PHAR2911 · Pharmaceutics And Professional Practice
Physicochemical Methods, Solubility & Stability
This chapter covers the physicochemical properties that decide whether an oral drug ever reaches the bloodstream — solubility versus dissolution, the pH-partition rule (Henderson–Hasselbalch + log P) for ionisable drugs, the BCS 2×2 of solubility × permeability, and the degradation pathways that fix a product's shelf life. It is heavily examined because it is the quantitative backbone of PHAR2911 pharmaceutics: expect calculate the unionised fraction, name the BCS class and the fix, and match a degradation pathway to its control questions.
What this chapter covers
- 01Solubility (equilibrium ceiling) vs dissolution (kinetic rate)
- 02Noyes–Whitney: surface area, particle size & the ≥75%/45 min spec
- 03pH-partition hypothesis & the unionised form
- 04Henderson–Hasselbalch for weak acids and weak bases
- 05log P and lipophilic membrane partitioning
- 06BCS classes I–IV (solubility × permeability) & the rate-limiting step
- 07Beer–Lambert standard-curve quantitation (A = εbC)
- 08Degradation by hydrolysis & oxidation; shelf life / expiry
Fraction unionised of a weak base at two pH sites
- +1Write the ratio for a base. From Henderson–Hasselbalch, log([B]/[BH+]) = pH − pKa, so [B]/[BH+] = 10(pH − pKa); the unionised fraction = ratio / (1 + ratio).
- +1Stomach (pH 1.4): pH − pKa = 1.4 − 9.4 = −8, so [B]/[BH+] = 10−8. Unionised fraction = 10−8/(1 + 10−8) ≈ 10−8 ≈ 0.00001% unionised — essentially all ionised.
- +1Plasma (pH 7.4): pH − pKa = 7.4 − 9.4 = −2, so [B]/[BH+] = 10−2 = 0.01. Unionised fraction = 0.01/(1 + 0.01) ≈ 0.0099 ≈ 1% unionised.
- +1Interpret. The weak base is more unionised (more able to cross a lipid membrane) at the higher pH — the mirror image of a weak acid. Even so, both sites leave it mostly ionised, so its absorption depends strongly on local pH and on log P.
Key terms
- Solubility (Cs)
- The maximum amount of a drug that dissolves in a given solvent at equilibrium at a stated temperature — a thermodynamic ceiling, not a rate.
- Dissolution
- The kinetic process (and its rate) by which solid drug goes into solution; for many immediate-release oral products it is the rate-limiting step before absorption. Pharmacopoeial spec: typically ≥75% released in 45 min at 37 °C.
- pH-partition hypothesis
- The principle that a drug crosses lipid membranes mainly in its unionised (uncharged) form, so absorption tracks the unionised fraction set by local pH relative to pKa.
- Henderson–Hasselbalch equation
- pH = pKa + log([ionised]/[unionised]); gives the ionised:unionised ratio for a weak acid ([A−]/[HA]) or weak base ([B]/[BH+]). At pH = pKa the drug is 50% ionised.
- log P
- The logarithm of the octanol/water partition coefficient (log of Coctanol/Cwater); a measure of lipophilicity — how readily the unionised form partitions into a lipid membrane.
- Biopharmaceutics Classification System (BCS)
- A 2×2 scheme classifying drugs by solubility × permeability into Classes I (high/high), II (low solubility, dissolution-limited), III (permeation-limited) and IV (both low).
Physicochemical Methods, Solubility & Stability FAQ
What is the difference between solubility and dissolution?
Solubility is the equilibrium ceiling — how much drug can dissolve in a solvent at a given temperature. Dissolution is the rate at which the solid gets there. A drug can be quite soluble yet dissolve slowly, or poorly soluble yet dissolve what little it can quickly. For most oral immediate-release products dissolution is the rate-limiting step for absorption, which is why exams test the distinction directly.
Why is a weak acid better absorbed in the stomach and a weak base in the intestine?
Only the unionised form crosses lipid membranes. A weak acid is pushed toward its unionised HA form at low pH (the acidic stomach), while a weak base is pushed toward its unionised B form at higher pH (the more alkaline intestine). Use Henderson–Hasselbalch to compute pH − pKa, then 10(pH−pKa) for the ratio. Note: despite a low unionised fraction, the small intestine still dominates absorption because of its huge surface area.
What is a BCS Class II drug and how do you fix it?
Class II = low solubility but high permeability, so absorption is dissolution-rate limited. Because the membrane is not the bottleneck, the fix targets the solid and its surface area: reduce particle size (micronisation), use salts, solid dispersions, or wetting agents to speed dissolution — not increasing the dose.
How does the Beer–Lambert law quantify a dissolved drug?
Beer–Lambert states A = εbC, so absorbance is proportional to concentration over the linear region. A standard curve of known concentrations lets you convert a measured absorbance into a concentration; read unknowns only on the linear part and dilute samples that are too concentrated. This is how the pharmaceutics lab turns UV readings of dissolution samples into mg per tablet.
What are the main drug degradation pathways and how is shelf life set?
The two chief chemical pathways are hydrolysis (water attacking ester or amide bonds) and oxidation (reaction with oxygen, often catalysed by light, heat and trace metals). Controls are matched to the pathway — dry/buffer/cool for hydrolysis, antioxidants/chelators/dark/cold for oxidation. Shelf life (expiry) is the deadline at which potency can no longer be guaranteed to meet spec (typically when it would fall below about 90% of label).
Exam move
Treat this chapter as one chain, not four topics: a dose must dissolve (≥75%/45 min, driven by surface area), present its unionised form to cross the membrane (Henderson–Hasselbalch + log P), survive degradation (hydrolysis/oxidation, set by shelf life), and the BCS class tells you which step is the bottleneck. Drill the three calculation patterns until they are automatic — unionised fraction = 1/(1+10(pH−pKa)) for an acid (invert for a base), Beer–Lambert C = A/(εb) off a standard curve, and BCS class → named fix — and always sanity-check the direction (acid more unionised at low pH, base at high pH) before trusting the arithmetic. For any structure given, name the degradation pathway from the bond (ester/amide → hydrolysis) and state its matched control. (Assessment weighting is not officially confirmed for 2026 — see your unit outline.)
