Physicochemical characterization permeability

Sobel AT, Branellec AL, Blanc CJ, Lagrue GA (1977) Physicochemical characterization of a vascular permeability factor produced by Con A-stimulated human lymphocytes. J Immunol 119 1230... 

The ex vivo methods lend themselves easily for the performance of mechanistic investigations. In order to optimize selection of drug candidates prior to further clinical development, it is important to decipher the contributive roles of permeation, metabolism, efflux, and toxicity. This will then make it possible to properly channel the optimization process, for instance, by permeation enhancement, mucoadhesion, modification of the physicochemical characteristics of the drug, or even change in the route of administration in case the drug and/or formulation turns out to be too toxic. Regarding permeability studies, it is possible not only to quantify passive diffusion but also to identify and characterize (compound)-specific carrier-mediated transport routes. These tools have been used to identify and characterize the relative contribution of... 

In this section, discussion of physicochemical profiling is limited to solubility, permeability, drug stability, and limited solid-state characterization (as we will see in Section 3.4, there are other physical-mechanical properties that must also be considered). For convenience, methods available for physicochemical profiling are discussed under the following categories computational tools (sometimes referred to as in silico tools), HTS methods, and in-depth physicochemical profiling.16... 

Permeation of a model solute across skin in presence of an enhancer is dependent not only on the inherent capacity of the enhancer to permeabi-lize skin but also on the physicochemical interactions of the enhancer with the model solute. An end point used to characterize the effect of an enhancer on skin permeability should be able to decouple these two effects. This assures the generality of the results. 

The substance-specific kinetic constants, kx and k2, and partition coefficient Ksw (see Equations 3.1 and 3.2) can be determined in two ways. In theory, kinetic parameters characterizing the uptake of analytes can be estimated using semiempirical correlations employing mass transfer coefficients, physicochemical properties (mainly diffusivities and permeabilities in various media), and hydro-dynamic parameters.38 39 However, because of the complexity of the flow of water around passive sampling devices (usually nonstreamlined objects) during field exposures, it is difficult to estimate uptake parameters from first principles. In most cases, laboratory experiments are needed for the calibration of both equilibrium and kinetic samplers. 

Many types of modeling techniques are available in the discovery phase of drug development, from structure activity relationships (SAR) to physiology based pharmacokinetics (PBPK) and pharmacokinetics-/pharmacodynamics (PK/PD) to help choosing some of the lead compounds. Some tests that are carried out by discovery include techniques related to structure determination, metabolism, and permeability NMR, MS/MS, elemental analysis, PAMPA, CACO-2, and in vitro metabolic stability. Although they are important as a part of physicochemical molecular characterization under the biopharmaceutics umbrella, they will not be discussed here. The reader can find relevant information in numerous monographs [9,10]. 

In the past, membrane material selection for gas separations (2 ) and liquid separations has often followed either an Edlsonlan or a common sense approach. For example, almost every polymer that can be formed Into a film has been characterized In terms of gas permeability (at least for a few common gases). In this volume, Chern et al. ( ) and Lloyd and Meluch W discuss membrane material selection In terms of physicochemical Interactions for gas mixture separations and liquid mixture separations, respectively. Hoehn (5 ) presents similar arguments for membrane material selection In general. In comparison to the wide variety of polymers investigated... 

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