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.


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When dissolved in aqueous media at low to moderate concentrations, the (HB+)(A) salt will ordinarily exist in the form of dissociated HB+)(A and A ions:



As previously discussed, the free acid and free base are subject to their individual ionic equilibrium expressions. So Equation 16 can be expanded as:



Equation 17 is simply another way to express the neutralization reaction of Equation 16, and the complete equilibrium constant expression for this reaction would be:



Recognizing again that the concentration of water is a constant factor, one can define the neutralization constant (K N ) expression as:



Comparison of Equation 19 with the weak-acid ionization constant expression of Equation 3 and the weak base ionization constant expression of Equation 6 leads to a simple relation that defines K N :



As previously defined in Equation 12, the product of the concentration terms for the hydronium and hydroxide ions equals the autoionization constant of water, so:



Equating Equations 20 and 21, and collecting the various constants on the left-hand side yields the relation:



Equation 22 is nothing more than the equilibrium constant expression associated with the chemical reaction of Equation 16. If one defines the salt formation constant as:




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