The significance of acid/base properties in drug discovery

Abstract

While drug discovery scientists take heed of various guidelines concerning drug-like character, the influence of acid/base properties often remains under-scrutinised. Ionisation constants (pK(a) values) are fundamental to the variability of the biopharmaceutical characteristics of drugs and to underlying parameters such as logD and solubility. pK(a) values affect physicochemical properties such as aqueous solubility, which in turn influences drug formulation approaches. More importantly, absorption, distribution, metabolism, excretion and toxicity (ADMET) are profoundly affected by the charge state of compounds under varying pH conditions. Consideration of pK(a) values in conjunction with other molecular properties is of great significance and has the potential to be used to further improve the efficiency of drug discovery. Given the recent low annual output of new drugs from pharmaceutical companies, this review will provide a timely reminder of an important molecular property that influences clinical success.

Figure 1

The drug discovery process.

Figure 2

Diagram illustrating the key properties that are influenced by the acid/base character of drugs. Each node highlights an important facet of drug discovery and development.

Figure 3

(A), Proportion of compound categories for ionisable oral drugs. (B), pK_a distributions of oral drugs containing a single acidic functional group, or (C) single basic functional group. Compounds with the following criteria were classified as always ionised: acids with pK_a values < 0 and bases with pK_a values > 12, plus compounds with permanently charged groups (e.g., quaternary nitrogen atoms). Acids with pK_a values above 10 or bases with pK_a values below 0.0 were considered neutral. The remaining ionisable compounds (acid pK_a range 0-10 and base pK_a range 0-12) were divided into the following groups: single acid-containing substances, single base-containing substances, compounds with two acidic groups, compounds with two basic groups, simple ampholytes (one acidic and one basic group) and other complex combinations of acidic and basic groups (complex ampholytes). pK_a values were binned into single log unit ranges (i.e. 0.0 < X ≤ 1.0, 1.0 < X ≤ 2.0, etc.). The histogram column heights are expressed as a percentage.

Figure 3

(A), Proportion of compound categories for ionisable oral drugs. (B), pK_a distributions of oral drugs containing a single acidic functional group, or (C) single basic functional group. Compounds with the following criteria were classified as always ionised: acids with pK_a values < 0 and bases with pK_a values > 12, plus compounds with permanently charged groups (e.g., quaternary nitrogen atoms). Acids with pK_a values above 10 or bases with pK_a values below 0.0 were considered neutral. The remaining ionisable compounds (acid pK_a range 0-10 and base pK_a range 0-12) were divided into the following groups: single acid-containing substances, single base-containing substances, compounds with two acidic groups, compounds with two basic groups, simple ampholytes (one acidic and one basic group) and other complex combinations of acidic and basic groups (complex ampholytes). pK_a values were binned into single log unit ranges (i.e. 0.0 < X ≤ 1.0, 1.0 < X ≤ 2.0, etc.). The histogram column heights are expressed as a percentage.

Figure 3

(A), Proportion of compound categories for ionisable oral drugs. (B), pK_a distributions of oral drugs containing a single acidic functional group, or (C) single basic functional group. Compounds with the following criteria were classified as always ionised: acids with pK_a values < 0 and bases with pK_a values > 12, plus compounds with permanently charged groups (e.g., quaternary nitrogen atoms). Acids with pK_a values above 10 or bases with pK_a values below 0.0 were considered neutral. The remaining ionisable compounds (acid pK_a range 0-10 and base pK_a range 0-12) were divided into the following groups: single acid-containing substances, single base-containing substances, compounds with two acidic groups, compounds with two basic groups, simple ampholytes (one acidic and one basic group) and other complex combinations of acidic and basic groups (complex ampholytes). pK_a values were binned into single log unit ranges (i.e. 0.0 < X ≤ 1.0, 1.0 < X ≤ 2.0, etc.). The histogram column heights are expressed as a percentage.

Plot showing the % protonated species against pH for a compound with a single acidic group (pK_a 4.0).

Plot showing the % protonated species against pH for a compound with a single basic group (p K_a 9.0).