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People are often told to take aspirin with food, but that advice connects directly to acid-base chemistry. A weakly acidic drug can exist in both ionised and unionised forms, and the balance between those forms changes with pH, which then affects solubility, membrane crossing and irritation risk.
Use the PDF for classwork, homework or revision. It includes key ideas, activities, questions, an extend task and success-criteria proof.
Aspirin has a pKa of 3.5. The stomach is strongly acidic, while the small intestine is much less acidic.
📚 Core Content
Many medicines are not locked into a single chemical form in the body. Instead, they exist in equilibrium between protonated and deprotonated forms, and the surrounding pH shifts that balance.
A weak acid can exist as HA and A-. A weak base can exist as an unprotonated base and a protonated cation. These forms differ in charge, which means they differ in polarity and in how easily they move through different environments.
The Henderson-Hasselbalch equation links pH, pKa and the ratio of deprotonated to protonated forms for a weak acid.
For a weak acid, this gives a quick rule: lower-pH environments favour the protonated unionised form, while higher-pH environments favour the deprotonated ionised form.
Aspirin is a useful case because its acid-base behaviour changes strongly between the stomach and the small intestine.
Aspirin has a pKa of 3.5. In the stomach at around pH 1 to 2, the pH is below the pKa, so aspirin exists mostly as the unionised weak acid. In the small intestine at around pH 6 to 7, the pH is above the pKa, so aspirin exists mostly as the ionised form.
| Location | Typical pH | Aspirin form favoured | Main implication |
|---|---|---|---|
| Stomach | 1-2 | Mostly HA (unionised) | Crosses lipid membranes more easily |
| Small intestine | 6-7 | Mostly A- (ionised) | More water-soluble, less membrane-permeable |
This does not mean the stomach is always the only important absorption site, but it does show the key principle: unionised form crosses lipid membranes more readily.
For a weak acid such as aspirin, pH relative to pKa controls whether the drug is mainly in the unionised acid form or the ionised conjugate-base form. That shift changes membrane permeability.
Ionisation changes how a drug moves through the body because membranes are largely lipid-like, while ionised particles interact strongly with water.
The unionised form is generally less polar and therefore crosses lipid membranes more easily. The ionised form is generally more water-soluble, but less able to cross hydrophobic barriers such as cell membranes.
Drug chemists do not only ask what a molecule does. They also ask how to formulate it so it dissolves and can be delivered effectively.
Some drugs are given as salt forms, such as morphine sulfate or lignocaine HCl, because converting the drug into an ionic salt can improve solubility in water and make formulation easier.
You should also be able to compare the relative acid strength of drug molecules using Ka or pKa. A larger Ka means a stronger acid, while a smaller pKa means a stronger acid.
📊 Data Interpretation
| Drug | Type | pKa | Environment pH | Form favoured |
|---|---|---|---|---|
| Aspirin | Weak acid | 3.5 | 1.5 | Mostly unionised HA |
| Aspirin | Weak acid | 3.5 | 6.5 | Mostly ionised A- |
| Drug X | Weak acid | 5.0 | 7.0 | Mostly ionised A- |
| Drug Y | Weak acid | 2.0 | 1.0 | Mostly unionised HA |
This kind of table reinforces the fast logic: for a weak acid, if pH is below pKa the unionised acid is favoured; if pH is above pKa the ionised conjugate base is favoured.
✏️ Worked Examples
Given: Aspirin is a weak acid with pKa = 3.5. Stomach pH = 1.5.
Find: The ratio [A-]/[HA].
Method:
pH = pKa + log([A-]/[HA])
1.5 = 3.5 + log([A-]/[HA])
log([A-]/[HA]) = -2.0
[A-]/[HA] = 10-2 = 0.01
Answer: The ionised-to-unionised ratio is 0.01 : 1, so aspirin is mostly unionised in the stomach.
Given: Drug A has pKa = 2.8, Drug B has pKa = 4.1, Drug C has pKa = 5.0.
Find: Order of acid strength from strongest to weakest.
Method: Lower pKa means stronger acid.
2.8 < 4.1 < 5.0
Answer: Drug A is strongest, then Drug B, then Drug C.
