How much will dissolve?
A drug must dissolve before it can be absorbed — a powder sitting undissolved in the gut does nothing. So one of the first numbers we measure is solubility: the maximum amount that will dissolve in a given solvent at a given temperature, the point at which the solution is saturated. For an ionizable drug, solubility depends sharply on pH, so we also pin down the [[phc-intrinsic-solubility|intrinsic solubility]] — the solubility of the *neutral, uncharged* molecule. That single pH-independent value is the bedrock from which pH-dependent solubility is calculated.
pKa: where the molecule charges up
Most drugs are weak acids or weak bases, meaning they switch between a neutral form and a charged (ionized) form depending on the surrounding pH. The [[phc-pka|pKa]] is the pH at which the molecule is exactly half ionized and half neutral — the tipping point. The Henderson-Hasselbalch equation turns pKa and pH into the ratio of the two forms, so you can predict, at any pH, how much of the drug is charged.
Why care? Two reasons. First, the charged form is far more water-soluble, so pKa tells you how solubility will swing between stomach acid and intestinal fluid. Second, the pH-partition hypothesis says membranes are crossed mainly by the *neutral* form. So the charged form helps dissolving, while the neutral form helps absorbing — a genuine tug-of-war that pKa lets you anticipate.
Worked example — a weak base, pKa = 8.0 Henderson-Hasselbalch (base): pH = pKa + log([base]/[BH+]) In stomach (pH 2.0): log([base]/[BH+]) = pH - pKa = 2.0 - 8.0 = -6.0 [base]/[BH+] = 10^-6 -> essentially 100% ionized (charged) Consequence: high aqueous solubility, but poorly absorbed here. In small intestine (pH 6.5): log([base]/[BH+]) = 6.5 - 8.0 = -1.5 [base]/[BH+] = 10^-1.5 = 0.032 fraction neutral = 0.032 / (1 + 0.032) = 3.1% Consequence: only ~3% neutral, yet that small neutral fraction is what diffuses across the gut wall.
log P: water versus oil
The third number is the [[phc-partition-coefficient|partition coefficient]], written as log P. Shake a drug with a mixture of octanol (a stand-in for fatty membranes) and water, let it settle, and measure how the drug splits between the two layers. P is the ratio of concentrations; log P is its logarithm. A high log P means the drug prefers oil — lipophilic, membrane-loving but often water-shy. A low or negative log P means it prefers water — hydrophilic, easily dissolved but reluctant to cross membranes.
Read the three together and a story emerges. Good oral absorption usually needs a balance: enough solubility to dissolve, enough lipophilicity to cross membranes. A drug too far toward either extreme is a formulation challenge. When solubility is the bottleneck for an ionizable drug, one of the cleanest fixes is salt formation — pairing the drug with a counter-ion to make a far more soluble salt — which is exactly the subject of the next guide.