Physicochemical profiling

The partition coefScient is defined as the ratio of the concentration of a solute in the organic phase to its concentration in the water phase. This definition applies to the same neutral microspecies. However, many small molecules of pharmaceutical, agricultural and environmental interest may assume different protomeric and tautomeric forms, which increases the complexity of the above (simple) definition. Indeed, many small molecules contain moieties that ionize in water, thus contributing to a decrease in lipophilicity. The distribution coefficient, log D y, measures the pH-dependent distribution of drug in octa-nol-water phases at pH xy. 

Practically, the determination of log D at fixed pH is simpler than the log P measurement, which may require multiple titration experiments and/or extrapolations to the neutral state of the compound. Moreover, by using some specific ranges of pH e.g., pH 1-2 for stomach or neutral pH 6.5 for jejunum), one can better simulate the medium in the gastrointestinal tract. 

Data quality and quantity are important issues when addressing the limitations of the existing calculated log P models. The amount of data for log P prediction is one of the largest in the field. The MedChem database contains the largest commercially available collection, with over 60 000 measurements of log P and 

Many models for log P prediction have been developed and published in the literature, which is a consequence of the availability of a large amount of log P data. There are much fewer log D models and, moreover, models built with large datasets are almost exclusively from large companies.One can distinguish two main groups for log P calculation fragmental and based on descriptors calculated for the whole molecule.  

The log P is to a large extent an additive property. Thus, not surprisingly, a considerable number of fragmental methods to predict this property have been published. The general equation for this group of methods can be represented as  

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Kerns, E. H., Di, L. Physicochemical profiling overview of the screens. Drug Discov. Today Technol. 2004, 1, 343-348. Van de Waterbeemd, H. Physicochemical approaches to drug absorption. In Drug Eioavailability (Methods and Principles in Medicinal Chemistry), Van de Waterbeemd, H., Lennernas, H., Artursson, P. (eds.), Wiley-VGH, Weinheim, 2003, pp. 3-20. 

Van de Waterbeemd, H. Property-based lead optimization. In Biological and Physicochemical Profiling in Drug Research, Testa, B., Kramer, S. D., Wunderli-Allenspach, H., Folkers, G. (eds.), VHCA, Zurich and Wiley-VCH, Weinheim, 2006, pp. 25-45. 

This chapter considered ionizable drug-like molecules. Absorption properties that are influenced by the pKj were explored. The impact of the pKj-absorption relationship on key physicochemical profiling underlying absorption (solubihty, per-meabihty and ionization) was examined in detail and several simpUfying equations were discussed. The various diff relationships considered in the chapter are systematized in Table 3.2. Table 3.3 summarizes the apparent pfQ shift method for detecting aggregates in solubility profiles, when the apparent pff value derived from Henderson-Hasselbalch analysis of log S pH profile does not agree with the... 

Avdeef, A., Testa, B. Physicochemical profiling in drug research a brief state-of-the-art of experimental techniques. Cell. Mol. Life Sci. 2003, 59,1681-1689. 

Rapid physicochemical profiling as an aid to drug candidate selection. In ... 

Avdeev, A. Physicochemical profiling (solubility, permeation and charge state). Curr. Top. Med. Chem. 2001, 1, 277-351. 

Some Guidelines for a Typical Application of Gradient RPLC in Physicochemical Profiling... 

Jia, Z. Physicochemical profiling by capillary electrophoresis. Curr. Pharm. Anal. 2005, 7, 41-56. 

Biological and Physicochemical Profiling in Drug Research, Wiley-VCH, Weinheim and VHCA, Zurich, 2006. 

In this book we will focus on physicochemical profiling in support of improved prediction methods for absorption, the A in ADME. Metabolism and other components of ADME will be beyond the scope of this book. Furthermore, we will focus on properties related to passive absorption, and not directly consider active transport mechanisms. The most important physicochemical parameters associated with passive absorption are acid-base character (which determines the charge state of a molecule in a solution of a particular pH), lipophilicity (which determines distribution of a molecule between the aqueous and the lipid environments), solubility (which limits the concentration that a dosage form of a molecule can present to the solution and the rate at which the molecule dissolves from... 

The BCS scheme can be made more useful by incorporating a further improved basis of physicochemical profiling. For example, the role of pH in permeability measurements could be better defined. The use of simulated intestinal fluids for solubility measurements could be better promoted. The effects of fed/fasted states on absorption could be better address, in methods that have optimum clinical relevance. 

Within the project we also evaluated alternative methods as tools to obtain information on the toxicological and physicochemical profile of the pollutants. In this paragraph, an example of the application of QSARs models is reported a comparison is done between predicted values from different models or between QSARs evaluation and experimental values from internationally recognized databases. 

Keens, E. H., High throughput physicochemical profiling for drug discovery, J. Pharm. Sci. 2001, 90, 1838-1858. 

Avdeee, A., Physicochemical Profiling (Solubility, Permeability, and Charge State), Curr. Topics Med. Chem. 2001,... 

Avdeef, A., Physicochemical profiling (solubility, permeability and charge... 

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