Pharmaceutical Chemistry and Medicinal Chemistry
Core concepts
A candidate must be fluent in functional-group chemistry (acids/bases, esters, amides, amines, phenols), stereochemistry (chirality, enantiomers, racemates and their differing activity), and the ionization behavior that governs solubility and absorption. Know pKa reasoning: weak acids (e.g., carboxylic acids, phenols) and weak bases (amines) exist in protonated/deprotonated forms depending on pH, and this drives the pH-partition concept. Understand prodrugs (why a drug is masked and how it is released), bioisosterism, and the metabolic soft spots that limit half-life. Salt selection (hydrochloride vs sodium salt) changes solubility and stability, not intrinsic potency.
Stability and degradation
Learn the main degradation pathways: hydrolysis (esters, amides, lactams), oxidation (catechols, phenols, thiols), photolysis, and racemization. Link these to storage advice and to excipient incompatibilities. Analytical identity tests (IR for functional groups, UV for chromophores, titration for acidic/basic drugs) are commonly examined.
Traps in questions
- Confusing potency (affinity/efficacy at receptor) with physicochemical properties such as logP or solubility.
- Assuming a racemate has twice the activity of one enantiomer - usually only one enantiomer is active, and the other may be inactive or toxic.
- Forgetting that a salt form changes mass and therefore dose calculation (base vs salt content).
- Mixing up which functional group hydrolyzes fastest (esters generally faster than amides).
Worked example (rule of thumb)
For a weak acid with pKa 4, at plasma pH 7.4 the ratio of ionized to unionized is about 10^(7.4−4) ≈ 2500:1, so it is overwhelmingly ionized and poorly membrane-permeable; in acidic gastric pH it is largely unionized and more absorbable. Use the Henderson–Hasselbalch ratio whenever a question asks about absorption or renal reabsorption by pH.