Experimental Evidence for Ion Pairing Shake Flask vs pHMetric

In the standard shake-flask method log D is measured at several different values of pH. Different buffers are used to control each pH used in the study. (Unfortunately, the ionic strength is not generally controlled with a background electrolyte, such as NaCl.) Usually in a comprehensive study, ten or so such measurements are made (a laborious process) and values of log D are plotted against the pH (usually the operational scale, defined by the buffers used). This is the lipophilicity profile...

Centrifugal Partition Chromatography for Lipophilicity Measurements

Ruey-Shiuan Tsai, Giuseppe Lisa, Pierre-Alain Carrupt and Bernard Testa CPC Centrifugal partition chromatography DCCC Droplet counter-current chromatography HDES Hydrodynamic equilibrium systems HSES Hydrostatic equilibrium systems RP-HPLC Reversed-phase high-performance liquid chromatography D1 Distribution coefficient measured at isoelectric point Paik Partition coefficient in alkane water systems PM Partition coefficient in n-octanol water systems tR Retention time of the solute t0 Retention...

Positional Isomerism

Positional isomerism is a geometric factor of obvious significance in lipophilicity. In fact, it may be convenient to distinguish between Regioisomerism, which relates positional isomers whose interconversion is a high-energy process. Tautomerism, which involves the low-energy migration of a proton from one heteroatom to another. The example discussed in section 4.3.1.1 is a fit illustration of the importance of positional isomerism in the lipophilicity of bisubstituted benzenes. Similarly, the...

Advantages and Limitations of the CPC Method for log P Measurements

The CPC method is probably the most precise and accurate method existing thus far for partition coefficient measurements. The problems inherent in the SF method caused by the adsorption, instability, impurity and volatility of solutes, and the impurity of solvents are not at all disturbing in the CPC method. When using different phase volume ratios for the same compound, the differences in the obtained log P values are negligible. This novel method needs relatively short times for a measurement...

The Case of Anti Dopaminergic 6Methoxysa IicyIamides

In the course of studying the physico-chemical and structural properties of antidopa-minergic 6-methoxysalicylamides 32, 33 , the compound raclopride was shown by us to exist in water at pH 7.4 as a zwitterion with stereoelectronic features completely different from those of other classes of dopamine antagonists such as orthopramides. Using first-derivative UV spectroscopy, the uncharged rather than zwitterionic form of raclopride was found to partition predominantly into the octanol phase....

Fragment Additivity Method

The jr-system was used for some 15 years, but was destined to give way to a much more general fragmentation method of calculating log P. The substituent scheme was only applicable, in general, to substituted benzene derivatives. For other compounds, the problem immediately arose, what does one take as parent and what as substituent Moreover, rather serious errors occurred in the application and interpretation of lipophilicity calculations using the substituent approach. Hansch and Anderson 23...

Contents

A Personal Foreword VII List of Contributors 1 Lipophilicity The Empirical Tool and the Fundamental Objective. An Introduction V. Pliska, B. Testa and H. Van de Waterbeemd 1.1 Setting the 1.2 Biological Aspects 1.3 The Molecule in the 1.4 Some Pragmatic 1.4.1 Definitions and 1.4.2 Experimental 1.4.3 Computational 1.5 Objectives of the References 2 Lipophilicity A History 7 2.1 Introduction 2.2 Measurement of Lipophilicity 2.3 Calculation of Lipophilicity 2.3.1 Substitution Method 2.3.2 Fragment...

Lipophilicity and Biological Activity

It is considered that our understanding of the role of lipophilicity in drug action is the single most significant result to come from the development of QSARs over the past three decades 84 , Quantitative correlations with lipophilicity have been established with regard to relative potencies at receptor sites, the regulation of drug transport, protein binding, pharmacokinetics, toxicity, drug metabolism, and enzyme induction. Such correlations have been established in the fields of human drug...

Calculation of the Interaction Energy

Two theoretical methods can be used for calculating the interaction energy (A E). The supermolecular variation method which determines AE as the difference between the energy of the cluster (supermolecule) and the energies of the isolated systems. The perturbational method gives A directly as the sum of physically distinct contributions such as electrostatic, induction, dispersion, and exchange-repulsion. Both the methods have advantages and drawbacks. The supermolecular approach is...

Stationary Phases Column Packings 531 Overview

HPLC stationary phase materials have been reviewed and compared on several occasions, e.g., in 21, 22 , In order to obtain log w values closely resembling log P a values, it has been suggested to coat the solid phase with 1-octanol 3, 4, 23 , However, this appeared of limited practical use due to a rapid bleeding of the column. A more successful approach is used at Zeneca 24, 25 . 1-Octanol adsorbed onto a hyflo-supercel diatomaceous earth solid support is more stable. When such a system is...

Stationary Phase

As mentioned above, in reversed-phase chromatography - i. e., the chromatographic approach to deriving lipophilicity descriptors - hydrophobic, nonpolar material is used as the stationary phase. In some cases 20, 21 cellulose plates were used. According to Geiss 22 this material has no reversed-phase properties. Silica-gel plates, impregnated by hand with paraffin, silicone or other oils deserve mention here in addition, commercially available octadecyl silylated silica-gel (ODS) materials are...

