Pharmaceutical Chemistry and Medicinal Chemistry
Medicinal chemistry questions on this exam test whether you can connect molecular structure to physicochemical behaviour and then to a clinical consequence - not whether you can recite a synthetic route. Expect ionisation and pKa, partition coefficient, salt selection, stereochemistry, and the main degradation pathways of a drug molecule.
Structure drives behaviour
- Ionisation follows Henderson–Hasselbalch: for a weak acid, pH = pKa + log([A⁻]/[HA]); for a weak base, pH = pKa + log([B]/[BH⁺]).
- Only the uncharged fraction crosses lipid membranes well; the charged fraction is more water soluble.
- logP (neutral species) and logD (at a stated pH) predict absorption and CNS penetration.
- Esters and amides hydrolyse, amides far more slowly. Catechols, phenols and thiols oxidise. Light, heat and trace metals accelerate both.
Worked example
Aspirin has pKa ≈ 3.5. What fraction is unionised in the stomach at pH 1.5? 1.5 = 3.5 + log([A⁻]/[HA]), so the log ratio is −2 and [A⁻]/[HA] = 0.01. Fraction unionised = 1/(1 + 0.01) ≈ 0.99, about 99%. That is why aspirin is absorbed from the stomach, whereas at plasma pH 7.4 the charged salicylate predominates and is largely trapped outside cells.
Traps
Calculating the ionised fraction and reporting it as unionised; quoting logP without stating the ionisation state; assuming a more soluble salt is automatically better absorbed; forgetting that chirality changes both affinity and kinetics (S-warfarin is the more potent enantiomer).