Ionizable compounds

Equilibriiun reactions The interaction of ionizable compounds in which the products obtained tend to revert to the substance from which they were formed until a balance is reached in which both reactants and pacts are present in definite ratios. 

Tam et al. [37-47] developed an impressive generalized method for the determination of ionization constants and molar absorptivity curves of individual species, using diode-array UV spectrophotometry, coupled to an automated pH titrator. Species selection was effected by target factor analysis. Multiprotic compounds with overlapping pK s have been investigated binary mixtures of ionizable compounds have been considered assessment of inicroconstants have been reported. 

Tam, K. Y. Multiwavelength spectrophotometric determination of add dissociation constants. Part VI. Deconvolution of binary mixtures of ionizable compounds. Anal. Lett. 2000, 33, 145-161. 

However, Clog P and, more generally, Hpophilidty descriptors referring to octanol-water are not the only lipophilicity parameters to be taken into account As mentioned above, isotropic and anisotropic Hpophilidty values gave rise to two different Hpophilidty scales for ionized compounds and thus it is recommended to test both of them (after checking the absence of any coHnearity) when looking for a QSAR model involving ions. 

Relationships between lipophilicity and retention parameters obtained by RPLC methods using isocratic or gradient condition are reviewed. Advantages and limitations of the two approaches are also pointed out, and general guidelines to determine partition coefficients in 1-octanol-water are proposed. Finally, more recent literature data on Hpophilicity determination by capillary electrophoresis of neutral compounds and neutral forms of ionizable compounds are compiled. Quotation is restricted to key references for every method presented - an exhaustive listing is only given for the last few years. 

The CHI parameter approximates the percentage of organic modifier in the mobile phase for eluting the compounds and can be used for high-throughput determination of physicochemical properties (50-100 compounds per day). CHI is a system property index, and depends on the nature of the stationary phase and the organic modifier as well as the pH of the mobile phase for ionizable compounds. 

CE was early identified as a powerful experimental technique to monitor the partitioning of neutral solutes and the neutral form of ionizable compounds [67]. In the search of partitioning parameters closer than log Poa to the pharmacokinetic behavior of dmg compounds [68] several different CE experimental conditions were explored and recently reviewed in detail [5, 69]. 

Similarly to RPLC, there is a strong Unear correlation between the logarithm of the retention factor measured by MEKC (logfe) for neutral solutes or the neutral form of ionizable compounds and log P supplementary material (see Sechon 13.5), numerous papers reported good correlations between log Pod and log k. 

Scherrer, R. A. The treatment of ionizable compounds in quantitative structure-activity smdies with special consideration to ion partitioning. In Pesticide Synthesis Throi h Rational Approaches (ACS Symp. Ser. 255), Magee, P. S., Kohn, G. K., Menn, J. J. (eds.), American Chemical Society, Washington, DC, 1984, pp. 225-246. 

Hence, two drugs of similar ogP may differ greatly in logZ) at physiological pH, with profound consequences for their pharmacological activity. As a consequence, log/ values of ionizable compounds are often quoted at pH 7.4, and equations similar to those above are used in pH-metric techniques [117-124] to determine either log/ or logZ). A compilation of the principal relationships linking partition and distribution coefficients is available in Refs. 125 and 126. 

However, the half-wave transfer potential is not a constant when ionizable compounds are eoneerned, beeause their transfer behavior depends on their degree of disso-eiation and henee on the pH of the aqueous phase. For instance, with a basic drug B that can be protonated onee to give BH, it has been shown [230] that Agy-... 

In both cases, the half-wave potential shifts by RT/ ziF)vaN per pH unit, and a typical example of such a behavior is given in Fig. 9 for the transfer of two acidic fi-diketones at the water-nitrobenzene interface. These results were unexpected, since a current wave is measured at a pH where the compound of interest is by a very large majority neutral, but they in fact represent the typical behavior of ionizable compounds at the ITIES and prove that the interfacial potential and the transfer of protons plays a key role for the distribution in biphasic systems. 

