Chemistry • Year 12 • Module 8 • Lesson 12
Acid-Base Properties of Drug Molecules
Synthesise data, evaluate claims, and produce Band 5–6 responses integrating quantitative and conceptual reasoning about ionisation, bioavailability and pharmaceutical formulation.
1. Data + scenario evaluation — aspirin bioavailability and formulation decisions
Scenario
A pharmaceutical research team at CSL (Commonwealth Serum Laboratories, Melbourne) is reviewing the oral bioavailability profile of two aspirin formulations: standard aspirin tablets and enteric-coated aspirin. Standard tablets dissolve in the stomach (pH ≈ 1.5). Enteric-coated tablets are designed to resist gastric acid and dissolve in the small intestine (pH ≈ 6.5). The team notes that the TGA’s bioavailability guidance for aspirin records that the drug is rapidly absorbed from the stomach as well as the upper intestine, and that co-administration of antacids measurably reduces peak plasma concentration. Aspirin pKa = 3.5; ibuprofen pKa = 4.91.
| Environment | pH | [A−]/[HA] | % un-ionised |
|---|---|---|---|
| Fasting stomach | 1.5 | 0.010 | 99.0 |
| Fed stomach | 3.5 | 1.00 | 50.0 |
| Small intestine (duodenum) | 6.5 | 1000 | 0.10 |
| Blood plasma | 7.4 | 7943 | 0.013 |
Extended-response prompt (8 marks)
Evaluate the two aspirin formulations in terms of their acid-base chemistry and absorption profiles. In your response you must:
- Define bioavailability and explain why the ionisation state of aspirin influences it.
- Use Table 1 to compare the proportion of un-ionised aspirin in the stomach versus the small intestine, and explain what this means for absorption at each site.
- Explain the chemical reason that antacid co-administration reduces the peak plasma concentration of aspirin (reference to Henderson–Hasselbalch required).
- Assess, using evidence from Table 1, whether the CSL team should be concerned that enteric-coated aspirin delivers significantly lower bioavailability. Use data to support your judgement.
2. Source critique — evaluate a pharmaceutical claim
Source — excerpt from a hypothetical consumer health article published in an Australian pharmacy magazine:
“Aspirin is well absorbed in the small intestine because that is where most drug absorption takes place. The stomach is too acidic to allow aspirin to pass through, since acid environments break apart drug molecules and prevent them from crossing cell membranes. Taking aspirin with an antacid therefore improves absorption by creating a more hospitable environment. Because ibuprofen has a higher pKa than aspirin, it is a stronger acid and therefore less safe for gastric use.”
This source contains multiple scientific errors. 7 marks
2.1 Identify two distinct scientific errors in the passage. For each error: (a) state the incorrect claim, (b) explain the correct chemistry, and (c) describe how the error could be tested experimentally. 6 marks
Error 1:
Error 2:
2.2 The article claims that ibuprofen is a “stronger acid” than aspirin because its pKa is higher. Explain whether this is correct, using Ka and pKa definitions. 1 mark
Q1 — Marking criteria (8 marks)
- 1 mark — Bioavailability correctly defined as the proportion of an administered dose that reaches the systemic circulation in active form.
- 1 mark — Correct link: un-ionised aspirin crosses lipid membranes more easily → greater absorption → greater bioavailability.
- 2 marks — Data used: stomach (pH 1.5) gives 99% un-ionised (high membrane permeability, significant gastric absorption) vs small intestine (pH 6.5) gives 0.10% un-ionised (low lipid-solubility, absorption primarily by passive diffusion of a very small fraction). One mark per environment.
- 2 marks — Antacid raises stomach pH (e.g. towards 4–5); H–H shows log([A−]/[HA]) = pH − pKa increases; more ionised form present; less un-ionised aspirin to diffuse across membrane; peak plasma concentration falls. Both the H–H application and the conclusion needed for 2 marks.
- 2 marks — Evidence-based judgement: enteric-coated aspirin delivers aspirin at intestinal pH where only ~0.10% is un-ionised; however, the large surface area of the intestine and high dissolution may compensate; TGA data suggest both formulations achieve therapeutic plasma levels, so concern is moderate rather than severe. Award marks for a reasoned judgement that uses Table 1 data and acknowledges competing factors.
Q2.1 — Error 1: aspirin not absorbed in the stomach
(a) Incorrect claim: “The stomach is too acidic to allow aspirin to pass through.”
(b) Correct chemistry: The low stomach pH (1–2) is actually below aspirin’s pKa (3.5), so the Henderson–Hasselbalch equation gives [A−]/[HA] = 0.01, meaning ~99% of aspirin is in the un-ionised HA form. The un-ionised form is uncharged and lipid-soluble, allowing it to cross the gastric mucosa by passive diffusion. Aspirin is therefore well absorbed in the stomach, not blocked by it. TGA bioavailability data confirm rapid gastric absorption.
(c) Experimental test: Measure plasma aspirin concentration over time in subjects given aspirin alone vs aspirin with a nasogastric bypass to deliver drug directly to the intestine; stomach absorption would be confirmed if the “no-stomach” group shows delayed peak plasma concentration.
Q2.1 — Error 2: antacid “improves” aspirin absorption
(a) Incorrect claim: “Taking aspirin with an antacid therefore improves absorption.”
(b) Correct chemistry: An antacid raises stomach pH from ~1.5 towards 4–5 or higher. Applying Henderson–Hasselbalch, at pH 4.5: log([A−]/[HA]) = 4.5 − 3.5 = +1, so [A−]/[HA] = 10, meaning ~91% is now ionised. The proportion of un-ionised (membrane-permeable) aspirin falls sharply. This reduces rather than improves gastric absorption; consistent with TGA bioavailability data showing reduced peak plasma aspirin concentration with antacid co-administration.
(c) Experimental test: Pharmacokinetic study measuring AUC (area under the plasma-concentration-time curve) and Cmax for aspirin alone vs aspirin + antacid in healthy volunteers; a lower AUC/Cmax with antacid confirms reduced absorption.
Q2.2 — pKa and acid strength (1 mark)
The claim is incorrect. A higher pKa means a weaker acid (pKa = −log Ka, so higher pKa corresponds to smaller Ka and less proton donation). Ibuprofen (pKa = 4.91) is a weaker acid than aspirin (pKa = 3.5), not a stronger one.