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Greek Pharmacist License study materials
Greek Pharmacist License study resources

Greek Pharmacist License: Pharmaceutical Chemistry and Medicinal Chemistry

Greek Pharmacist License · Work through your exam, one topic at a time.

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Pharmaceutical Chemistry and Medicinal Chemistry

This domain tests whether you can move from a molecular structure or a physicochemical constant to a predicted behaviour in the body - ionisation, lipophilicity, stereochemistry, metabolism and the structural logic behind drug design. Items usually give a structure, a pKa, a logP or a metabolic pathway and ask for a quantitative or qualitative prediction.

Ionisation and pH

  • Henderson–Hasselbalch: weak acids pH = pKa + log([A⁻]/[HA]); weak bases pH = pKa + log([B]/[BH⁺]).
  • Only the uncharged species crosses lipid membranes appreciably; the charged species is trapped where it is formed (ion trapping).
  • Salt selection (hydrochloride, sodium, mesylate) changes solubility, dissolution rate and hygroscopicity, not intrinsic receptor affinity.
  • Acidic drugs ionise more at alkaline pH; basic drugs ionise more at acidic pH - remember the direction, not just the formula.

Lipophilicity and drug-likeness

  • logP is the partition coefficient of the unionised form; logD is the distribution coefficient at a stated pH. logD7.4 is the value that matters at plasma pH.
  • Lipinski rule of five for oral absorption: MW ≤ 500, logP ≤ 5, H-bond donors ≤ 5, H-bond acceptors ≤ 10. More than one violation predicts poor oral bioavailability.
  • A methyl or halogen substituent raises logP by roughly 0.5 units; a hydroxyl or carboxyl group lowers it.
  • Bioisosteric replacement (–COOH → tetrazole, –O– → –NH–, –OH → –NH₂) preserves activity while altering acidity, metabolism or patentability.

Metabolism and stereochemistry

  • Phase I reactions (CYP450 oxidation, ester hydrolysis, reduction) introduce or unmask a functional group; Phase II reactions (glucuronidation, sulfation, acetylation, glutathione conjugation) increase water solubility for excretion.
  • Metabolic soft spots sit at benzylic and allylic positions, N-methyl groups, esters and activated aromatics. Fluorine substitution or methylation blocks oxidation.
  • Enantiomers differ in both potency and clearance: S-warfarin is several-fold more potent than R-warfarin, S-thalidomide carries the teratogenic risk, S-omeprazole is the active proton-pump inhibitor.
  • Prodrugs (enalapril to enalaprilat, codeine to morphine, valaciclovir to aciclovir) are designed to solve an absorption, stability or targeting problem.

Worked example

A weak base with pKa 8.4 is taken orally; the duodenal pH is 6.0. Calculate the fraction uncharged. Using pH = pKa + log([B]/[BH⁺]): 6.0 = 8.4 + log ratio, so log ratio = −2.4 and the ratio is about 0.004. That is roughly 0.4% unionised and 99.6% protonated. At plasma pH 7.4 the ratio is 0.1, so about 9% is uncharged. Reasoning: absorption is driven by the small uncharged fraction but the duodenal surface area is large, and the same pH gradient explains accumulation of basic drugs in slightly acidic compartments such as milk.

Traps that cost marks

Applying the acid form of the equation to a base; treating logP and logD as interchangeable; ignoring that a racemate's activity is not simply the sum of its enantiomers; forgetting that Phase II metabolites are usually inactive but can be reactive (acyl glucuronides).