Strategy for the Prediction and Selection of Drug Substance Salt Forms - Pharmaceutical Technology

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Strategy for the Prediction and Selection of Drug Substance Salt Forms
Through consideration of the ionic equilibria of acids and bases, one may readily calculate the formation constant of a salt species solely on the basis of knowledge of the pKA value of the acid and the pKB value of the base.


Pharmaceutical Technology


Once formed, the conjugate base of an acidic substance (i.e., the anion of that acid) would also be capable of reacting with water:



Because aqueous solutions of anions are commonly prepared by the dissolution of a salt containing that anion, reactions of the type described by Equation 8 are often termed hydrolysis reactions. Equation 8 is necessarily characterized by a base ionization constant expression:



and a corresponding pK B defined in the usual manner.

However, because these ionic equilibria are taking place in aqueous media, the autoionization of water:



must also be considered. The equilibrium constant for this reaction would be:



In aqueous solutions, the concentration of water is effectively a constant (55.55 M), and so Equation 11 simplifies to:



K W is known as the autoionization constant of water and is sometimes identified as the ion product of water. The magnitude of K W is very small, being equal to 1.007 X 10–14 at a temperature of 25 C (15). Substitution of Equation 12 into Equation 9 yields the relation:



However, the concentration terms in Equation 13 constitute the ionization constant expression for the conjugate acid of the conjugate base, providing the very useful relation regarding the relative strengths of conjugate acids and bases:



The same relation between ionization constants of a conjugate acid–base pair can be developed if one were to begin with the conjugate acid of a basic substance, so Equation 14 is recognized as a general property of conjugate acid–base pairs.

Ionic equilibria of salts

Salts are chemical compounds formed by the transfer of a proton from an acid (HA) to a base (B) capable of accepting that proton:


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