Experimental Determination of Permeability

The concentration of permanent gases below one atmosphere of pressure generally does not affect the permeability coefficient. However, strong effects have been observed on the permeability of organic compounds. The permeability of organic vapors such as aromas, flavors, and solvents is usually strongly dependent on concentration. Readers interested in this topic may consult references Crank and Park [6] and Giacin and Hernandez [7]. 

Two basic methods are used for determination of permeability, isostatic and quasi-isostatic. In both methods, experiments are run at constant temperature. Isostatic methods use continuous flow on both sides of the film to provide constant permeant concentration (Fig. 14.9). This system is employed in the Mocon Oxtran 

QuasHsostatic methods use flow to provide constant permeant concentration on the high partial pressure side, but allow accumulation on the low partial pressure side (Figs. 14.4 and 14.10). As long as accumulation is limited so that the concentration stays low, the partial pressure difference can be treated as constant. 

The calculations of permeability (P) and diffusion (D) coefficients from the continuous flow method are illustrated in Fig. 14.11. P and D are calculated as follows  

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Hooton (H48) noted some pitfalls in the experimental determination of permeabilities and in the practical utilization of the results. In an experimental determination, accurate results will not be obtained unless the sample has been vacuum saturated and, even if it is, equilibrium flow in accordance with d Arcy s law may not occur because water is being used up to continue hydration. In practice, a concrete sample is probably not often saturated throughout if it is not, capillary forces, as well as the pressure difference. alTect the rate of flow. Applications of results obtained with pastes to concrete are further complicated by the presence in the latter of cracks, poorly compacted areas and other inhomogeneities. 

In situ perfusion of intestinal segments provides an excellent alternative to everted rings or isolated intestinal tissue for experimental determination of permeability [75]. The perfusion technique has been characterized extensively using rat as an animal model. A number of in situ flow patterns have been utilized to... 

The experimental determination of permeability by the method of Sisko and Brunstrum [13] is obtained from the rate of fall of the level of the oil in the burette. Then from Eqn 18-3 we get. 2... 

Acquire Basic Data. Because of the novelty of membrane-based gas separations, a scarcity of important design data often b encoitntered. Some tabulations do exist. Cor exat e. Table 20.1-1 and T es 20.4-1 and 20.4-2, which are discussed later. In addition, membrane manufacturers can be of help for common systems. If one b considering unusual systems or novel membranes, some experimental determination of permeabilities is likely to be necessary. Procedures and equipment for such measurements are described in later sections. 

Since experimental determination of intestinal absorption is quite demanding, Caco-2 cell monolayers have been successfully used to model passive drug absorption. Several models for the prediction of Caco-2 permeability using PSA were developed, including those of van de Waterbeemd et al. [5] and Palm et al. [22] who found that relationships between Caco-2 permeability and PSA is stronger than with Clog D, Krarup et al. [23] who used dynamic PSA calculated for water accessible molecular surface and Bergstrom et al. [24]. 

Both dynamic melting and equilibrium transport melting require that the porosity when two nuclides are fractionated from one another is similar to the size of the larger of the partition coefficients for the two nuclides. Given the low values of the experimental determinations of Du and Dxh, the porosities required to explain the observational data in these models are generally less than 0.5% and often times closer to 0.1%. Such low porosity estimates have been criticized based on physical grounds given the low estimated mantle permeability derived from the extent of melt connection observed in experiments (Paul 2001). 

Fig. 37), suggesting that desolvation of the polar bonds in the molecule is a major determinant of permeability. Consistent with this, good correlations were found between the permeabilities of these peptides and their partition coefficients between heptane-ethylene glycol (r2 = 0.87) or the differences in partition coefficients between n-octanol-buffer and isooctane-buffer (r2 = 0.82) both these buffer systems provide experimental estimates of hydrogen-bonding potential. These results are qualitatively identical with those described earlier for the permeability of these peptides across Caco-2 cell monolayers. 

Experimental determination of He diffusion was attempted by Duddridge et al. (1991), who injected He-rich gas at a depth of 35 m into permeable limestones cut by a fault. They recorded a pulse of He in shallow soil gas 5-20 hours later within 10 m of the fault suboutcrop and up to 53 hours later 20 m from the fault suboutcrop. However, the concentration increase recorded (0.032 ppm) is well within the error of the analytical system (mass spectrometer with constant pressure inlet, as discussed below, and analytical sensitivity of 0.030 ppm), the data are patchy with many samples showing no pulse, and there is no estimate of background variation or the effect of changing environmental conditions. Conclusions about diffusion rates based on these data may not be reliable. 

