Compound polar surfaces

For polar, charged surfaces, this situation is completely different. For polar surfaces such as ZnO, one surface is terminated by oxygen anions while the other terminated with Zn cations. One surface has an overall negative charge, while the other has an overall excess positive charge. As a result, a dipole moment builds proportional to the dimension of a particle. In non-layered compounds, polar surfaces have to reconstruct such that the external surface charge is reduced. Freundl l describes three ways in which the system can adapt in order to reduce the overall charge in the first layer of the surface ... 

Other polymers used in the PSA industry include synthetic polyisoprenes and polybutadienes, styrene-butadiene rubbers, butadiene-acrylonitrile rubbers, polychloroprenes, and some polyisobutylenes. With the exception of pure polyisobutylenes, these polymer backbones retain some unsaturation, which makes them susceptible to oxidation and UV degradation. The rubbers require compounding with tackifiers and, if desired, plasticizers or oils to make them tacky. To improve performance and to make them more processible, diene-based polymers are typically compounded with additional stabilizers, chemical crosslinkers, and solvents for coating. Emulsion polymerized styrene butadiene rubbers (SBRs) are a common basis for PSA formulation [121]. The tackified SBR PSAs show improved cohesive strength as the Mooney viscosity and percent bound styrene in the rubber increases. The peel performance typically is best with 24—40% bound styrene in the rubber. To increase adhesion to polar surfaces, carboxylated SBRs have been used for PSA formulation. Blends of SBR and natural rubber are commonly used to improve long-term stability of the adhesives. 

Investigation of the differences in crystal packing between (431) and (426) from comparison of their respective X-ray structures, revealed that (431) was more tightly packed than (442), reflected in their respective melting points of 235 and 170 °C. It was postulated that the absence of in vivo activity for (431) may be explained by the resultant reduction in water solubility and dissolution rate compared with (426). The comparatively high calculated polar surface area of (431) (122.5A ) compared with (426) (89.3 A ) was also proposed as a factor influencing the marked difference in bioavailability between the two related compounds. Compound (426) (SLV-319) is currently being developed with Bristol-Myers Squibb for the potential treatment of obesity and other metabolic disorders. Phase I trials for obesity were started in April 2004. Earlier Phase I clinical trials for the treatment of schizophrenia and psychosis, which commenced in April 2002, appear to have been abandoned. 

Fig. 19.7. Correlation between predicted oral absorption based on polar surface area (PSA) and in vivo oral bioavailability for a series of beta-blockers. The nonlinearity is related to the different levels of P-gp efflux and differences in CYP3A4 metabolism of these compounds [25],...

Absorption, in general, is treated as a physicochemical transport process based on computations of logP (the octanol/water partition coefficient) and solubility governed by factors such as polar surface area on the molecule. It is conceivable that SNPs in drug transporter genes will affect the pharmacokinetic properties of compounds and, therefore, these may have to be taken into consideration in the design process. 

Recent analyses demonstrating comparable mean values of lipophilicity, H-bond donors, and polar surface area between older (pre-1983) and newer (1983-2002) oral drugs suggest that these physicochemical attributes are fundamental characteristics of successful drugs. The noted increasing lipophilicity of compounds entering clinical development in recent years may have contributed to a commensurate higher rate of attrition [5,6]. 

Of the physicochemical descriptors, lipophilicity (as described by clogP and Topological Polar Surface Area (TPSA) gave the strongest overall correlation to incidence of adverse in vivo outcomes, whether analyzed in terms of free or total drug threshold concentrations. In the case of free drug threshold analysis, a Random Forest statistical method indicated that there was a higher chance of a compound with TPSA <70... 

Hydrophobicity increases the BBB permeability of compounds, whereas the polar surface and its interaction with the atomic mass of compounds decrease the BBB permeation rate. 

If a meta disubstituted compound is symmetrical, and the biological activities differ between hydrophobic and polar substituents, then expect possible ring rotation to maximize hydrophobic and polar interactions between the ring substituents and the hydro-phobic and polar surface. 

Several in silica models for prediction of oral absorption are available [133-136]. Simple models are based on only few descriptors like logP, logD, or polar surface area (PSA), while they are only applicable if the compounds are passively absorbed. In case of absorption via active transporters or if efflux is involved, prediction of absorption is still not successful. 

We can also look at other literature datasets to gain an idea of how similar our compounds are to compounds for which QMPRPlus gives very good predictions. We have looked at four simple descriptors molecular weight, topological polar surface area [40], chemical complexity [41], and rotatable bond count, using John Bradshaw s... 

Tab. 15.3 Median values for molecular weight, polar surface area, chemical complexity, and rotatable bond count for literature datasets and for a set of Roche compounds...

Roche datasets, (b) Cumulative topological polar surface area (A ) distributions of compounds in the Gasteiger [33] and Roche datasets, (c) Cumulative chemical complexity distributions of compounds in the Gasteiger [33] and Roche datasets, (d) Cumulative rotatable bond count distributions of compounds in the Gasteiger [33] and Roche datasets. 

SMARTS expression [42]. From Table 15.3, it is clear that the compounds in our test set are significantly different in size, polar surface area and complexity, compared to the kinds of molecules that are often used in the generation of algorithms for the prediction of solubility. 

As mentioned above, hydrogen bonding and molecular size, in combination with lipophilicity have an important influence on oral absorption. A number of methods are available to compute these properties. A further example of the correlation between H-bonding, expressed as polar surface area, is found in Figure 3.12 [24,25]. Such a sigmoidal relationship is found for compounds which are absorbed by passive diffusion only and not hindered by efflux or metabolism, and which are not involved in active uptake. Otherwise deviations will be foimd [25]. 

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