Pharmaceutical Chemistry and Pharmaceutics
This domain covers what the molecule is and how it becomes a product: ionisation and solubility, salt and ester selection, chirality, chemical stability, excipients, and the physical pharmacy behind dosage forms.
Ionisation governs behaviour
For a weak base, pH = pKa + log([un-ionised base]/[ionised conjugate acid]). A base with pKa 8.4 in plasma at pH 7.4 gives a ratio of 10^(7.4 − 8.4) = 0.1, so roughly 91% is ionised: water-soluble, poorly lipid-permeable, slow across membranes. Lowering formulation pH increases solubility but may accelerate acid-catalysed hydrolysis, so solubility and stability must be balanced.
Salts, esters and prodrugs
Salts (hydrochloride, sodium, mesylate) change dissolution rate and handling, not intrinsic activity. Esters mask a polar group to improve absorption. Prodrugs need metabolic activation: enalapril → enalaprilat, codeine → morphine via CYP2D6, valaciclovir → aciclovir.
Stability and formulation
Hydrolysis (aspirin, esters), oxidation (epinephrine, ascorbic acid, catalysed by light and trace metals), photolysis (nifedipine) and polymorphism - crystal forms with different dissolution and bioavailability - are classic themes. Excipients are not inert: calcium binds tetracyclines and fluoroquinolones, and benzyl alcohol is avoided in neonates.
Worked example
A weak base of pKa 8.4 is formulated for injection. At pH 7.4 it is 91% ionised and stays dissolved but diffuses poorly; at pH 9.4 the ratio flips to 10:1 un-ionised, improving membrane transit but risking precipitation. The formulator chooses a pH that keeps drug dissolved with a suitable buffer or co-solvent while remaining chemically stable in the chosen container.
Traps
- Believing a salt form is a different drug.
- Ignoring chiral switches: S-warfarin is several times more potent than R-warfarin; esomeprazole is the S-enantiomer of omeprazole.
- Refrigerating a product when cold causes precipitation or a viscosity change.