Determination of permeability distributions from experimental velocities 138... 

In a recent study we used a BCS with six classes, where the solubility was classified as either low or high in accordance with the cutoff values set by the FDA and the permeability was classified as low (FA < 20%), intermediate (20% < FA < 80%), or high (FA > 80%) [55], This classification was chosen because we believe it provides a better tool for absorption ranking of compounds in drug discovery than the stricter permeability classification provided by the FDA. Experimental determinations of the Caco-2 permeability and intrinsic solubility were performed in-house, and PLS in silico models based on PTSAs were derived. In comparison to the experimentally determined data, the combination of the two in silico models resulted in 87% of the compounds being sorted into the correct class. The compounds included in a reference test set given by the FDA were correctly sorted with an accuracy of 77%. To summarize, these results indicate that more sophisticated in silico models combining computational analysis of the solubility and permeability can successfully estimate the absorption process both qualitatively and quantitatively [55]. 

We may consider in this light some of the epithelial parameters that have been measured. It is important to note here that the experimental determination of the strength of transport as well as the water permeability, Lp, is often made using osmotic gradients established with an impermeant species such as sucrose. To include the effects of such species Eqn. 33 is commonly modified [19] to... 

We have seen that the basic issues of coupled water transport can be formulated in quite a general way. This general framework has been applied to the several elementary models discussed in this chapter but may equally well be applied to comprehensive computer simulations of epithelial function. For any model, comparison with experimental data necessitates computing the fluxes at equal bathing media, the derivatives of these fluxes with respect to the bath conditions, the bath conditions required for mucosal and serosal transport equilibrium, and the strength of transport. Via the formulation of non-equilibrium thermodynamics the flux derivatives can be related to the experimentally determined epithelial permeabilities. For analytical work, the fluxes and flux derivatives at equal bathing solutions can be used to assess transport isotonicity, and, with less certainty, estimate the strength of transport. 

Arbter, R., Beraud, J. M., Binetruy, C., et al. Experimental determination of the permeability of textiles A benchmark exercise , Composites Part A Applied Science and Manufacturing, 42,1157-1168, 2011. 

Experimental determination of microscopic characteristics is based on the Debye-Langevin (eq. (4.2.28)) and Lorentz-Lorentz (eq. (4.2.30)) equations. They connect macroscopic molecular characteristics, measured directly in physical experiment, with microscopic ones. Measuring dielectric permeability s in an electrostatic field, the molar polarization 11 can be found ... 

For heterogeneous media composed of solvent and fibers, it was proposed to treat the fiber array as an effective medium, where the hydrodynamic drag is characterized by only one parameter, i.e., Darcy s permeability. This hydrodynamic parameter can be experimentally determined or estimated based upon the structural details of the network [297]. Using Brinkman s equation [49] to compute the drag on a sphere, and combining it with Einstein s equation relating the diffusion and friction coefficients, the following expression was obtained ... 

Reliable determination of all three functions depends on the information content associated with the experiments. The conventional experimental design does not provide sufficient information to determine all three functions accurately [34], Another consideration is that conventional analyses are all based on the assumption that the sample is uniform, and use an average value for porosity and an apparent value for permeability. Clearly, these properties vary spatially, and failure to account for the effects of spatial variations in the properties will lead to errors in the estimates of the functions [16]. 

Fig. 15.4. Relationship between experimentally determined and PTSA-predicted Caco-2 permeability. PLS predicted permeability from PTSAs (predicted log Caco-2) is plotted versus experimentally obtained Caco-2 data (observed log Caco-2) [1 7]. The PTSAs used for the prediction were (in order of importance) PSA, fraction of total surface area that was polar...

The volume is divided into five sections. Part one looks at the experimental study of membrane permeability and oral absorption. In Part two, problems of measuring and prediction solubility, as one of the key determinants in the absorption process, will be discussed in detail. In the next part, progress in the science around transporter proteins and gut wall metabolism and their effect on the overall absorption process is presented. Part four looks at the in silico approaches and models to predict permeability, absorption and bioavailability. In the last part of the book, a number of drug development issues will be highlighted, which could have an important impact of the overall delivery strategies for oral pharmaceutical products. 

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