Ionisation, pKa and Lipophilicity
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Lesson 1 of 12
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Drug Ionisation and pKa
Most drugs are weak acids or weak bases that exist in both ionised (charged) and un-ionised forms in solution. The degree of ionisation depends on the drug's pKa and the pH of the medium. The Henderson-Hasselbalch equation describes this relationship: for acids, pH = pKa + log([A-]/[HA]); for bases, pH = pKa + log([B]/[BH+]). At a pH equal to the pKa, exactly 50% of the drug is ionised and 50% is un-ionised.
This has profound clinical implications. The un-ionised form of a drug is lipid-soluble and can cross biological membranes by passive diffusion, while the ionised form is water-soluble and is largely membrane-impermeant. Gastric pH (~1.5) favours absorption of weak acids (e.g., aspirin pKa 3.5 — mostly un-ionised in stomach). Small intestinal pH (6-7.5) favours absorption of weak bases (e.g., morphine pKa 8.0). Ion trapping occurs when a drug becomes trapped in a compartment because the local pH drives it into the ionised form.
Lipophilicity (logP)
Lipophilicity is measured as the partition coefficient (P) between octanol and water: logP = log[drug]octanol/[drug]water. A higher logP indicates greater lipophilicity. Lipophilic drugs: cross the blood-brain barrier more readily, have larger volumes of distribution, are metabolised by cytochrome P450 enzymes, and have longer half-lives. Hydrophilic drugs: are renally excreted, have lower Vd, and reduced protein binding. logD accounts for ionisation at a specific pH: logD = logP − log(1 + 10^(pH-pKa)) for weak acids.
Biopharmaceutics Classification System (BCS)
The BCS classifies drugs based on solubility and permeability: Class I (high solubility, high permeability) — e.g. paracetamol, metoprolol — good oral bioavailability; Class II (low solubility, high permeability) — e.g. ibuprofen, phenytoin — dissolution-limited, formulation important; Class III (high solubility, low permeability) — e.g. metformin, atenolol — permeability-limited; Class IV (low solubility, low permeability) — poor oral bioavailability. The BCS guides formulation decisions and biowaiver applications in generic drug development.