Correlations of log Values with log Poct and Other log P Scales

Although log k or preferably log kw values are good lipophilicity indices per se, very often a direct correlation or even conversion into log Poct values is performed. The mean reason is that one would like to have a comparison with standard experimental lipophilicity values or to calculated log P values, which also refer to the 1-octanol water system. Figure 4. Typical log Pact versus log k plot. Relationships are found for closely related compounds, namely phenylureas ( ), phenoxycarboxylic...

Diprotic Molecules with Two Different Ion Pair Partitionings

Niflumic acid partitions into octanol as a neutral species, an anion, and a cation 8 . Solution of Eq. (19) for three-log P case of a diprotic molecule produces the complicated equation 0 1 + 10p fa2 - pH + IC*82 + P 1 2 pH Eq. (29) is illustrated with the examples niflumic acid in Fig. 13a, nitrazepam in Fig. 13b, buprenorphine in Fig. 13c, and quinine in Fig. 13 d. Niflumic acid and quinine also illustrate the effect of salt on the partitioning of ions. Buprenorphine.HCl (23 C. 0.1SM KCl)...

Electronic Conjugations 4311 In Aromatic Systems

Substituents in aromatic rings may influence each other in a number of ways depending on their chemical nature, mutual position, and the presence of other substituents. For example, methyl groups have relatively little electronic interactions with the aromatic ring and with each other. Their incremental contribution to the lipophilicity of, e.g., xylenes, is additive as expected and independent from their relative position (or-tho versus meta versus para). Such groups are well-behaved in...

Interactions Involving Polar Groups

Polar groups decrease lipophilicity by characteristic increments. When two or more such groups are present, the solute is often found to be more lipophilic than calculated by the simple addition of increments, implying that two or more polar groups may interact to prevent each other from expressing its full polarity. This phenomenon is very well known and amply documented in the literature 7-9 , There is thus little need for us to go into too many details in describing such intramolecular...

References

Ed. Engl. 6, 195-280 (1967) 2 Fujita, T., Iwasa, J., and Hansch, C.,. . Am. Chem., Soc. 86, 5175-5180 (1964) 3 Berthelot, M., and Jungfleisch, E., Ann. Chim. Phys. 26, (4) 396-407 (1872) 4 Meyer, H.,Arch. Exp. Pathol. Pharmacol. 42, 109-118 (1899) 5 Overton, E., Studien Uber die Narkose. Fischer Jena 1901 6 Seidell, A., Orig. Com. 8th Intern. Congr. Appl. Chem. 17, 85-89 (1912) 7 Gaudette, L. E., and Brodie, B. B., Biochem. Pharmacol. 2, 89-96 (1959) 8 Leo, A.,...

Partitioning of the Amino Acids Phenylalanine and Tryptophanylphenylalanine

The pH-metric technique has a practical low log P limit of detection that is approximately -2. For hydrophilic molecules with log P of -2, the octanol-containing and the aqueous titration curves differ in the buffer region by about 0.01 pH units. This is about the level of reproducibility of a good research-grade pH electrode. One would not expect the technique to work with amino acids most amino acids are very hydrophilic and are charged in the interval pH 2-12. Even when the molecule is...

Outlook Molecular Polymorphism in Drug Design

A discussion of intermolecular forces encoded in lipophilicity section 4.2 , intramolecular interactions influencing lipophilicity section 4.3 , and structural factors influencing intramolecular interactions section 4.4 shows very clearly their intercon-nectedness and interdependence. A schematic representation of these relation is proposed in Fig. 9, which can be simplified as follows Table 4. Major intramolecular and intermolecular processes underlying molecular polymorphism Intramolecular...

Thermodynamics of Partitioning 2421 Phase Transfer

Dearden 31 pointed out in his review in 1985 that a thermodynamic analysis of partitioning cannot explain the partitioning process fully, because each parameter enthalpy, entropy reflects the difference between behavior in each phase, and tells us nothing directly about the absolute contributions in each phase. It is only by the thermodynamic investigation of gas-water and gas-lipid octanol partition that the contribution of each phase can be properly assessed. In terms of the driving force for...

Lipophilicity Measurement by Reversed Phase High Performance Liquid Chromatography RPHPLC

Han van de Waterbeemd, Manfred Kansy, Bj rn Wagner and Holger Fischer HIC Hydrophobic interaction chromatography IAM Immobilized artificial membrane chromatography LSER Linear solvation energy relationships MLC Micellar liquid chromatography ODP Octadecylpolyvinyl copolymer QSAR Quantitative structure-activity relationships QSRR Quantitative structure-retention relationships RP-HPLC Reversed-phase high-performace liquid chromatography JRP-IPC Reversed-phase ion-pair chromatography RPLC...

Bjerrum Difference Plots

The Bjerrum difference plots 3, 21,27, 28 are probably the most important graphical tools in the initial stages of equilibrium analysis. The difference curve is a plot of hH, the average number of bound protons that is, the hydrogen ion-binding capacity , versus pcH -log H . Such a plot can be obtained by subtracting a titration curve containing no sample blank titration from a titration curve with sample, hence the name difference curve. Another way of looking at it is the following. Since one...

Principle of Lipophilicity Measurements by RPLC 521 Description of the Method

Lipophilicity of organic compounds can be measured with any standard HPLC equipment. Usually UV detection can be used, but any other detection method is appropriate e.g., refractive index or electrochemical . The choice of the stationary and mobile phase are discussed in section 5.3 and 5.4. The lipophilicity index measured by RPLC is derived from the capacity factor k or sometimes written as k' given by where tx and t0 are the retention times of the solute and of an unretained compound. This...