Chemistry • Year 12 • Module 8 • Lesson 12
Acid-Base Properties of Drug Molecules
Secure the vocabulary, the pH–pKa rule, and the ionised/unionised distinction before moving to calculations.
1. Term–definition match
The ten definitions below are shuffled. In the right-hand column write the matching term from this list: weak acid, ionised form, unionised form, pKa, Henderson–Hasselbalch equation, bioavailability, salt form, conjugate base, Ka, membrane permeability. 10 marks
| # | Definition (shuffled) | Matching term |
|---|---|---|
| 1.1 | The uncharged form of a drug molecule that crosses lipid membranes more readily. | |
| 1.2 | The charged form of a drug molecule; more water-soluble but less membrane-permeable. | |
| 1.3 | An acid that only partially dissociates in water, existing in equilibrium between HA and A−. | |
| 1.4 | The negative logarithm of the acid dissociation constant; a measure of acid strength. | |
| 1.5 | The equation pH = pKa + log([A−]/[HA]), used to find the ratio of ionised to unionised drug. | |
| 1.6 | The acid dissociation equilibrium constant for a weak acid. | |
| 1.7 | The species produced when a weak acid HA donates a proton: A−. | |
| 1.8 | The proportion of an administered dose that reaches the bloodstream in an active form. | |
| 1.9 | An ionic form of a drug (e.g. morphine sulfate) often used to improve aqueous solubility. | |
| 1.10 | The ease with which a drug molecule crosses a biological membrane, higher for uncharged lipid-soluble forms. |
2. True or false — with correction
Circle T or F. If the statement is false, write the corrected version on the line. 10 marks (1 T/F + 1 correction each)
2.1 For a weak acid drug, if pH < pKa the ionised form A− is favoured. T / F
2.2 The unionised form of a drug is generally more able to cross lipid cell membranes than the ionised form. T / F
2.3 Aspirin (pKa 3.5) is mostly ionised in the stomach at pH 1–2. T / F
2.4 A lower pKa value means the acid is stronger. T / F
2.5 Drug salt forms such as morphine sulfate are formulated to improve membrane permeability rather than aqueous solubility. T / F
3. Function recall
Answer each in 1–2 sentences using precise terms from the lesson. 8 marks (2 each)
3.1 What is the role of pH relative to pKa in determining the dominant form of a weak acid drug?
3.2 Why does the unionised form of aspirin cross the stomach lining more easily than the ionised form?
3.3 What is the function of converting a drug to its salt form (e.g. lignocaine HCl)?
3.4 What does it mean for a drug to have “good bioavailability”?
4. Build a concept map
Draw labelled arrows between the five terms below to show how they connect. Each arrow must carry a linking phrase (e.g. “determines”, “favours”, “increases”). Aim for at least 5 labelled arrows. 5 marks
Supplied terms: stomach pH (1–2) · pKa of aspirin (3.5) · unionised HA form · lipid membrane crossing · drug absorption.
5. Cloze paragraph — fill in the blanks
Use the word bank to complete the paragraph. Each word is used once. 7 marks
Word bank: unionised • ionised • pKa • Henderson–Hasselbalch • lipid • solubility • stomach
Many drug molecules are weak acids that exist in equilibrium between their _________________ (HA) and _________________ (A−) forms. The _________________ equation pH = pKa + log([A−]/[HA]) allows us to determine which form is favoured at any given pH. If the environmental pH is lower than the drug’s _________________, the unionised form is favoured. This is why aspirin, with a pKa of 3.5, is mostly un-ionised in the _________________ at pH 1–2. The unionised form is less polar and therefore crosses _________________ membranes more easily, which affects both absorption and the drug’s _________________ profile.
Q1 — Term–definition matches
1.1 unionised form • 1.2 ionised form • 1.3 weak acid • 1.4 pKa • 1.5 Henderson–Hasselbalch equation • 1.6 Ka • 1.7 conjugate base • 1.8 bioavailability • 1.9 salt form • 1.10 membrane permeability.
Q2 — True / false with correction
2.1 False. Correction: for a weak acid, if pH < pKa the unionised form HA is favoured (not the ionised form A−).
2.2 True.
2.3 False. Correction: aspirin (pKa 3.5) is mostly unionised in the stomach at pH 1–2 because the pH is well below the pKa.
2.4 True.
2.5 False. Correction: drug salt forms are primarily formulated to improve aqueous solubility and ease of administration; membrane crossing typically depends on the unionised neutral form.
Q3.1 — Role of pH relative to pKa
For a weak acid, comparing pH with pKa determines which form is favoured: pH below pKa favours the unionised acid HA, while pH above pKa favours the ionised conjugate base A−. The Henderson–Hasselbalch equation quantifies this ratio.
Q3.2 — Unionised form and membrane crossing
The unionised form is uncharged and less polar, so it interacts weakly with water and can dissolve into the lipid bilayer of the cell membrane. The ionised (charged) form interacts strongly with water and cannot easily pass through the hydrophobic interior of a lipid membrane.
Q3.3 — Function of salt forms
Converting a drug to an ionic salt (e.g. lignocaine HCl) greatly increases its aqueous solubility, making it easier to dissolve in body fluids and to formulate as an injectable or oral solution. This improves delivery to the site of action.
Q3.4 — Good bioavailability
Good bioavailability means that a high proportion of the administered dose reaches the systemic circulation in its active form. For an oral drug this requires adequate dissolution, absorption across the gastrointestinal membrane, and survival of first-pass metabolism.
Q4 — Sample concept map
Acceptable arrows include: stomach pH (1–2) is lower than → pKa of aspirin (3.5) • stomach pH and pKa together determine → unionised HA form [favoured] • unionised HA form enables greater → lipid membrane crossing • lipid membrane crossing leads to → drug absorption • pKa of aspirin (3.5) compared to pH controls → unionised HA form. Any biologically correct linking phrases accepted.
Q5 — Cloze answers (in order)
unionised / ionised / Henderson–Hasselbalch / pKa / stomach / lipid / solubility.