Aqueous boundary layer

The release of steroids such as progesterone from films of PCL and its copolymers with lactic acid has been shown to be rapid (Fig. 10) and to exhibit the expected (time)l/2 kinetics when corrected for the contribution of an aqueous boundary layer (68). The kinetics were consistent with phase separation of the steroid in the polymer and a Fickian diffusion process. The release rates, reflecting the permeability coefficient, depended on the method of film preparation and were greater with compression molded films than solution cast films. In vivo release rates from films implanted in rabbits was very rapid, being essentially identical to the rate of excretion of a bolus injection of progesterone, i. e., the rate of excretion rather than the rate of release from the polymer was rate determining. 

FIGURE 10 In vitro rates of release of progesterone from PCL films, illustrating their dependence on the film thickness and drug load. The deviation from (time)l/2 kinetics reflects the contribution of an aqueous boundary layer. The solid lines were calculated assuming an aqueous boundary layer thickness of 19 ym. (From Ref. 68.)... 

The evaluation of the apparent ionization constants (i) can indicate in partition experiments the extent to which a charged form of the drug partitions into the octanol or liposome bilayer domains, (ii) can indicate in solubility measurements, the presence of aggregates in saturated solutions and whether the aggregates are ionized or neutral and the extent to which salts of dmgs form, and (iii) can indicate in permeability measurements, whether the aqueous boundary layer adjacent to the membrane barrier, Umits the transport of drugs across artificial phospholipid membranes [parallel artificial membrane permeation assay (PAMPA)] or across monolayers of cultured cells [Caco-2, Madin-Darby canine kidney (MDCK), etc.]. 

Permeability-pH profiles, log Pe - pH curves in arhficial membrane models (log Pjpp - pH in cehular models), generally have sigmoidal shape, similar to that of log Dod - pH cf. Fig. 3.1). However, one feature is unique to permeabihty profiles the upper horizontal part of the sigmoidal curves may be verhcally depressed, due to the drug transport resistance arising from the aqueous boundary layer (ABL) adjacent to the two sides of the membrane barrier. Hence, the true membrane contribution to transport may be obscured when water is the rate-limiting resistance to transport. This is especially true if sparingly soluble molecules are considered and if the solutions on either or both sides of the membrane barrier are poorly stirred (often a problem with 96-well microhter plate formats). 

Karlsson, J. P. Artursson, P., A method for the determination of cellular permeability coefficients and aqueous boundary layer thickness in monolayers of intestinal epithelial (Caco-2) cells grown in permeable filter chambers, Int. J. Pharm. 7, 55-64 (1991). 

V. TRANSMONOLAYER AND AQUEOUS BOUNDARY LAYER CONTROLLED KINETICS... 

Figure 21 Linearized double reciprocal plot of the effective permeability coefficients and corresponding stirring rates to determine the power dependency of the stirring rate and mass transfer resistances for the aqueous boundary layers and the Caco-2 cell monolayer in the Transwell system. 

Table 12 Effective Permeability Coefficients and Thicknesses of the Aqueous Boundary Layer of the Caco-2 Cell Monolayer/ Transwell System as a Function of Stirring by Planar Rotating Shaker3...

Case 1 Aqueous Boundary Layer-Controlled Permeants... 

Figure 28 The biophysical model for passive diffusion and concurrent intracellular metabolism of a drug for a simple A-to-B reaction process. Concentration-distance profiles are depicted in the aqueous boundary layer and intracellular domain for the drug and metabolite. The bottom diagram depicts the direction of the fluxes of drug and metabolite viewed from the donor and receiver sides of the cell monolayer. Details of basic assumptions are found in the text.

Here, Pe takes into account the aqueous boundary layers (/W), transcellular diffusion with metabolism, the paracellular pathway (Pparaceu), and the filter support (PF). It is assumed that drug diffusing through the paracellular route escapes metabolism and contributes insignificantly to the appearance of intact drug in the receiver. 

Figure 31 Scheme for the protein-binding, diffusional, and partitioning processes and barriers that are encountered by a highly lipophilic and membrane-interactive drug (D) as it permeates through a cell within a continuous monolayer, h and h, thicknesses of the aqueous boundary layers. kd and ka, dissociation and association binding constants, respectively. P, protein molecule. Permeability coefficients Effective, Pe aqueous boundary layer, PABL and PW apical membrane, Pap basolateral membrane, Pbl. 

Figure 35 Relationship between the uptake permeability coefficient and the free drug concentration. PAEL is the permeability of the free drug across the aqueous boundary layer, and P BL is the same for the drug-albumin complex. [Redrawn from Raub et al. (1993) with permission from the publisher.]...

The identification and characterization of cell culture systems (e.g., Caco-2-cells) that mimic in vivo biological barriers (e.g., intestinal mucosa) have afforded pharmaceutical scientists the opportunity to rapidly and efficiently assess the permeability of drugs through these barriers in vitro. The results generated from these types of in vitro studies are generally expressed as effective permeability coefficients (Pe). If Pe is properly corrected to account for the barrier effects of the filter (PF) and the aqueous boundary layer (PAbl) as previously described in Section II.C, the results provide the permeability coefficient for the cell monolayer... 

It was postulated that the aqueous pores are available to all molecular species, both ionic and non-ionic, while the lipoidal pathway is accessible only to un-ionised species. In addition, Ho and co-workers introduced the concept of the aqueous boundary layer (ABL) [9, 10], The ABL is considered a stagnant water layer adjacent to the apical membrane surface that is created by incomplete mixing of luminal contents near the intestinal cell surface. The influence of drug structure on permeability in these domains will be different for example ABL permeability (Paq) is inversely related to solute size, whereas membrane permeability (Pm) is dependent on both size and charge. Using this model, the apparent permeability coefficient (Papp) through the biomembrane may therefore be expressed as a function of the resistance of the ABL and... 

Figure 2.2 Schematic diagram of the physical model for passive transport of solutes across the intestinal membrane. The bulk aqueous solution with an aqueous boundary layer (ABL) on the mucosal side is followed by a heterogeneous membrane consisting of lipoidal and aqueous channel pathways and thereafter by a sink on the serosal side. (Adapted from Ho et al. [5]).

SLM Simple flux equation based on film theory considering aqueous boundary layer resistance and membrane diffusion Optimal condition determined with respect to pH of the aqueous phase [57,58]... 

Figure 19.12 (a) Experimental setup to determine the exchange dynamics of a combined NAPL-water system using the slow stirring method (SSM). (6) - (d) Measured and calculated aqueous concentrations of benzene m/p-xylene and naphthalene. The solid lines give the result of the linear bottleneck exchange model with an aqueous boundary layer thickness of 8bl = 2.4 x 1CT2 cm = 240 pm (adapted from Schluep et al., 2000). 

FIGURE 3.1 Concentration profiles in a passive sampling device. The driving force of accumulation is the difference in chemical potentials of the analyte between the bulk water and the sorption phase. The mass transfer of an analyte is governed by the overall resistance along the whole diffusional path, including contributions from the individual barriers (e.g., aqueous boundary layer, biofilm layer, and membrane). 

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