Factors influencing solubility of drugs – quantitative approach MCQs With Answer

Introduction: Understanding the factors influencing solubility of drugs is essential for B.Pharm students studying drug formulation, bioavailability and pharmacokinetics. This quantitative approach covers key concepts such as intrinsic solubility, pKa and the Henderson–Hasselbalch relationship, partition coefficient (log P/log D), temperature effects, salt formation, co‑solvents, surfactants, crystal form and particle size. Practical measurement methods, solubility curves and predictive models (Yalkowsky, van’t Hoff) help quantify solubility changes and optimize drug delivery. Clear grasp of these variables enables rational selection of formulation strategies to enhance dissolution and absorption. Now let’s test your knowledge with 50 MCQs on this topic.

Q1. Which equation quantitatively relates the degree of ionization to pH and pKa for a weak acid?

• Henderson–Hasselbalch equation
• van’t Hoff equation
• Noyes–Whitney equation
• Arrhenius equation

Correct Answer: Henderson–Hasselbalch equation

Q2. Intrinsic solubility (S0) of a drug is defined as:

• The solubility of the ionized form at any pH
• The solubility of the unionized form in pure water
• The solubility in presence of surfactant
• The solubility at elevated temperature

Correct Answer: The solubility of the unionized form in pure water

Q3. For a weak base with pKa = 8.0, at pH 6.0 the fraction ionized is approximately:

• 1% ionized
• 9% ionized
• 99% ionized
• 50% ionized

Correct Answer: 99% ionized

Q4. Which factor most directly affects a drug’s lipophilicity and membrane permeation?

• Particle size
• Log P (partition coefficient)
• Salt form
• Buffer capacity

Correct Answer: Log P (partition coefficient)

Q5. The van’t Hoff equation is used to estimate which solubility-related parameter?

• Effect of pH on ionization
• Temperature dependence of solubility (enthalpy of solution)
• Effect of particle size on dissolution rate
• Micellar solubilization capacity

Correct Answer: Temperature dependence of solubility (enthalpy of solution)

Q6. Yalkowsky’s log-linear model predicts solubility change due to:

• pH variation
• Co‑solvent concentration
• Particle size reduction
• Salt formation

Correct Answer: Co‑solvent concentration

Q7. Increasing temperature typically affects solubility of most solids by:

• Decreasing solubility for all drugs
• Increasing solubility if dissolution is endothermic
• No change in solubility
• Always causing precipitation

Correct Answer: Increasing solubility if dissolution is endothermic

Q8. Which solid-state property can significantly decrease aqueous solubility?

• Amorphous form
• Hydrate formation
• High crystal lattice energy (stable polymorph)
• Micronization

Correct Answer: High crystal lattice energy (stable polymorph)

Q9. Noyes–Whitney equation describes the effect of which factor on dissolution rate?

• Ionization constant
• Surface area and saturation solubility
• Log P alone
• Buffer ionic strength only

Correct Answer: Surface area and saturation solubility

Q10. Salt formation is commonly used to improve drug solubility because:

• It always increases lipophilicity
• It converts a poorly soluble neutral drug into a more soluble ionic form
• It reduces dissolution rate
• It prevents ionization

Correct Answer: It converts a poorly soluble neutral drug into a more soluble ionic form

Q11. Which phenomenon describes decreased solubility when a common ion is present?

• Salting in
• Common-ion effect
• Micellar solubilization
• Co‑solvency

Correct Answer: Common-ion effect

Q12. Log D differs from log P because log D:

• Measures intrinsic solubility only
• Accounts for pH-dependent ionization
• Is temperature-dependent only
• Is always equal to log P

Correct Answer: Accounts for pH-dependent ionization

Q13. Which experimental method quantifies drug solubility by separating undissolved drug and analyzing supernatant?

• Microscopy
• Equilibrium solubility method (shake‑flask)
• DSC thermal analysis
• IR spectroscopy without separation

Correct Answer: Equilibrium solubility method (shake‑flask)

Q14. For a weak acid, increasing the pH above its pKa will generally:

• Decrease solubility
• Increase solubility due to ionization
• Have no effect
• Cause precipitation of the ionized form

Correct Answer: Increase solubility due to ionization

Q15. Which additive increases solubility by forming inclusion complexes with hydrophobic drugs?

• Cyclodextrins
• Sodium chloride
• Hydroxyapatite
• Graphite

Correct Answer: Cyclodextrins

Q16. The solubility parameter most useful for predicting drug–solvent miscibility is:

• pKa
• Hildebrand or Hansen solubility parameters
• Noyes–Whitney constant
• Melting point only

Correct Answer: Hildebrand or Hansen solubility parameters

Q17. Which effect describes increased solubility of a nonpolar drug in presence of salts at moderate ionic strength?

