Ionization constants/properties

Chemical Properties. Hydrogen cyanide is a weak acid its ionization constant is of the same magnitude as that of the natural amino acids (qv). Its stmcture is that of a linear, triply bonded molecule, HC=N. 

This chapter considers ionizable drug-Uke molecules and the effect of such ionization on pharmaceutic properties. Most medicinal substances are ionizable [1]. The biological medium into which these substances distribute embraces a range of pH values. The ionization constant, pK, can teU the pharmaceutical scientist to what degree the molecule is charged in solution at a particular pH. This is important to know, since the charge state of the molecule strongly influences its other physicochemical properties. 

The cosolvent will lower the dielectric constant of the mixed solvent, independent of the properties of the solute molecule. The ionization constant of acids will increase and that of bases will decrease (see Sections 3.3.3 and 3.3.4), the result of which is to increase the fraction of uncharged substance in... 

Roseman, T. J. Yalkowsky, S. H., Physical properties of prostaglandin F2a (tromethamine salt) Solubility behavior, surface properties, and ionization constants, J. Pharm. Sci. 62, 1680-1685 (1973). 

The dielectric properties of the solvent have also an influence on the ionization constant of an incompletely ionized substrate. By the process of ion dissociation the concentration of associated ions is decreased this results because the latter are in equilibrium with non-ionized species and the ionization equilibrium will be restored by the formation of additional associated ions. 

Thermogravimetry Hygroscopicity Solubility Characteristics Partition Coefficients Ionization Constants Micromeritic Properties... 

The papers in the second section deal primarily with the liquid phase itself rather than with its equilibrium vapor. They cover effects of electrolytes on mixed solvents with respect to solubilities, solvation and liquid structure, distribution coefficients, chemical potentials, activity coefficients, work functions, heat capacities, heats of solution, volumes of transfer, free energies of transfer, electrical potentials, conductances, ionization constants, electrostatic theory, osmotic coefficients, acidity functions, viscosities, and related properties and behavior. 

Of the new methods that have emerged for studying covalent hydration, PMR has been most used. With its aid added to the two most fruitful of the earlier methods—ionization constants and ultraviolet (UV) spectra—many new and often unsuspected facts have emerged. The various physical methods have been particularly revealing when a nucleus with substituents that display a range of inductive, mesomeric, and steric properties has been used. As a result, more is now known about the mechanism of hydration, and many new patterns of hydration have emerged. 

E. Blanc calculated for the ionization of constants of phosphorous acid Ki=0 05, and isT2—2 4 XlO-5. I. M. Kolthoff found that the first ionization constant Ky increases from 0 016 in 0 001 Jkf-soln. to 0 062 in O lJf-soln. and the second ionization constant K2, calculated from the H -ion cone, of mixtures of a secondary phosphite with hydrochloric acid is O O07 at 18°. The first stage of phosphorous acid titration may be conducted with methyl-orange as indicator using a comparison soln. with ps—Z 85. A sharp end-point for the second stage is obtained with thymolphthalein as indicator. For the anodic oxidation of the phosphites, vide infra, perphosphates. P. Pascal studied the magnetic properties. 

The three independent rate constants /cqK, and kfc = kf + k, Kf fully determine the kinetic properties of Scheme 2, because the rate constants kf for enolization are related to those of the reverse reactions, Equation (9), where Kw is the ionization constant of water. We use primed symbols for the enolization of the neutral ketone K. In the rate equation for enolization, the terms k(f and k e ATW/AT are kinetically indistinguishable (see Equation (10) below). 

The rate of hydrogen exchange depends on the protolytic properties of both the solvent and the substrate. In fact there is a correspondence between the magnitude of the rate constants for deuterium exchange with ND3 and the conventional ionization constants of hydrocarbons which were used by Conant and Wheland (1932) and by McEwen (1936) to obtain the first quantitative estimates of the acidity of hydrocarbons. To do this, they determined the equilibrium of metallation of hydrocarbons by organo-alkali metal compounds. This reaction was described by Shorygin (1910) and is represented by the equation... 

Photon correlation spectroscopy, carried out under very dilute conditions, has unambiguously demonstrated the expansion of carboxylic emulsion polymers at high pH, but it may not always be useful in predicting properties of practical interest. Of special concern is the apparent decrease in the intrinsic ionization constant of surface carboxyls at very low concentration. Since most uses of emulsion polymer occur at high concentrations, the measurement of particle-particle interactions is of great practical importance (21J. It has been found that the sedimentation and viscometric techniques closely reflect viscosity changes in latexes at much higher solids. Extension of the PCS approach to more concentrated systems is underway but not without problems (22). 

Following on from the substituent constant methods, a number of other approaches have been applied to the prediction of pKa. The main prediction methods for pKa are summarized in Table 3.4. Of the methods to calculate pKa some are derived from atom and fragment values, others are derived from molecule orbital properties. Because of the problems of modeling ionization constants for molecules with multiple ionizable functional groups, the accuracy and predictivity of these methods remains questionable. 

Some ionizing solvents are of major importance in analytical chemistry whilst others are of peripheral interest. A useful subdivision is into protonic solvents such as water and the common acids, or non-protonic solvents which do not have protons available. Typical of the latter subgroup would be sulphur dioxide and bromine trifluoride. Non-protonic ionizing solvents have little application in chemical analysis and subsequent discussions will be restricted to protonic solvents. Ionizing solvents have one property in common, self-ionization, which reflects their ability to produce ionization of a solute some typical examples are given in table 3.2. Equilibrium constants for these reactions are known as self-ionization constants. 

Our primary objective was to develop a computational technique which would correlate the ionization constant of a weak electrolyte (e.g., weak acid, ionic complexes) in water and the ionization constant of the same electrolyte in a mixed-aqueous solvent. Consideration of Equations 8, 22, and 28 suggested that plots of experimental pKa vs. some linear combination of the reciprocals of bulk dielectric constants of the two solvents might yield the desirable functions. However, an acceptable plot should have the following properties it should be continuous without any maximum or minimum the plot should include the pKa values of an acid for as many systems as possible and the plot should be preferably linear. The empirical equation that fits this plot would be the function sought. Furthermore, the function should be analogous to some theoretical model so that a physical interpretation of the ionization process is still possible. 

If we take a series of compounds which are related by structural substitutions, such as benzene derivatives, then we can assign the effects of the structural changes to the ratio KBJKB. if we select this property as a standard. Such a system of correlation was first proposed by Hammett and revised and extended by Jaff " to account for the effects of meta and para substituents on the reactivity of benzene derivatives. For convenience, the ionization constant of benzoic acia queous solution at 25°C was chosen as standard and for each meta or para substituent a, a value of ionization constant for benzoic acid and Ka the ionization constant of the corresponding, substituted benzoic acid. 

---