Ionization of weak acids

The proportion of ionized and unionized forms of a chemical compound can be readily calculated according to the above equation. It can be easily seen that pK is also a pH value at which 50% of the compound exists in ionized form. The ionization of weak acids increases as the pH increases, whereas the ionization of weak bases increases when the pH decreases. As the proportion of an ionized chemical increases, the diffusion of the chemical through the biological membranes is greatly impaired, and this attenuates toxicokinetic processes. For example, the common drug acetosalicylic acid (aspirin), a weak acid, is readily absorbed from the stomach because most of its dose is in an unionized form at the acidic pH of the stomach. 

Equilibrium constants can be written for the ionization of weak acids and weak bases, just as for any other equilibria. For the equation... 

Reverse-phase chromatography is used mainly for the separation of nonionic substances because ionic, and hence strongly polar, compounds show very little affinity for the non-polar stationary phase. However, ionization of weak acids (or weak bases) may be suppressed in solvents with low (or high) pH values. The effect of such a reduction in the ionization is to make the compound more soluble in the non-polar stationary phase but the pH of the solvent must not exceed the permitted range for bonded phases, i.e. pH 2-8. 

IONIZATION OF WEAK ACIDS AND WEAK BASES THE HENDERSON-HASSELBALCH EQUATION... 

Ionization of Weak Acids and Weak Bases the Henderson-Hasselbalch Equation... 

Ka is an equilibrium constant governing the ionization of weak acids. 

As will be seen, the large amount of quantitative structure-activity relationship (QSAR) modeling that has been carried out for soil sorption has almost exclusively involved nonionic organic compounds. For strongly ionizing and inorganic chemicals, no QSARs are available. However, Bintein and Devillers (1994) developed a soil sorption QSAR that incorporated correction factors for ionization of weak acids and bases. 

Calculations regarding the influence of pH upon the ionization of weak acids and bases may be solved by applying the Henderson-Hasselbalch equation (pH - pKz = log[base/acid]), which may be familiar to you from taking a class in biochemistry. 

This equation essentially describes the relationship between pH and the degree of ionization of weak acids and bases. When applied to drugs, the equation tells us that when pH equals the apparent equilibrium dissociation constant of the drug (pKJ, 50 percent of the drug will be in the unionized form and 50 percent will be in the ionized form (i.e., log[base/acid] = 0 and antilog of 0 = 1, or unity). Application of the Henderson-Hasselbalch equation can, therefore, allow one to mathematically determine the exact proportion of ionized and nonionized species of a drug in a particular body compartment if the pKa of the drug and the pH of the local environment are known. 

The LC methods discussed before were based mainly on physico-chemical interactions between the solute on the one hand and the two chromatographic phases on the other. Although we have seen that in RPLC the degree of ionization of weakly acidic or basic solutes may be a major factor in the control of retention and selectivity, the ionic species themselves were not exploited purposefully to realize or enhance the separation. In fact, in a typical RPLC system all fully ionized solutes will show little retention and therefore little resolution can be achieved between different ions. The methods described in this section make positive use of the ionic character of solutes to create a chromatographically selective system. 

Thermodynamics is a branch of physical chemistry that deals quantitatively with the inter-exchange of heat and work evolved in physical and chemical processes. This subject is widely utilized to explain equilibrium systems in physical pharmacy. For example, a pharmaceutical scientist may use equilibrium thermodynamics to study isotonic solutions, solubility of drugs, distributions of drugs in different phases, or ionization of weak acids and weak bases. Even though the gas laws are not usually directly related to pharmaceutical science (with some exceptions such as aerosols), these concepts must be introduced when dealing with simple thermodynamic systems of gases and the universal gas constant, R. 

Strong acids and bases ionize completely in solution, while weak acids and bases partially ionize. The partial ionization of weak acids and bases creates solutions in which an equilibrium is established. 

Consider a cocrystal A HB where the components A and HB are in 1 1 ratio and HB is a monoprotic weak acid. A and HB represent the API and ligand, respectively. The equilibrium equations for cocrystal dissociation (assuming no complexation in solution) and ionization of weak acid HB are as given below ... 

In mobile phases containing 10-50 mM phosphate or acetate buffers of pH 2-8.5, the ionization of weak acids (at pH <7) or bases (at pH >7) can be more or less suppressed to improve separation and peak symmetry. By adjusting the pH in the range 1.5 U around the differences in the degree of ionization of the individual sample components can often be utilized to control the separation selectivity. The retention is usually adjusted by the addition of up to 30-40% acetonitrile, methanol, or tetrahydrofuran to the mobile phase. 

