Chemistry · Year 12 · Module 8 · Lesson 12

HSC Exam Practice

Acid-Base Properties of Drug Molecules

10 questions / 3 sections / 35 marks total

Section 1

Short answer

1.Definitions and recall

1.1

Define pKa and explain how it is related to the acid dissociation constant Ka.

2marks Band 3

1.2

Distinguish between the ionised and unionised forms of a weak acid drug in terms of charge, polarity, and ability to cross lipid membranes.

3marks Band 3–4

1.3

Identify the dominant form (unionised HA or ionised A⁻) of a weak acid drug with pKa = 5.2 when placed in an environment of pH 3.0. Give a reason for your answer.

2marks Band 3

1.4

Outline why drug chemists often formulate drugs as salt forms, such as morphine sulfate or lignocaine HCl, rather than as the neutral molecule alone.

2marks Band 3–4

1.5

Three drugs have pKa values of 2.3, 4.7, and 6.1 respectively. Rank them from strongest to weakest acid and justify your ranking.

2marks Band 4

1.6

Compare the expected absorption in the stomach of a weak acid drug (pKa = 4.5) with a weak base drug (pKa of conjugate acid = 8.0) at stomach pH 1.5. Account for the difference using acid-base theory.

4marks Band 4–5

Section 2

Data response

2.Henderson–Hasselbalch calculation and interpretation

2.1

Aspirin (pKa = 3.5) is administered orally. Blood plasma has pH = 7.4.

(a) Calculate the [A⁻]/[HA] ratio for aspirin in blood plasma using the Henderson–Hasselbalch equation. Show all working.

(b) Interpret the biological significance of this ratio. What does it mean for aspirin distribution in the blood?

(c) State one assumption you have made in applying Henderson–Hasselbalch to plasma, and identify one factor not captured by this equation that also affects drug distribution.

6marks Band 4–5

2.2

The table below shows data for four drugs. Use the data to answer the sub-questions.

Drug	Type	pKa	% un-ionised at pH 7.4
Aspirin	Weak acid	3.5	0.013
Ibuprofen	Weak acid	4.91	0.032
Morphine	Weak base	8.0 (BH⁺)	79.9
Drug P	Weak acid	7.4	50.0

(a) Identify which drug is most likely to cross cell membranes from the blood at pH 7.4 and give a quantitative reason.

(b) Explain the % un-ionised value of 50.0% for Drug P at pH 7.4 without performing a calculation.

4marks Band 4–5

Section 3

Extended response

3.Evaluate and analyse

3.1

Analyse how the acid-base properties of a drug molecule determine its behaviour as it passes from the stomach to the bloodstream. In your response, discuss the role of pKa, Henderson–Hasselbalch equilibria, ionisation state and membrane permeability. Use aspirin and one other named drug molecule as examples.

8marks Band 5–6

3.2

A PBS formulary document states: “Enteric-coated aspirin tablets eliminate all gastrointestinal risk associated with aspirin by preventing contact between aspirin and the stomach lining.”

Identify the scientific flaw in this claim and explain the correct chemistry and pharmacology.

4marks Band 5

Answer key

Marking criteria and model answers

1.1 (2 marks)

pKa = −log₁₀(Ka). It is the negative logarithm of the acid dissociation constant (1 mark). A lower pKa corresponds to a larger Ka and therefore a stronger acid (1 mark).

1.2 (3 marks)

Ionised form (A⁻): charged, polar, more water-soluble, poor membrane permeability (1 mark). Unionised form (HA): uncharged, less polar, less water-soluble, able to dissolve in and cross lipid membranes (1 mark). The unionised form crosses lipid membranes more readily because the hydrophobic membrane interior repels charged/polar species (1 mark).

1.3 (2 marks)

Unionised HA form (1 mark). pH (3.0) is less than pKa (5.2), so the Henderson–Hasselbalch equation gives a negative log ratio, meaning [HA] > [A⁻]; the unionised acid form is favoured (1 mark).

1.4 (2 marks)

Salt forms (ionic) have greatly improved aqueous solubility compared with the neutral molecule (1 mark), making the drug easier to dissolve, formulate and deliver (as injections, solutions or fast-dissolving tablets); membrane crossing still depends on the in-vivo equilibrium generating the un-ionised form (1 mark).

1.5 (2 marks)

Strongest to weakest: pKa 2.3 > pKa 4.7 > pKa 6.1 (i.e. drug with pKa 2.3 is strongest) (1 mark). Lower pKa = larger Ka = greater tendency to donate a proton = stronger acid (1 mark).

