hydrochloric acid, a Ka of 1.26 X 106 means that the product of the molar concentrations of the conjugate acid, [H3O+], and the conjugate base, [Cl-], is huge relative to the denominator term, [HCl]. In other words, there essentially is no un-reacted HCl left in an aqueous solution of hydrochloric acid. At the other extreme is ephedrine HCl with a pKa of 9.6 or a Ka of 2.51 X 10-10. Here, the denominator representing the concentration of ephedrine HCl greatly predominates over that of the products, which, in this example, is ephedrine (conjugate base) and H3O+ (conjugate acid). In other words, the protonated form of ephedrine is a very poor proton donor. It holds onto the proton. Free ephedrine (the conjugate base in this reaction) is an excellent proton acceptor.
A general rule for determining whether a chemical is strong or weak acid or base is
• pKa <2: strong acid; conjugate base has no meaningful basic properties in water
• pKa 8 to 10: very weak acid; conjugate base getting stronger
• pKa >12: essentially no acidic properties in water; strong conjugate base
This delineation is only approximate. Other properties also become important when considering cautions in handling acids and bases. Phenol has a pKa of 9.9, slightly less than that of ephedrine HCl. Why is phenol considered corrosive to the skin, whereas ephedrine HCl or free ephedrine is considered innocuous when applied to the skin? Phenol has the ability to partition through the normally protective lipid layers of the skin. Because of this property, this extremely weak acid has carried the name carbolic acid. Thus, the pKa simply tells a person the acid properties of the protonated form of the chemical. It does not represent anything else concerning other potential toxicities.
Using the drug's pKa, the formulation or compounding pharmacist can adjust the pH to ensure maximum water solubility (ionic form of the drug) or maximum solubility in nonpolar media (un-ionic form). This is where understanding the drug's acid-base chemistry becomes important. Note Reactions 2.4 and 2.5:
Conj. Acid HbO+
Conj. Acid HBO+
Acids can be divided into two types, HA and BH+, on the basis of the ionic form of the acid (or conjugate base). HA acids go from un-ionized acids to ionized conjugate bases (Rx. 2.4). In contrast, BH+ acids go from ionized (polar) acids to un-ionized (nonpolar) conjugate bases (Rx. 2.5). In general, pharmaceutically important HA acids include the inorganic acids (e.g., HCl, H2SO4), enols (e.g., barbiturates, hydantoins), carboxylic acids (e.g., low-molecular-weight organic acids, arylacetic acids, N-aryl anthranilic acids, salicylic acids), and amides and imides (e.g., sulfonamides and saccharin, respectively). The chemistry is simpler for the pharmaceutically important BH+ acids: They are all pro-tonated amines. A poly functional drug can have several pKa's (e.g., amoxicillin). The latter's ionic state is based on amoxicillin's ionic state at physiological pH 7.4.
The percent ionization of a drug is calculated by using Equation 2.3 for HA acids and Equation 2.4 for BH+ acids.
% ionization =
% ionization =
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