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


In Equation 2, the quantities in square brackets represent the molar concentrations of the various species, and the γ quantities are the activity coefficients of those species. For an acid capable of ionizing into a univalent anion, γH + and γA will be approximately equal, and γHA can be approximated as unity, so that the concentration-based equilibrium constant expression can be simply written as:



For weak acids, the magnitude of K A is very small, and therefore, the resulting H3O+ and A ions will be produced in small amounts. Under those conditions, both γH+ and γA will be approximately equal to one, facilitating the approximation that the thermodynamic equilibrium constant, K, equals the concentration-based ionization constant, K A . Making use of the Sørensen scale, one can define the pK A of a weak acid as:



A strong acid is defined as a substance that reacts completely with water so that the acid ionization constant defined in Equation 2 or 3 is very large. This situation can only be achieved if the conjugate base of the strong acid is very weak. A weak acid will be characterized by an acid ionization constant that is considerably less than unity, so that the position of equilibrium in the reaction represented in Equation 1 favors the existence of nonionized free acid. The implication of these properties is that the conjugate base of the weak acid must be moderately strong.

A discussion of the ionic equilibria associated with basic substances exactly parallels that just developed for acidic substances. A base is a substance capable of accepting a proton donated by another substance, such as water:



The basic substance (B) that originally accepted the proton becomes the conjugate acid (BH+ ) of that substance, since the conjugate acid could conceivably donate a proton to an even stronger base than the original substance. The concentration-based ionization constant expression corresponding to Equation 5 is:



and pK B is defined as:



A strong base is a substance that reacts completely with water, so the base ionization constant defined in Equation 6 is effectively infinite. This situation can only be realized if the conjugate acid of the strong base is very weak. Since the conjugate acid of a weak base will be moderately strong, the base ionization constant will be considerably less than one, and the position of equilibrium in the reaction represented in Equation 5 will favor the existence of a nonionized free base.


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