Of particular interest when considering ionizable compounds is the difference of lipophilicity between the neutral species and one of its ionic forms, because ionization dramatically alters intramolecular interactions (such as electronic conjugation, internal ionic and hydrogen bonds, polarity, hydrophilic folding, and shielding). In a given solvent system, diff (log is approximately constant for compounds with similar chemical... 

QSARs based on ionic compounds have thus been dramatically restricted due to the neglect of ion partitioning, which consequently meant that no technique was dedicated to such measurements and that modeling never took account of ionic species. To become fully accepted, potentiometry and electrochemistry at the ITIES need now to prove interesting in QSARs. As numerous lipophilicity data of ionizable compounds become available, one can expect that solvatochromic equations for ions will soon be developed in various solvent systems, which would greatly facilitate QSAR studies. 

Lochmiiller, C. H., Hsu, S.-H., and Reese, C., Prediction of the retention behavior of ionizable compounds in reversed-phase LC using factor-analytical modeling, /. Chromatogr. Sci., 34, 77, 1996. 

Kirkland J.J., Henderson J.W., Martosella J.D., Bidlingmeyer B.A., Vasta-Rus-sell J., and Adams Jr. J.B., A highly stable alkyl-amide silica-based column packing for HPLC of polar and ionizable compounds, LC-GC, 17 (7), 634,1999. 

In 1940 Jacobs [25] made use of the Henderson-Hasselbalch equation to relate pH and pKa to membrane transport of ionizable compounds. Extensive experimentation by a group of investigators in the early 1950s [16,26-30] quantitated many of the aforementioned observations concerning the influence of... 

The partition coefficient is needed to determine the moles lost to the membrane, VM CM(t). If ionizable compounds are considered, then one must decide on the types of partition coefficient to use -Kp (true pH-independent partition coefficient) or Kd (pH-dependent apparent partition coefficient). If the permeability assay is based on the measurement of the total concentrations, Cn(t) and CA(t), summed over all charge-state forms of the molecule, and only the uncharged molecules transport across the membrane to an appreciable extent, it is necessary to consider the apparent partition (distribution) coefficient, Kd, in order to explain the pH dependence of permeability. 

Johansson, P.-A. Gustavii, K., Potentiometric titration of ionizable compounds in two phase systems. 2. Determination of partition coefficients of organic acids and bases, Acta Pharm. Suecica 13, 407 -20 (1976). 

For weak acids, e.g., salicylic acid, the dependency on a pH gradient becomes complex since both the passive diffusion and the active transport process will be dependent on the proton concentration in the apical solution [61, 63, 98, 105] and a lowering of the pH from 7.4 to 6.5 will increase the apical to basolateral transport more than 20-fold. Similarly, for weak bases such as alfentanil or cimetidine, a lowering of the pH to 6.5 will decrease the passive transport towards the basolateral side [105]. The transport of the ionizable compound will, due to the pH partition hypothesis, follow the pKa curve. 

McFarland et al. recently [1] published the results of studies carried out on 22 crystalline compounds. Their water solubilities were determined using pSOL [21], an automated instrument employing the pH-metric method described by Avdeef and coworkers [22]. This technique assures that it is the thermodynamic equilibrium solubility that is measured. While only ionizable compounds can be determined by this method, their solubilities are expressed as the molarity of the unionized molecular species, the intrinsic solubility, SQ. This avoids confusion about a compound s overall solubility dependence on pH. Thus, S0, is analogous to P, the octanol/water partition coefficient in both situations, the ionized species are implicitly factored out. In order to use pSOL, one must have knowledge of the various pKas involved therefore, in principle, one can compute the total solubility of a compound over an entire pH range. However, the intrinsic solubility will be our focus here. There was one zwitterionic compound in this dataset. To obtain best results, this compound was formulated as the zwitterion rather than the neutral form in the HYBOT [23] calculations. 

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