Pharmaceutical Chemistry and Medicinal Chemistry
Pharmaceutical Chemistry and Medicinal Chemistry tests structure-property relationships: how functional groups, ionization, lipophilicity, stereochemistry, and salt form determine stability, absorption, and target binding. The exam expects mechanistic reasoning, not just recognition of drug classes.
Core rules
- Ionization follows Henderson-Hasselbalch; the fraction ionized depends on pH relative to pKa.
- LogP and logD describe lipophilicity; logD is pH-dependent and more relevant at physiological pH.
- Prodrugs improve absorption or target delivery and must be bioconverted to release the active drug.
- Stereochemistry can change potency, metabolism, and toxicity; enantiomers are not automatically interchangeable.
- Salt selection affects solubility, hygroscopicity, and molecular weight, so potency must be calculated on the active moiety.
Worked example
Lidocaine is a weak base with pKa about 7.9. At plasma pH 7.4, use pH = pKa + log([base]/[acid]). Thus 7.4 = 7.9 + log(B/BH+), so log(B/BH+) = -0.5 and B/BH+ = 0.316. The ionized fraction is BH+/(B + BH+) = 1/(1 + 0.316) = 0.76, or about 76%. This helps explain why small pH shifts can alter the balance of lipid-soluble and charged species.
Traps
Do not use the pKa of the wrong conjugate acid or base. Do not treat a salt as if it were pure active drug; molecular weight changes the dose. Do not assume a prodrug is active in vitro. Do not ignore chiral inversion or enantiomer-specific clearance. In stability questions, distinguish hydrolysis, oxidation, and photodegradation rather than calling all loss degradation.