pH partition hypothesis for aspirin and codeine
A medicinal chemist compares aspirin (acetylsalicylic acid, pKa 3.5) and codeine (a weak base, pKa of conjugate acid 8.2). A patient takes both drugs orally. The stomach has pH 1.5 and the small intestine has pH 7.4. The chemist uses the pH partition hypothesis, which states that the uncharged form of a drug crosses lipid membranes more readily than the charged form. She calculates the ratio of ionised to unionised molecules for each drug in each compartment and predicts where each drug will be absorbed. She then reads that codeine is well absorbed from the small intestine despite being largely ionised there, which appears to contradict her prediction. She must decide whether the hypothesis is wrong or merely incomplete, and what other factors could explain codeine absorption.
1. Calculate the percentage ionisation of aspirin at pH 1.5 and at pH 7.4.
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For a weak acid, use the Henderson-Hasselbalch equation:
pH = pKa + log([A-]/[HA])
At pH 1.5:
1.5 = 3.5 + log([A-]/[HA])
log([A-]/[HA]) = -2.0
[A-]/[HA] = 0.010
Percentage ionised = 0.010/(1 + 0.010) x 100 = 0.99%, approximately 1%.
At pH 7.4:
7.4 = 3.5 + log([A-]/[HA])
log([A-]/[HA]) = 3.9
[A-]/[HA] = 10^3.9 = 7943
Percentage ionised = 7943/(1 + 7943) x 100 = 99.99%, essentially 100%.
Aspirin is almost entirely unionised in the stomach and almost entirely ionised in the blood.
2. Predict and justify the main site of absorption of aspirin and codeine using the pH partition hypothesis.
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Aspirin is a weak acid. In the stomach at pH 1.5 it is about 99% unionised, so it can cross lipid membranes readily and should be absorbed mainly from the stomach, although the small intestine has a much larger surface area. In the intestine at pH 7.4 it is almost entirely ionised and poorly absorbed.
Codeine is a weak base. At stomach pH 1.5 it is essentially fully protonated and ionised, so the hypothesis predicts little absorption there. At intestinal pH 7.4, using pH = pKa + log([B]/[BH+]), log([B]/[BH+]) = 7.4 - 8.2 = -0.8, so [B]/[BH+] = 0.158. The ionised fraction is 1/(1 + 0.158) = 0.863, about 86%. Thus about 14% is unionised in the intestine. That unionised fraction, together with the large intestinal surface area, makes the small intestine the main predicted site of codeine absorption.
3. Evaluate the claim that codeine absorption from the small intestine contradicts the pH partition hypothesis.
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The observation does not show that the pH partition hypothesis is wrong; it shows that it is incomplete. The hypothesis correctly predicts that the unionised form crosses membranes more readily, and codeine does have a small unionised fraction in the intestine. However, absorption depends on more than the fraction unionised. The small intestine has a very large surface area, a long residence time, and good blood flow. Drug transporters can move ionised molecules across membranes, and efflux transporters can remove them. Solubility, formulation, gastric emptying, and the pH microclimate near the membrane also matter. Therefore codeine can be well absorbed despite being largely ionised. The hypothesis is a useful first model, but it cannot predict bioavailability on its own.