Understanding the solubility profile of drugs—how pKa, pH, and partition coefficient influence solubility and permeability—is essential for B. Pharm students. This introduction covers key concepts like ionization, Henderson-Hasselbalch relationships, log P and log D (lipophilicity), pH-dependent solubility curves, salt formation, and formulation strategies to enhance bioavailability. You will learn experimental methods (shake‑flask, potentiometric titration) and how pH and partitioning affect absorption, distribution, and formulation decisions. Mastery of these terms helps predict drug behavior in vivo and guide development choices. Now let’s test your knowledge with 30 MCQs on this topic.
Q1. What does the pKa of a drug molecule represent?
- The pH at which the drug is completely ionized
- The pH at which the concentrations of the protonated and deprotonated forms are equal
- The octanol‑water partition coefficient
- The pH of maximum solubility
Correct Answer: The pH at which the concentrations of the protonated and deprotonated forms are equal
Q2. According to the Henderson‑Hasselbalch equation, which factor primarily determines percent ionization of a weak acid?
- Absolute solubility in water
- Difference between solution pH and the acid’s pKa
- Octanol solubility
- Molecular weight of the acid
Correct Answer: Difference between solution pH and the acid’s pKa
Q3. What does log P measure?
- The logarithm of aqueous solubility at pH 7.4
- The ratio of concentrations of unionized drug between octanol and water
- The pKa of a drug
- The diffusion coefficient across a membrane
Correct Answer: The ratio of concentrations of unionized drug between octanol and water
Q4. How does ionization generally affect aqueous solubility of a drug?
- Ionization usually decreases aqueous solubility
- Ionization usually increases aqueous solubility for polar ionic species
- Ionization has no effect on solubility
- Ionization only affects solid state properties
Correct Answer: Ionization usually increases aqueous solubility for polar ionic species
Q5. Which term describes pH‑dependent lipophilicity (partitioning of all species at a given pH)?
- log P
- log D
- pKa
- pKb
Correct Answer: log D
Q6. For a weak base with pKa 8.0, at pH 6.0 what is the predominant form?
- Predominantly unionized base
- Predominantly ionized (protonated) base
- Equal ionized and unionized
- Cannot determine without log P
Correct Answer: Predominantly ionized (protonated) base
Q7. The pH‑partition hypothesis predicts drug absorption is greatest when:
- The drug is highly ionized in the gastrointestinal lumen
- The drug is mainly unionized in the absorbing membrane and lumen
- The drug has highest log P regardless of ionization
- The drug is formulated as a salt
Correct Answer: The drug is mainly unionized in the absorbing membrane and lumen
Q8. Which experimental method is commonly used to measure log P by direct partitioning?
- Potentiometric titration
- Shake‑flask (octanol–water) method
- Mass spectrometry only
- HPLC retention time without calibration
Correct Answer: Shake‑flask (octanol–water) method
Q9. When forming a salt to improve solubility, which statement is true?
- Salt formation always reduces intrinsic dissolution rate
- Salt formation can increase aqueous solubility and dissolution rate
- Salts are only used for weak acids, not bases
- Salt formation has no impact on pKa
Correct Answer: Salt formation can increase aqueous solubility and dissolution rate
Q10. Which property does log D at pH 7.4 best reflect?
- Intrinsic solubility of the unionized form
- Apparent lipophilicity of the drug mixture (ionized + unionized) at physiological pH
- The melting point of the compound
- The drug’s chemical stability in acid
Correct Answer: Apparent lipophilicity of the drug mixture (ionized + unionized) at physiological pH
Q11. How does increasing lipophilicity (higher log P) generally affect membrane permeability?
- Permeability generally decreases indefinitely with log P
- Permeability generally increases up to a point, then may decline due to poor aqueous solubility
- Permeability is independent of lipophilicity
- Permeability is solely determined by pKa
Correct Answer: Permeability generally increases up to a point, then may decline due to poor aqueous solubility
Q12. Which drug type is most likely to show a U‑shaped pH‑solubility profile (higher solubility at both low and high pH)?
- Neutral nonionizable compound
- Zwitterionic ampholyte
- Strong monoprotic acid
- Hydrophobic neutral base
Correct Answer: Zwitterionic ampholyte
Q13. Which equation is used to calculate percent ionization of a weak base?
- Percent ionization = 100 / (1 + 10^(pH – pKa))
- Percent ionization = 100 × 10^(pH – pKa)
- Percent ionization = 100 / (1 + 10^(pKa – pH))
- Percent ionization = (pKa × pH) / 100
Correct Answer: Percent ionization = 100 / (1 + 10^(pH – pKa))
Q14. Which of the following decreases apparent partitioning into octanol for an ionizable drug at a given pH?
- High fraction of unionized species
- High fraction of ionized species
- Low aqueous solubility of the unionized form
- Presence of a nonpolar substituent
Correct Answer: High fraction of ionized species
Q15. Potentiometric titration for pKa determination relies primarily on measuring:
- Change in absorbance with pH
- Spectral shift in NMR signals
- pH change as titrant is added and buffering capacity
- Octanol‑water partitioning at various pH
Correct Answer: pH change as titrant is added and buffering capacity
Q16. For a weak acid with pKa 4.5, which formulation pH will maximize its solubility in aqueous solution?
