Pharmaceutical Chemistry and Medicinal Chemistry
Core concepts
Candidates must connect molecular structure to physicochemical behaviour and to biological effect. Key themes: functional-group acidity/basicity and the Henderson–Hasselbalch relationship (ionisation vs pH, and how it governs absorption and renal reabsorption); stereochemistry (enantiomers, racemates, eutomers/distomers, the thalidomide and ibuprofen examples); prodrug design (ester prodrugs such as enalapril and oseltamivir, designed to improve oral bioavailability); and structure–activity relationships in the main drug classes (β-lactams, sulfonamides, benzodiazepines, dihydropyridines). Know the classic degradation pathways - hydrolysis of esters and amides, oxidation, photolysis - and the functional groups that make a molecule labile.
Traps
Questions often test pKa reasoning rather than memorised numbers: an acidic drug (e.g. aspirin, pKa ~3.5) is largely unionised in the stomach and absorbed there, while a weak base is ionised in gastric acid and absorbed in the intestine. Another trap is confusing a prodrug with an active metabolite, or assuming that a chiral centre always means the drug is marketed as a single enantiomer. Salt forms (hydrochloride, sodium, mesylate) change solubility and stability, not the intrinsic pharmacophore.
Rule of thumb
For any 'where is it absorbed / will it cross a membrane' question, apply: unionised form permeates; acidification favours absorption of acids, alkalinisation favours absorption of bases. For degradation questions, ask 'is there an ester/amide (hydrolysis), a catechol/amine (oxidation), or an aryl ketone (photolysis)?'
Worked example
Aspirin (pKa 3.5) in gastric pH ~1.5: pH < pKa, so the unionised fraction dominates and gastric absorption is favoured. In plasma pH 7.4 the drug is largely ionised, which traps it extracellularly and limits CNS entry.