🧠 Activities
1 A weak acid drug has pKa = 4.0 in an environment of pH 6.0. Calculate [A-]/[HA] and state which form is favoured.
2 Aspirin has pKa = 3.5. At pH 2.5, calculate [A-]/[HA] and interpret the result.
3 A weak acid drug has pKa = 5.0 at pH 5.0. What is the ratio [A-]/[HA], and what does this tell you?
1 Why does the unionised form of a drug usually cross lipid membranes more easily than the ionised form?
2 Why might a chemist prepare a drug as morphine sulfate or lignocaine HCl instead of only using the neutral molecule?
3 Explain why aspirin may be more membrane-permeable in the stomach, yet still be taken with food.
1. For a weak acid, what does the Henderson-Hasselbalch equation compare?
2. A weak acid drug is placed in an environment where pH is greater than pKa. Which form is favoured?
3. Aspirin has pKa 3.5. In the stomach at pH 1.5, which statement is most accurate?
4. Why are some drugs given as salt forms such as morphine sulfate or lignocaine HCl?
5. Which statement about relative acid strength is correct?
1. A weak acid drug has pKa = 4.5 and is in an environment of pH 6.5. Calculate the ratio [A-]/[HA] and state which form is favoured. 4 marks
2. Explain how ionisation state affects absorption, distribution and membrane permeability of drug molecules. 5 marks
3. Evaluate the statement: “Because aspirin is more unionised in the stomach, it should always be taken on an empty stomach.” In your answer, refer to pKa, stomach pH, membrane permeability and gastrointestinal side effects. 5 marks
Return to the opening aspirin scenario and refine your explanation using equilibrium and pKa language.
1. pH - pKa = 2.0, so log([A-]/[HA]) = 2.0 and the ratio is 100 : 1. The ionised form A- is favoured.
2. pH - pKa = -1.0, so log([A-]/[HA]) = -1.0 and the ratio is 0.1 : 1. Aspirin is mostly unionised at pH 2.5.
3. If pH = pKa, then log([A-]/[HA]) = 0 and the ratio is 1 : 1. The ionised and unionised forms are present in equal amounts.
1. The unionised form is less charged and less polar, so it interacts less strongly with water and can move through lipid membranes more easily.
2. Salt forms are used because they can improve aqueous solubility and make the drug easier to formulate, dissolve and deliver.
3. Aspirin is more membrane-permeable in the stomach because the low pH favours the unionised form. It may still be taken with food because stomach irritation and gastrointestinal side effects also matter.
1. A — for a weak acid, Henderson-Hasselbalch compares A- with HA.
2. C — when pH is above pKa, the ionised weak-acid form A- is favoured.
3. D — stomach pH is below aspirin pKa, so the unionised form is favoured.
4. B — salt forms are commonly chosen to improve solubility and formulation.
5. A — lower pKa means stronger acid.
Q1 (4 marks): Using Henderson-Hasselbalch, pH = pKa + log([A-]/[HA]). Substituting gives 6.5 = 4.5 + log([A-]/[HA]). Therefore log([A-]/[HA]) = 2.0, so [A-]/[HA] = 102 = 100. The ratio is 100 : 1, so the ionised form A- is strongly favoured.
Q2 (5 marks): Ionisation state affects how a drug behaves because ionised and unionised forms differ in charge and polarity. The unionised form is generally less polar and crosses lipid membranes more easily, so it is often more membrane-permeable. The ionised form is generally more water-soluble, which can help it dissolve and distribute in aqueous body fluids, but it usually crosses lipid barriers less easily. As a result, ionisation affects absorption, distribution and the balance between solubility and membrane transport.
Q3 (5 marks): The statement is too simplistic. Aspirin is a weak acid with pKa 3.5, and stomach pH around 1 to 2 is below that value, so the unionised form is favoured in the stomach. This means aspirin can cross lipid membranes more readily there. However, that does not mean it should always be taken on an empty stomach, because aspirin can irritate the stomach lining and gastrointestinal side effects must also be considered. Taking it with food can help reduce irritation risk. Overall, acid-base chemistry supports greater unionised aspirin in the stomach, but safe use must balance permeability with side effects.
Sprint through questions on the acid-base chemistry of drug molecules. Pool: lessons 1–12.
Tick when you've finished the activities and checked your answers.