• Salting out
• Salting in
• Common-ion effect
• Buffering effect

Correct Answer: Salting in

Q18. Which quantity represents molar solubility?

• mg/mL
• mol/L
• log P units
• pKa units

Correct Answer: mol/L

Q19. Supersaturation is important in oral delivery because:

• It reduces absorption
• It provides transiently higher concentration driving absorption
• It stabilizes solid drug forms indefinitely
• It prevents permeation across membranes

Correct Answer: It provides transiently higher concentration driving absorption

Q20. Which approach quantitatively models pH-dependent solubility curves of ionizable drugs?

• Henderson–Hasselbalch applied to solubility (pH‑solubility profile)
• Noyes–Whitney dissolution only
• Arrhenius temperature model
• Partition coefficient alone

Correct Answer: Henderson–Hasselbalch applied to solubility (pH‑solubility profile)

Q21. A drug has intrinsic solubility S0 = 0.001 M and is a weak acid with pKa 5. If pH = 7, the total solubility (approx.) will be:

• 0.001 M
• 0.1 M
• 0.01 M
• 0.0001 M

Correct Answer: 0.01 M

Q22. Particle size reduction increases apparent solubility mainly by:

• Changing pKa
• Increasing surface energy and saturation solubility (Ostwald–Freundlich)
• Decreasing dissolution rate
• Converting to ionized form

Correct Answer: Increasing surface energy and saturation solubility (Ostwald–Freundlich)

Q23. Which analytical technique can be used to determine the solid form and explain solubility differences between polymorphs?

• X-ray powder diffraction (XRPD)
• UV–Vis without solid analysis
• pH meter
• Gravimetric balance only

Correct Answer: X-ray powder diffraction (XRPD)

Q24. Micellar solubilization is most relevant for which class of additives?

• Buffers
• Surfactants (e.g., SDS, Tween 80)
• Organic acids
• Salts of weak acids

Correct Answer: Surfactants (e.g., SDS, Tween 80)

Q25. PKa of a drug influences pHmax. pHmax is defined as:

• pH where intrinsic solubility is maximal
• pH at which solubility of drug and its salt are equal
• pH of maximum buffer capacity
• pH where drug is completely nonpolar

Correct Answer: pH at which solubility of drug and its salt are equal

Q26. Which is a quantitative descriptor of hydrophilicity used in QSAR and solubility prediction?

• pKa only
• Log P and polar surface area (PSA)
• Melting point only
• Particle size alone

Correct Answer: Log P and polar surface area (PSA)

Q27. The term “salting out” refers to:

• Increased solubility of a drug by salt addition
• Reduced solubility of nonionic or weakly polar solutes due to salt addition
• Complexation with cyclodextrin
• Micelle formation enhancing solubility

Correct Answer: Reduced solubility of nonionic or weakly polar solutes due to salt addition

Q28. Which parameter is directly measured in shake‑flask solubility experiments?

• Log P in octanol/water
• Equilibrium concentration of drug in aqueous phase
• Surface area of particles
• Melting point depression

Correct Answer: Equilibrium concentration of drug in aqueous phase

Q29. Complexation with EDTA would most likely improve solubility of a drug by:

• Forming inclusion complexes
• Chelating metal ions to prevent drug–metal interactions
• Increasing pKa of the drug
• Decreasing temperature sensitivity

Correct Answer: Chelating metal ions to prevent drug–metal interactions

Q30. Which of the following increases dissolution rate but not intrinsic solubility?

• Changing polymorph to a more soluble form
• Adding cyclodextrin to complex the drug
• Micronization (particle size reduction)
• Salt formation to increase S0

Correct Answer: Micronization (particle size reduction)

Q31. A drug with very high log P (e.g., >5) typically shows:

• High aqueous solubility
• Poor aqueous solubility and high membrane permeability
• pH-dependent solubility only
• No relevance to solubility

Correct Answer: Poor aqueous solubility and high membrane permeability

Q32. The Henderson–Hasselbalch form used for solubility predicts total solubility of a weak base as S = S0(1 + 10^(pKa-pH)). This implies at pH much lower than pKa, solubility will be:

• Approximately S0
• Much greater than S0
• Zero
• Independent of pH

Correct Answer: Much greater than S0

Q33. Which is NOT a common strategy to enhance aqueous solubility of poorly soluble drugs?

• Salt formation
• Particle size reduction
• Use of hydrophobic excipients only
• Use of co‑solvents or surfactants

Correct Answer: Use of hydrophobic excipients only

Q34. The Ostwald solubility concept explains that smaller particles have higher solubility due to:

• Lower surface energy
• Higher vapor pressure only
• Increased surface curvature raising chemical potential
• Change in pKa

Correct Answer: Increased surface curvature raising chemical potential

Q35. Which term describes the maximum solute concentration that can exist in solution at equilibrium with solid phase?

