The expression of OCT1 and OCT2 was also investigated in BeWo cells, an established human choriocarcinoma trophoblastic cell line frequently used as an in vitro model of the rate-limiting barrier for maternal-fetal exchange of drugs and nutrients within the placenta. 4-Di-1-ASP was taken up into BeWo cells by a low-affinity, carrier-mediated process exhibiting a Km of 580+/-110 microM and Vmax of 97+/-9 nmol/mg protein/30 min, and asymmetric transport was observed, with greater permeability in the apical to basolateral (maternal-to-fetal) direction. However, RT-PCR revealed no expression of OCT1 or OCT2 in either BeWo cells or primary cultured human cytotrophoblast cells, and OCT substrates such as TEA and choline did not inhibit the uptake of 4-Di-1-ASP. Although the uptake of this fluorescent compound in BeWo cells is not mediated by an OCT, the colocalization experiments with fluorescence microscopy and inhibition studies confirmed significant mitochondrial uptake of 4-Di-1-ASP. Transport of 4-Di-1-ASP into the nuclear region of BeWo cells was also observed, which is likely mediated by a nucleoside transporter.

A mechanistic study of danazol dissolution in ionic surfactant solutions.

This study examined the dissolution mechanism of the neutral drug danazol into solutions of the ionic surfactant sodium dodecyl sulfate (SDS). The effect of counterion concentration on drug dissolution was also studied by controlling the solution ionic strength (IS). The laminar flow apparatus of Shah and Nelson was chosen to measure in vitro dissolution rates for its simulation of physiological hydrodynamics. A mathematical model was developed to test the proposed mechanism for dissolution. Transport of the dissolved drug away from the tablet surface is the slow step in the process. Two major physicochemical properties, drug solubility in surfactant solutions and the effective diffusion coefficients used in the model, were measured in separate experiments for use in the transport model. Pulsed field proton nuclear magnetic resonance spectroscopy ((1)H NMR) was used to measure the drug diffusion coefficient. Actual drug dissolution rates were determined by multiplying the measured effluent drug concentration in the aqueous medium by its flow rate. The assumption of a transport-controlled dissolution rate was tested by plotting the measured dissolution rates as a function of medium flow rate in a log-log plot. A slope of 1/3 is predicted by the model and slopes of 0.26 to 0.32 were found experimentally, suggesting that the transport controlled mechanism is accurate. The model-predicted dissolution rates were compared with the experimental data. For SDS solutions without IS control, the model calculated data are 20-35% lower than the experimental results, whereas with IS control, the error is only 0.4-4%. We believe that there is significant electrostatic interaction between micelles in processes with low IS or poor IS control. In that situation, the nuclear magnetic resonance (NMR)-measured drug diffusivity would not be its actual value in the dissolution process.