- pH 2.0
- pH 4.5
- pH 7.0
- pH 1.0
Correct Answer: pH 7.0
Q17. Which phenomenon explains why cosolvents (e.g., ethanol) increase apparent solubility of hydrophobic drugs?
- Increase in pKa value
- Decrease in solvent polarity and improved solvation of the unionized form
- Formation of covalent adducts with the drug
- Ion pairing with counterions
Correct Answer: Decrease in solvent polarity and improved solvation of the unionized form
Q18. What is ion pairing and how can it affect solubility/partitioning?
- Noncovalent association of ionized drug with counterion that can increase lipophilicity and membrane permeation
- Formation of a covalent salt that reduces solubility
- Biotransformation in the liver forming metabolites
- Proton transfer to buffer without affecting partitioning
Correct Answer: Noncovalent association of ionized drug with counterion that can increase lipophilicity and membrane permeation
Q19. The intrinsic solubility (S0) of a drug refers to:
- Solubility of the drug’s most soluble salt form
- Solubility of the unionized pure drug in water
- Solubility in octanol
- Solubility in simulated gastric fluid only
Correct Answer: Solubility of the unionized pure drug in water
Q20. Which factor is NOT directly influenced by drug pKa?
- Fraction ionized at a given pH
- Aqueous solubility at different pH
- Intrinsic melting point of the drug crystal
- Choice of salt form for formulation
Correct Answer: Intrinsic melting point of the drug crystal
Q21. A drug has log P = 4.5 and log D at pH 7.4 = 1.0. What does this indicate?
- Drug is entirely unionized at pH 7.4
- Drug is more ionized at pH 7.4, reducing apparent lipophilicity
- Log D must equal log P for all pH values
- Drug is insoluble in both phases
Correct Answer: Drug is more ionized at pH 7.4, reducing apparent lipophilicity
Q22. In pH‑solubility profiling, which plot best shows the relationship between solubility and pH?
- Solubility (y‑axis) vs. pH (x‑axis) curve
- Log P vs. molecular weight
- Melting point vs. pKa
- Percent ionization vs. temperature
Correct Answer: Solubility (y‑axis) vs. pH (x‑axis) curve
Q23. Which of the following improves oral absorption of a weakly basic drug that precipitates in the intestine?
- Raising intestinal pH further
- Using enteric coatings that release drug in stomach only
- Formulating as a salt or using solubilizing excipients to prevent precipitation
- Decreasing gastric residence time
Correct Answer: Formulating as a salt or using solubilizing excipients to prevent precipitation
Q24. Which descriptor is most useful when comparing lipophilicity of two neutral molecules?
- log D at pH 1
- log P
- pKa
- Percent ionization at pH 7.4
Correct Answer: log P
Q25. When a weak acid drug is placed into a buffer 3 pH units above its pKa, what fraction is ionized approximately?
- About 0.1% ionized
- About 50% ionized
- About 99.9% ionized
- About 10% ionized
Correct Answer: About 99.9% ionized
Q26. Which statement about ampholytes (molecules with both acidic and basic groups) is correct?
- They have a single pKa only
- They may exhibit zwitterionic forms and complex pH‑solubility behavior
- They are always highly lipophilic
- They cannot form salts
Correct Answer: They may exhibit zwitterionic forms and complex pH‑solubility behavior
Q27. Why is knowledge of pKa important for preformulation scientists?
- To predict color changes in solution
- To decide pH adjustment, salt selection, and anticipate solubility/permeability tradeoffs
- To determine molecular weight only
- It is not relevant at preformulation stage
Correct Answer: To decide pH adjustment, salt selection, and anticipate solubility/permeability tradeoffs
Q28. Which of the following will NOT shift the apparent pKa of a drug significantly?
- Changing solvent composition (adding cosolvent)
- High ionic strength or specific ion binding
- Changing temperature moderately (a few degrees)
- Forming a tightly bound covalent derivative
Correct Answer: Changing temperature moderately (a few degrees)
Q29. In the shake‑flask method, which precaution improves accuracy of measured log P?
- Using very low drug concentrations below detection limits
- Ensuring equilibrium is reached and avoiding emulsion formation
- Mixing vigorously to form stable emulsions
- Measuring only the octanol phase without analyzing aqueous phase
Correct Answer: Ensuring equilibrium is reached and avoiding emulsion formation
Q30. Which concept links pKa, solubility, and oral bioavailability most directly?
- BCS classification and pH‑dependent solubility/permeability balance
- Melting point depression
- Colorimetric assay design
- Manufacturing scale‑up processes only
Correct Answer: BCS classification and pH‑dependent solubility/permeability balance
I am a Registered Pharmacist under the Pharmacy Act, 1948, and the founder of PharmacyFreak.com. I hold a Bachelor of Pharmacy degree from Rungta College of Pharmaceutical Science and Research. With a strong academic foundation and practical knowledge, I am committed to providing accurate, easy-to-understand content to support pharmacy students and professionals. My aim is to make complex pharmaceutical concepts accessible and useful for real-world application.
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