The analogous problem of determining changes in the standard thermodynamic functions associated with the ionization of weak acids from the relation between the equilibrium constant (K) and the temperature has received further attention within the last two years. Ives and Mardsen (1965) have expressed In A as a fonction of several orthogonal polynomials of the temperature. Their method has several advantages but... 

Acidification of urine —increases ionization of weak bases —> increases renal elimination. Alkalinization of urine — increases ionization of weak acids —> increases renal elimination. 

In RPLC, acidic pH of 2.5-3 is used for many applications. The low pH suppresses the ionization of weakly acidic analytes, leading to higher retention.2,3,11 Surface silanols are not ionized at low pH, lessening tailing with basic solutes. Most silica-based bonded phases are not stable below pH 2 due to acid catalyzed hydrolytic cleavage of the bonded groups.23 Common acids used for mobile phase preparations are phosphoric acid, trifluoroacetic acid (TFA), formic acid, and acetic acid. However, basic analytes are ionized at low pH and might not be retained. 

Many potential candidate drugs are weak acids or bases, therefore, one of the most pertinent determinations carried out prior to development is the pKa or ionization constant. Strong acids, e.g., HC1, are ionized at all pH values, whereas the ionization of weak acids is dependent on pH. It is useful to know the extent to which the molecule is ionized at a certain pH, since properties such as solubility, stability, drug absorption and activity are affected by this parameter. The basic theory of the ionization constant is covered by most physical chemistry textbooks, and a most useful text is that by Albert and Sargeant (1984). Fundamental to our appreciation of the determination of this parameter, however, is the Bronstead and Lowry theory of acids and bases. This states that an acid is a substance that can donate a hydrogen ion, and a base is one that can accept a proton. 

A weak acid ionizes only slightly in solution, perhaps only to a few percent, and in solution between the molecular acid is in equilibrium with its ions. There are thousands of known weak acids and five of the more common ones are listed below with the equation for their equilibrium in solution. The equilibrium constant for the ionization of weak acids is symbolized Ka, and is called the acid-ionization constant. 

Textbooks of analytical chemistry should be consulted for further details concerning the ionization of weak acids and bases and the theory of indicators, buffer solutions, and acid-alkali titrations. 

Some of the most important processes in chemical and biological SYSTEMS ARE ACID-BASE REACTIONS IN AQUEOUS SOLUTIONS. In THIS FIRST OF TWO CHAPTERS ON THE PROPERTIES OF ACIDS AND BASES, WE WILL STUDY THE DEFINITIONS OF ACIDS AND BASES, THE pH SCALE, THE IONIZATION OF WEAK ACIDS AND WEAK BASES, AND THE RELATIONSHIP BETWEEN ACID STRENGTH AND MOLECULAR STRUCTURE. WE WILL ALSO LOOK AT OXIDES THAT CAN ACT AS ACIDS OR BASES. 

The ionization of weak bases is treated in the same way as the ionization of weak acids. When ammonia dissolves in water, it undergoes the reaction... 

Alkalinization of urine — increases ionization of weak acids —> increases renal elimination. 

The ionization of weak acids varies with both the temperature and the pressure. This process is accompanied by electrostriction of water around the charges that are created. The pressure dependence of the pH is... 

FIGURE 6.7. Titration curves of a soil and peat humic acid. The small wavy lines on the curves indicate endpoints for ionization of weak-acid groups having different, but overlapping, ionization constants. (From F. J. Stevenson. 1982. Humus Chemistry. Wiley, New York.)... 

Linear enthalpy-entropy compensation is well known to physical organic chemists and has been the subject of controversy since the relationship was first discovered experimentally. We have discussed the complications elsewhere and will only note here that the linearity found by Beetlestone et al. is statistically reliable for most of their examples. The most extensively studied set of small-solute compensation processes in water are the ionizations of weak acids. When acids such as acetic acid or benzoic acid are substituted in their nonpolar parts to form homologous series, the standard enthalpies and entropies of ionization are found to demonstrate compensation behavior with 7], values in the 280-290°K range but only after extraction of all the contributions to these quantities from the electronic rearrangements using methods developed by Hepler and Ives and their coworkers. The obvious conclusion is that this behavior in small-solute processes is due to solvation effects and thus a manifestation of some property of water. As a result of the comparison of their data with these small-solute examples, Beetlestone et al. suggested that bulk water also plays an important role in the protein processes they studied. 

The partial ionization of weak acids, bases, and salts in solution, most commonly in aqueous solution, can be considered to be a chemical equilibrium process. Examples include the ionization of acetic acid. 

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