Acid-Base Properties of Drug Molecules
In 1897, Felix Hoffmann synthesised aspirin with a pKa of 3.5 — a value that makes the drug ~99.7% unionised in the stomach (pH ≈ 1.5) and ~99.7% ionised in the small intestine (pH ≈ 6.5). That Henderson-Hasselbalch calculation explains why aspirin is absorbed primarily in the stomach and why buffered formulations (raising local pH) significantly reduce gastric irritation in daily doses exceeding 100 mg.
Practise this lesson
Four printable worksheets that build from the foundations up to exam-style questions — start at whatever level suits you.
Aspirin has a pKa of 3.5. The stomach is strongly acidic, while the small intestine is much less acidic.
- In which location would you expect aspirin to be more ionised, and why?
- How might that change affect both membrane permeability and side effects?
Know
- That many drugs are weak acids or weak bases in equilibrium between ionised and unionised forms
- The Henderson-Hasselbalch equation for weak acids
- Why some drugs are formulated as salt forms
Understand
- How pH relative to pKa controls the ionised-to-unionised ratio
- Why unionised forms cross lipid membranes more easily
- How acid strength and ionisation influence drug behaviour in the body
Can Do
- Apply Henderson-Hasselbalch to determine the ratio of ionised to unionised forms
- Interpret aspirin behaviour in the stomach and small intestine
- Rank relative acid strength from Ka or pKa data
Core Content
Drug molecules often exist in two forms at once
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.
Many drug molecules are weak acids or weak bases in equilibrium: HA ⇌ H⁺ + A⁻. HA = unionised (less polar, better membrane crossing); A⁻ = ionised (more polar, better aqueous solubility). Surrounding pH shifts the equilibrium between these two forms, directly affecting absorption and distribution.
Pause — copy the highlighted ionisation equilibrium into your book.
Comparing pH with pKa gives the balance of forms
We just saw that ionised and unionised forms behave very differently in the body. That raises the question: how do we actually calculate which form dominates at a given pH? This card answers it → the Henderson-Hasselbalch equation and the quick pH vs pKa rule.
The Henderson-Hasselbalch equation links pH, pKa and the ratio of deprotonated to protonated forms for a weak acid.
Henderson-Hasselbalch: pH = pKa + log([A⁻]/[HA]). Quick rule: pH < pKa → HA (unionised) favoured; pH > pKa → A⁻ (ionised) favoured. When pH = pKa, [A⁻]/[HA] = 1 (equal amounts). Higher pH favours deprotonation (ionised form) — NOT more protonation.
Pause — copy the highlighted Henderson-Hasselbalch rules into your book before the check below.
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.
Same molecule, different environment, different behaviour
We just saw how the Henderson-Hasselbalch equation predicts which drug form dominates. That raises the question: what does that mean for a real drug like aspirin moving through the digestive system? This card answers it → aspirin's shift from unionised in the stomach to ionised in the small intestine.
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 |
Aspirin pKa = 3.5. Stomach pH 1–2 → below pKa → mostly HA (unionised) → more membrane-permeable. Small intestine pH 6–7 → above pKa → mostly A⁻ (ionised) → more water-soluble, less membrane-permeable. Unionised form crosses lipid membranes more readily — the key absorption principle.
Pause — copy the highlighted aspirin location comparison, with the table structure, into your book.
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.
Charge helps in water, but hurts membrane crossing
We just saw how aspirin shifts between ionised and unionised depending on pH. That raises the question: why does that matter so much for drug movement through the body? This card answers it → why ionisation state controls membrane permeability vs aqueous solubility.
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.
Unionised form: less polar → better membrane permeability (can cross lipid bilayers). Ionised form: more polar → better aqueous solubility. Good drug design balances these competing properties. Ionisation state (pH vs pKa) controls which property dominates in each body environment.
Add the ionisation-permeability trade-off to your notes before the check below.
Formulation and acid strength are practical chemistry decisions
We just saw that ionised forms are more water-soluble. That raises the question: how do drug chemists exploit that to improve formulation — and how do we rank the acid strength of different drugs? This card answers it → salt forms for solubility and Ka/pKa ranking for acid strength.
Aspirin free acid has limited water solubility at ~3 g/L. The sodium salt of aspirin (sodium acetylsalicylate) dissolves at over 500 g/L. That 160-fold solubility difference means that the salt form can be formulated as a fast-dissolving tablet or effervescent drink — improving speed of absorption in acute pain situations. Drug chemists exploit salt formation specifically to solve solubility problems, not to change what the drug does.
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.
Salt forms (e.g., morphine sulfate, lignocaine HCl) are chosen to improve aqueous solubility and formulation — NOT primarily to improve membrane crossing, which depends on the unionised form. Acid strength: higher Ka = stronger acid; lower pKa = stronger acid. pKa and Ka move in opposite directions (pKa = –log Ka).
Pause — copy the highlighted salt form and pKa ranking rules into your book before the check below.
Use the pH-pKa comparison before doing full calculation
| 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
Using Henderson-Hasselbalch for Aspirin in the Stomach
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.
Ranking Relative Acid Strength from pKa
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.
Complete the Learn phase to unlock Practice.
Activities
Use Henderson-Hasselbalch, then explain what the ratio means chemically.
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?
Use ionisation logic to connect pH, formulation and drug movement.
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.
Check Your Understanding
Understand Band 3
1. For a weak acid, what does the Henderson-Hasselbalch equation compare?
Understand Band 4
2. A weak acid drug is placed in an environment where pH is greater than pKa. Which form is favoured?
Apply Band 4
3. Aspirin has pKa 3.5. In the stomach at pH 1.5, which statement is most accurate?
Analyse Band 5
4. Why are some drugs given as salt forms such as morphine sulfate or lignocaine HCl?
Analyse Band 5
5. Which statement about relative acid strength is correct?
Apply Band 4
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)
Analyse Band 5
2. Explain how ionisation state affects absorption, distribution and membrane permeability of drug molecules. (5 marks)
Evaluate Band 5–6
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)
Show All Answers
Activity 1
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.
Activity 2
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.
Multiple Choice
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.
Short Answer Model Answers
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.
Return to Hoffmann's 1897 aspirin and its pKa of 3.5. Now that you can apply the Henderson-Hasselbalch equation, quantify and explain the aspirin absorption story.
- Use Henderson-Hasselbalch to show that aspirin at stomach pH 1.5 is approximately 99.7% unionised — and explain in one sentence why that makes the stomach the primary absorption site.
- Why does enteric coating (which bypasses the stomach to release aspirin at pH 6.5) dramatically change the ionisation ratio — and what trade-off does this create for gastric safety versus absorption speed?
- How does the sodium salt of aspirin (sodium acetylsalicylate) solve a different problem from enteric coating, and what specific solubility improvement does it provide?
Review
State the Henderson-Hasselbalch equation and explain what each symbol means.
Aspirin pKa = 3.5. At stomach pH 1.5, is aspirin mainly ionised or mainly unionised? Calculate the ratio to confirm.
Explain why the unionised form of a drug crosses lipid membranes more easily than the ionised form.
Why are some drugs formulated as salt forms like morphine sulfate, and what problem does this solve?
Three drugs have pKa values of 2.1, 4.8 and 6.2. Rank them from strongest to weakest acid.