Chemistry • Year 12 • Module 8 • Lesson 14
Solubility, Polarity & Drug Delivery
Apply log P data, Lipinski’s Rule of Five and polarity reasoning to real drug-delivery scenarios, including an Australian clinical context.
1. Interpret drug property data
The table below shows selected physicochemical properties for six drugs. Use it to answer the questions that follow. 10 marks
| Drug | MW (Da) | log P | H-bond donors | H-bond acceptors | Water solubility | Common delivery route |
|---|---|---|---|---|---|---|
| Aspirin (acetylsalicylic acid) | 180 | 1.2 | 1 | 4 | Moderate | Oral tablet |
| Ibuprofen | 206 | 3.5 | 1 | 3 | Low–moderate | Oral tablet |
| Fentanyl | 336 | 4.1 | 0 | 3 | Low | Transdermal patch / IV |
| Morphine | 285 | 0.9 | 2 | 4 | Moderate | IV / oral |
| Insulin | 5808 | −1.6 | High (peptide) | High (peptide) | High | Subcutaneous injection |
| Nicotine | 162 | 1.2 | 0 | 2 | High | Transdermal patch |
Data adapted from DrugBank Online (2024) and PubChem (2024). Values are approximate and context-dependent.
1.1 Identify two drugs from the table that satisfy all four Lipinski Rule of Five criteria for good oral bioavailability. Justify each choice with reference to the data. 4 marks
1.2 Explain, using the data in the table, why insulin is not administered orally. Refer to at least two properties from the table in your answer. 3 marks
1.3 Account for why fentanyl and nicotine are both effectively delivered by transdermal patch, using their log P values and the polarity of skin barriers. 3 marks
2. Interpret a log P versus oral bioavailability graph
The graph below shows a stylised relationship between the log P of a drug and its estimated oral bioavailability (%). The data represents a general trend across a large series of drug-like molecules. 8 marks
2.1 Describe the overall trend shown in the graph between log P and oral bioavailability. 2 marks
2.2 Estimate the log P value at which oral bioavailability is highest. Explain, in chemical terms, why bioavailability decreases for drugs with very high log P (> 5). 3 marks
2.3 Using the graph and the lesson data table (Q1), place aspirin (log P = 1.2) and insulin (log P = −1.6) on the graph conceptually. Explain whether the graph is consistent with their known delivery routes. 3 marks
3. Australian case study — transdermal pain management
Read the scenario and answer the questions. 7 marks
Scenario. Australian hospitals and palliative care services make extensive use of fentanyl transdermal patches for sustained pain management. Fentanyl patches are applied to intact skin and replaced every 72 hours, delivering a near-constant low dose into the bloodstream. The TGA (Therapeutic Goods Administration) approves fentanyl patches under strict prescribing guidelines because of the risks associated with respiratory depression at high doses. Fentanyl (log P = 4.1, MW = 336 Da) is significantly more lipophilic than morphine (log P = 0.9, MW = 285 Da).
3.1 Explain, using the polarity and log P data, why fentanyl is more suitable than morphine for transdermal delivery. 3 marks
3.2 Describe one chemical advantage of 72-hour controlled release via a transdermal patch over an equivalent oral dose given every 4–6 hours. 2 marks
3.3 Identify one chemical limitation of the transdermal route for a drug with very low log P (< 0). 2 marks
4. Cause-and-effect chain — oral aspirin prodrug pathway
Aspirin (acetylsalicylic acid) is an ester prodrug of salicylic acid. Complete the chain below by writing the missing mechanism or consequence in each empty box. 5 marks
Overall outcome (So…):
Stuck? Recall from Card 3: ester hydrolysis; aspirin is converted to salicylic acid; the ester form protects the stomach slightly versus pure salicylic acid.Q1.1 — Two drugs satisfying all Rule of Five criteria
Accept any two of: Aspirin (MW 180 < 500; log P 1.2 < 5; 1 donor < 5; 4 acceptors < 10 — all criteria met) and Ibuprofen (MW 206 < 500; log P 3.5 < 5; 1 donor < 5; 3 acceptors < 10 — all criteria met). Morphine and fentanyl also meet all four criteria numerically. 2 marks per drug: 1 for identification, 1 for citing supporting data.
Q1.2 — Why insulin is not given orally
Insulin has MW = 5808 Da, far exceeding the 500 Da Rule of Five limit, so it would have very poor intestinal absorption from size alone. Its log P of −1.6 indicates it is highly hydrophilic and would not readily cross the lipid-rich intestinal membrane. It is also a peptide and would be digested by proteases in the gut before absorption. 1 mark per valid property-based reason (max 3).