• Intrinsic solubility only
• Saturation solubility
• Partition coefficient
• Buffer capacity

Correct Answer: Saturation solubility

Q36. In pH-solubility profiling, the steep portion of the curve around pKa indicates:

• Buffering capacity changes
• Rapid change in ionization and solubility with pH
• Thermal degradation
• Ionic strength independence

Correct Answer: Rapid change in ionization and solubility with pH

Q37. Which effect would be most likely if a crystalline drug is converted to an amorphous form?

• Decrease in apparent solubility
• Increase in apparent solubility and dissolution rate
• No change in solubility
• Immediate chemical degradation only

Correct Answer: Increase in apparent solubility and dissolution rate

Q38. Which is the best descriptor for extent of ionization of a weak acid at given pH?

• Degree of ionization calculated from Henderson–Hasselbalch
• Log P value
• Melting point
• Noyes–Whitney constant

Correct Answer: Degree of ionization calculated from Henderson–Hasselbalch

Q39. For a salt with low Ksp, the solubility can be predicted using:

• Henderson–Hasselbalch equation
• Solubility product (Ksp) expressions
• Log P correlations only
• Yalkowsky model only

Correct Answer: Solubility product (Ksp) expressions

Q40. Which parameter describes the free energy change associated with transferring a solute from water to octanol?

• pKa
• ΔG (related to log P)
• S0 only
• Melting enthalpy only

Correct Answer: ΔG (related to log P)

Q41. Which experimental observation would indicate micellar solubilization of a drug?

• Solubility increases sharply above critical micelle concentration (CMC)
• Solubility decreases with surfactant concentration
• pKa shifts dramatically
• No change with surfactant

Correct Answer: Solubility increases sharply above critical micelle concentration (CMC)

Q42. The term “pH-shift approach” in formulation refers to:

• Adjusting pH during processing to maintain stability and solubility
• Changing ambient pH in the stomach
• Altering drug chemical structure
• Using only organic solvents

Correct Answer: Adjusting pH during processing to maintain stability and solubility

Q43. Which is a quantitative consequence of polymorphism on solubility?

• Polymorphs have identical solubility
• More stable (lower energy) polymorphs generally have lower solubility
• Polymorphism affects only color
• Polymorphism affects only melting point but not solubility

Correct Answer: More stable (lower energy) polymorphs generally have lower solubility

Q44. The role of ionic strength in solubility studies is to:

• Never affect solubility
• Modify activity coefficients and thus apparent solubility
• Change drug pKa permanently
• Only affect solid-state properties

Correct Answer: Modify activity coefficients and thus apparent solubility

Q45. Which formulation strategy uses a hydrophilic polymer to maintain supersaturation and inhibit precipitation?

• Use of hydrophobic oils
• Amorphous solid dispersions with polymers (e.g., PVP, HPMC)
• Adding common ion salts
• Increasing particle size

Correct Answer: Amorphous solid dispersions with polymers (e.g., PVP, HPMC)

Q46. Log S (logarithm of solubility) is often used in modeling because:

• It linearizes many relationships and spans wide solubility ranges
• It removes units from solubility
• It is equivalent to pKa
• It eliminates temperature dependence

Correct Answer: It linearizes many relationships and spans wide solubility ranges

Q47. Which descriptor helps predict oral absorption combining solubility and permeability?

• Biopharmaceutics Classification System (BCS)
• Melting point alone
• pKa only
• Surface tension only

Correct Answer: Biopharmaceutics Classification System (BCS)

Q48. Which of the following will most likely lower the solubility of a weak base in aqueous solution?

• Increasing pH above pKa
• Decreasing pH well below pKa
• Adding cyclodextrin
• Using a co‑solvent

Correct Answer: Increasing pH above pKa

Q49. Which mathematical relationship relates dissolution rate to concentration gradient across diffusion layer?

• Henderson–Hasselbalch equation
• Noyes–Whitney equation
• van’t Hoff equation
• Hildebrand equation

Correct Answer: Noyes–Whitney equation

Q50. For a drug prone to precipitation after dilution, which strategy helps maintain solubility in vivo?

• Formulating as an amorphous solid without stabilizer
• Using precipitation inhibitors and hydrophilic polymers to sustain supersaturation
• Increasing drug load without excipients
• Avoiding any surfactant or polymer

Correct Answer: Using precipitation inhibitors and hydrophilic polymers to sustain supersaturation

G S Sachin

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.

Mail- Sachin@pharmacyfreak.com