1.6 (4 marks)

Weak acid (pKa 4.5) at stomach pH 1.5: pH < pKa, so [HA] >> [A⁻]; mostly un-ionised; lipid-soluble; likely absorbed in stomach (1 mark + 1 mark reasoning). Weak base (pKa of BH⁺ = 8.0) at stomach pH 1.5: pH (1.5) << pKa (8.0) of conjugate acid BH⁺, so the base B exists mainly as the protonated cation BH⁺; this is charged and cannot easily cross lipid membranes; absorption in the stomach is poor (1 mark + 1 mark reasoning).

2.1(a) (3 marks)

pH = pKa + log([A⁻]/[HA]) ⇒ 7.4 = 3.5 + log([A⁻]/[HA]) ⇒ log([A⁻]/[HA]) = 3.9 ⇒ [A⁻]/[HA] = 10^3.9 ≈ 7943 (1 mark for substitution, 1 mark for correct log step, 1 mark for final answer with correct magnitude).

2.1(b) (2 marks)

At blood pH 7.4, the ionised A⁻ form outnumbers the un-ionised HA form by ~7943 : 1, i.e. aspirin is almost entirely ionised in blood plasma (1 mark). This highly ionised form is more water-soluble and distributes readily in plasma, but cannot easily recross cell membranes; aspirin is effectively “trapped” in the circulation and extracellular fluid once it reaches blood (1 mark).

2.1(c) (1 mark)

Any one valid assumption (e.g. plasma behaves as a simple aqueous solution at constant pH; or equilibrium is reached rapidly). Any one additional factor (e.g. protein binding, first-pass metabolism, active transport).

2.2(a) (2 marks)

Morphine (weak base, 79.9% un-ionised at pH 7.4) is most likely to cross cell membranes (1 mark) because it has the highest proportion of the uncharged (un-ionised) lipid-soluble form available in blood (1 mark).

2.2(b) (2 marks)

When pH = pKa, the Henderson–Hasselbalch equation gives log([A⁻]/[HA]) = 0, so [A⁻]/[HA] = 1, meaning exactly equal concentrations of ionised and un-ionised forms → 50% un-ionised (1 mark each for reason and conclusion).

3.1 (8 marks) — Marking criteria

1 mark — Weak acid drug in equilibrium HA ⇌ H⁺ + A⁻; ratio governed by Henderson–Hasselbalch.
1 mark — Stomach (pH 1–2) < pKa of aspirin (3.5) → un-ionised form favoured; % un-ionised ~99%; high membrane permeability; aspirin absorbed in stomach.
1 mark — Correct Henderson–Hasselbalch application for stomach (e.g. pH 1.5: ratio = 0.01).
1 mark — Blood (pH 7.4) >> pKa → ionised A⁻ overwhelmingly favoured; aspirin trapped as ion in plasma; highly water-soluble; distributes in plasma.
1 mark — Un-ionised form is uncharged, less polar, compatible with lipid bilayer interior; ionised form repelled by hydrophobic membrane.
1 mark — Second named drug correctly used (e.g. ibuprofen pKa 4.91 in stomach at pH 1.5 → mostly un-ionised; or morphine as a weak base absorbed better in alkaline intestine).
1 mark — Logical structure: stomach absorption discussed, then distribution in blood, with clear links to ionisation state.
1 mark — Sophisticated conclusion or added insight (e.g. bioavailability depends on balance of solubility and permeability; PBS/TGA formulation context; salt forms used to aid solubility without sacrificing eventual un-ionised availability).

3.2 (4 marks)

Flaw: The claim that enteric coating “eliminates all gastrointestinal risk” is incorrect (1 mark). While enteric coating prevents dissolution in the stomach and reduces direct contact with the gastric mucosa, aspirin’s prostaglandin-inhibiting mechanism (COX inhibition) is systemic and occurs once aspirin is absorbed anywhere in the GI tract; it reduces the protective prostaglandin layer of the entire gut, not just the stomach (1 mark). Therefore GI irritation and bleeding risk are reduced but not eliminated by enteric coating (1 mark). Additionally, enteric-coated aspirin dissolves in the intestine where pH > pKa, meaning most aspirin is ionised there; this may actually reduce the rate of absorption compared with standard tablets, and systemic aspirin still inhibits prostaglandins throughout the GI mucosa (1 mark).