Q1.3 — Fentanyl and nicotine via transdermal route
Fentanyl (log P = 4.1) and nicotine (log P = 1.2) are both moderately to highly lipophilic. The outermost layer of skin (stratum corneum) is lipid-rich. To cross it, a drug must partition into this lipid environment. Lipophilic drugs with positive log P values preferentially partition into lipid layers, enabling them to diffuse through the skin barrier into underlying capillaries. A hydrophilic drug (log P < 0) would not partition into the stratum corneum and would be blocked. 1 mark each: log P values cited; link to lipid skin barrier; conclusion that lipophilic character enables skin penetration.
Q2.1 — Trend description
Oral bioavailability increases as log P rises from very negative values, reaches a peak around log P 1–2, then decreases as log P continues to rise above approximately 5. The relationship is an inverted U-shape: both very hydrophilic (log P < 0) and very lipophilic (log P > 5) drugs show low oral bioavailability.
Q2.2 — Peak log P and explanation of high-log P decrease
Peak bioavailability occurs around log P 1–2. Very high log P (> 5) drugs are strongly non-polar and have very low aqueous solubility. For oral absorption the drug must first dissolve in the aqueous gut lumen before crossing the intestinal membrane. If aqueous solubility is extremely low, dissolution becomes the rate-limiting step and little drug reaches the membrane, so bioavailability falls despite excellent lipid-membrane permeability. 1 mark for estimate; 2 marks for chemical explanation (low aqueous solubility limits dissolution in gut; dissolution is prerequisite for absorption).
Q2.3 — Aspirin and insulin on graph
Aspirin (log P = 1.2) falls near the graph’s peak region, consistent with reasonable oral bioavailability — matches its common oral delivery route. Insulin (log P = −1.6) falls on the extreme left at very low predicted bioavailability, consistent with the clinical fact that it must be injected rather than swallowed. The graph is therefore consistent with both routes. 1 mark per drug placement + reasoning (max 2); 1 mark for overall consistency statement.
Q3.1 — Fentanyl vs morphine for transdermal delivery
Fentanyl (log P = 4.1) is markedly more lipophilic than morphine (log P = 0.9). The stratum corneum is a lipid-rich barrier. A drug must dissolve into this layer to penetrate skin. Fentanyl’s higher log P means it partitions readily into the lipid stratum corneum and diffuses through into the dermis. Morphine’s lower log P means it has much weaker affinity for the lipid skin barrier and would penetrate skin very poorly. 1 mark each: log P values compared; link to lipid stratum corneum; conclusion that fentanyl penetrates and morphine does not.
Q3.2 — Chemical advantage of 72-hour patch over 4–6 hourly oral dosing
A transdermal patch provides a near-constant low rate of drug delivery from a reservoir, maintaining a stable plasma concentration within the therapeutic window over 72 hours. Oral doses given every 4–6 hours produce a repeated cycle of rising (peak) and falling (trough) plasma concentrations; peaks may enter the toxic range while troughs fall below therapeutic levels. The controlled release avoids these peaks and troughs.
Q3.3 — Limitation of transdermal route for low log P drug
A drug with very low log P (e.g. < 0) is strongly hydrophilic and has low affinity for the lipid stratum corneum. It would not partition into the skin’s lipid barrier and therefore could not diffuse through to the dermis. The transdermal route is essentially blocked for such drugs because they cannot cross the rate-limiting lipid layer of the skin. 1 mark for identifying low log P; 1 mark for linking to failure to partition into lipid skin barrier.
Q4 — Cause-and-effect chain
Box 2 (mechanism): Ester bonds in aspirin are hydrolysed by esterases in plasma and gut wall (and in the liver during first-pass metabolism), releasing acetic acid and salicylate ions.
Box 3 (active compound): Salicylic acid (salicylate) is released as the pharmacologically active form that inhibits COX enzymes.
Box 4 (stomach lining): The ester prodrug form of aspirin is less irritating to the stomach mucosa than pure salicylic acid; however, the acetic acid released on hydrolysis can still cause some irritation, and aspirin inhibits prostaglandin synthesis which normally protects the stomach lining.
Overall outcome: The prodrug form improves drug stability and delivery while the active salicylate produced in vivo achieves the therapeutic effect.