Ionization Henderson-Hasselbalch

This relationship is one form of the Henderson-Hasselbalch equation It is a useful relationship m chemistry and biochemistry One rarely needs to cal culate the pH of a solution—pH is more often mea sured than calculated It is much more common that one needs to know the degree of ionization of an acid at a particular pH and the Henderson-Hasselbalch equation gives that ratio... 

The Henderson-Hasselbalch equation is derived below. A weak acid, HA, ionizes as follows ... 

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... 

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... 

Using the Henderson-Hasselbalch equation, we can easily calculate the amount of ionized form of an acid or base present at a given pH, provided we know the pK,. 

The imidazole side-chain of histidine has a value of 6.0, making it a weaker base than the unsubstituted imidazole. This reflects the electron-withdrawing inductive effect of the amino group, or, more correctly the ammonium ion, since amino acids at pH values around neutrality exist as doubly charged zwitterionic forms (see Box 4.7). Using the Henderson-Hasselbalch equation, this translates to approximately 9% ionization of the heterocyclic side-chain of histidine at pH 7 (see Box 4.7). In proteins, plCa values for histidine side-chains are estimated to be in range 6-7, so that the level of ionization will, therefore, be somewhere between 9 and 50%, depending upon the protein. 

The most important shortcoming of GSE is that it is valid only for nonelectrolytes, whereas many drug compounds and compounds in screening libraries are acidic or basic. In this case the solubility is pH-dependent. If one assumes for simplicity s sake that the ionized form is infinitely soluble in water, then the Henderson-Hasselbalch equation can be used to calculate the solubility at a given... 

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

Ionization State of Amino Acids Each ionizable group of an amino acid can exist in one of two states, charged or neutral. The electric charge on the functional group is determined by the relationship between its pifa and the pH of the solution. This relationship is described by the Henderson-Hasselbalch equation. 

Amino acids in aqueous solution contain weakly acidic a-carboxyl groups and weakly basic a-amino groups. In addition, each of the acidic and basic amino acids contains an ionizable group in its side chain. Thus, both free amino acids and some amino acids combined in pep tide linkages can act as buffers. The quantitative relationship between the concentration of a weak acid (HA) and its conjugate base (A-) is described by the Henderson-Hasselbalch equation. 

An important step in the understanding of partitioning phenomena is the ability to link between a drug molecule s pKa and its pH-dependent solubility. The major tool for this estimation has been, for the past 80 years, the Henderson-Hasselbalch equation [133]. The ionized fraction of a drug can be calculated for any pH value if its pKa is known [134], as follows ... 

The pH of the gastrointestinal tract varies, being 1-2 in the stomach, 5-6 in the duodenum, 6-7 in the jejunum, 7-8 in the ileum, and 8-9 in the large intestine. This variation in pH influences the extent to which acidic or basic chemical substances are ionized, which influences the extent of their absorption. The degree of ionization of an acidic substance or a basic substance at a given pH can be expressed by the Henderson-Hasselbalch equations (equations (2) and (3), respectively) ... 

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

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. 

All amino acids contain ionizable groups that act as weak acids or bases, giving off or taking on protons when the pH is altered. As is true of all similar ionizations, these ionizations follow the Henderson-Hasselbalch equation ... 

Using the Henderson-Hasselbalch equation, calculate the pAa value for each ionizable group titrated. 

The majority of the pharmaceutical drugs are weak bases or weak acids. Among the marketed drugs, more than 75% are weak bases, 25% are weak acids, and 5% are nonionic [38]. Therefore, knowledge of pK i is useful for enhancing drug solubility and stability. The Henderson-Hasselbalch equation is used to describe the ionization of a weak acid or base ... 

The average pH of saliva is 6.4. Because the un-ionized form of a drug is the lipid-soluble-diffusible form, the piifa of the drug plays an important role in its absorption across the lipid membranes of the oral mucosa. The degree of ionization of a drug at a specified pH can be calculated using the Henderson-Hasselbalch equation as follows ... 

In other words, if A" is 10% ionized (to HA-f-OH"), then the Henderson-Hasselbalch equation cannot be used to estimate the pH of a solution of HA that has been 99% titrated. 

When constructing Table 1-3, we assumed that at the first equivalence point the a-carboxyl is completely ionized and that the /S-carboxyl is completely un-ionized. These assumptions, of course, are not entirely true the actual degree to which the a- and /S-carboxyls are ionized can be calculated using the Henderson-Hasselbalch equation. If we carry out the calculation, we find that the proportion of a-carboxyl that is still in the COOH form exactly equals the proportion of /3-carboxyl in the COO form. (At pH 2.98, we are just as far above the p/ a, for the a-carboxyl as we are below the for the /S-carboxyl.) Thus, to determine the net charge on the molecule, we are justified in tallying only the predominant ionic forms at each key point along the titration curve. 

Consider a system in which the substrate is a weak acid, HA, but only the ionized form, A, binds to the enzyme. The true substrate then is A. At a fixed concentration of total weak acid, the proportion that is in the proper ionic form can be calculated from the Henderson-Hasselbalch equation. Thus, at pH s= pKa, half of the total concentration is present as A. When the pH is one unit above the p-K , 10/11 of the total is present as A (i.e., the ratio of [A ]/[HA] = 10). When pH = pK +2, 100/101 of the total is present as A. When the pH is one unit less than pK, 1/11 of the total is present as A, ... 

Usually, when determining the ionization constants of acid-base groups on surface a use is made of not this equation but of the Henderson Hasselbalch equation ... 

The acidity or basicity of a drug substance is defined by the dissociation constant K, which is the equilibrium constant, more conveniently represented by its logarithmic parameter pK, reflecting the degree of ionization of a substance at a particular pH and described by the Henderson-Hasselbalch equations (37.2) and (37.3). ... 

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