Pharmaceutical Chemistry: Structure, Ionisation and Stability
Pharmaceutical Chemistry in the UPSC Drug Inspector examination tests whether you can connect molecular structure to physicochemical behaviour, stability and biological action. Items come from drug design and SAR, stereochemistry, prodrugs, functional-group reactivity, heterocyclic nomenclature and degradation pathways.
Rules that carry marks
- Ionisation governs distribution. Use Henderson–Hasselbalch: for a weak acid, pH = pKa + log([A⁻]/[HA]); for a weak base, pH = pKa + log([B]/[BH⁺]).
- Only the un-ionised fraction of a small molecule crosses lipid membranes appreciably; ionised species are excreted more readily in urine.
- Esters hydrolyse faster than amides; phenols and catechols oxidise; aryl halides resist hydrolysis; photolysis affects nitroaromatics, phenothiazines and nifedipine.
- Prodrugs and bioisosteres: enalapril is hydrolysed to enalaprilat; sulfasalazine is cleaved by colonic bacteria to 5-aminosalicylic acid and sulfapyridine; levodopa is a prodrug of dopamine.
- Stereochemistry: (S)-omeprazole is the active enantiomer; thalidomide illustrates how enantiomers can differ in teratogenic risk.
Worked example
Aspirin has pKa 3.5. In gastric fluid at pH 1.5: log([A⁻]/[HA]) = 1.5 − 3.5 = −2, so the ratio is 0.01 - about 1% is ionised and 99% unionised, favouring gastric absorption. At plasma pH 7.4: log ratio = 3.9, so [A⁻]/[HA] ≈ 8,000; the drug is almost entirely ionised and trapped in plasma, and urinary alkalinisation accelerates salicylate excretion.
Traps
Do not confuse pKa with pH; do not assume every ester is equally unstable; remember that amides are relatively resistant to hydrolysis; and never treat a chiral switch as automatically superior without pharmacokinetic evidence.