Experimental methods for solubility determination MCQs With Answer

Introduction: Experimental methods for solubility determination are fundamental for M.Pharm students involved in formulation development, quality control, and biopharmaceutical assessment. This blog presents concise, practice-oriented multiple-choice questions that cover equilibrium (shake‑flask) and kinetic solubility, analytical separation techniques (filtration, centrifugation, ultrafiltration), instrumental assays (UV, HPLC, nephelometry, potentiometric titration), and practical issues such as pH‑dependent solubility, polymorphism, cosolvent extrapolation and biorelevant media. Understanding these methods helps predict in vivo behavior, optimize dissolution, and avoid common artifacts. Each MCQ focuses on experimental design, data interpretation, and limitations so you build a solid, application‑driven grasp of solubility testing for drug substances and formulations.

Q1. What is the classical “shake‑flask” method primarily used to determine in solubility studies?

• Equilibrium (thermodynamic) solubility determined by equilibrating excess solid with solvent
• Instantaneous kinetic solubility measured during rapid dissolution
• Partition coefficient between octanol and water
• Turbidity‑based precipitation onset

Correct Answer: Equilibrium (thermodynamic) solubility determined by equilibrating excess solid with solvent

Q2. Which statement best describes “kinetic solubility”?

• The solubility measured after weeks when true equilibrium is reached
• The highest concentration observed before the first visible precipitation when a compound is diluted from DMSO
• Solubility measured using potentiometric titration only
• The solubility measured in biorelevant media at 37°C

Correct Answer: The highest concentration observed before the first visible precipitation when a compound is diluted from DMSO

Q3. Which separation technique is preferred to rapidly separate dissolved drug from undissolved particles while minimally disturbing equilibrium?

• Gravity filtration through glass fiber
• Ultrafiltration using centrifugal filter devices
• Simple decantation
• Shake‑flask without any separation

Correct Answer: Ultrafiltration using centrifugal filter devices

Q4. Potentiometric solubility titration relies primarily on measuring which parameter?

• Changes in solution turbidity as titrant is added
• Change in pH during acid/base titration to determine solubility and apparent pKa
• Electrical conductivity of the saturated solution
• UV absorbance at a fixed wavelength

Correct Answer: Change in pH during acid/base titration to determine solubility and apparent pKa

Q5. How does polymorphism influence measured solubility of a drug substance?

• All polymorphs have identical solubilities regardless of lattice energy
• Polymorphs with higher lattice energy are generally more soluble
• Different polymorphs exhibit different solubilities because lattice energy and crystal packing affect dissolution
• Polymorphism only affects melting point, not solubility

Correct Answer: Different polymorphs exhibit different solubilities because lattice energy and crystal packing affect dissolution

Q6. Which plot is commonly used with Van’t Hoff analysis to assess temperature dependence of solubility?

• Log S versus pH
• ln(solubility) versus 1/T (inverse temperature)
• Solubility versus agitation speed
• Absorbance versus concentration

Correct Answer: ln(solubility) versus 1/T (inverse temperature)

Q7. How is equilibrium time for a solubility experiment typically determined?

• By choosing an arbitrary overnight period without verification
• When measured concentration remains constant across several sequential time points
• By the first time point where any dissolved drug is detected
• When the suspension turns completely clear

Correct Answer: When measured concentration remains constant across several sequential time points

Q8. Why is HPLC often preferred over direct UV spectroscopy for quantifying dissolved drug in solubility assays?

• HPLC is faster and requires no method development
• HPLC provides chromatographic separation, avoiding interference from co‑solvents, degradation products or excipients
• UV spectroscopy cannot detect organic molecules
• HPLC eliminates the need for calibration curves

Correct Answer: HPLC provides chromatographic separation, avoiding interference from co‑solvents, degradation products or excipients

Q9. What is the main purpose of using biorelevant media (e.g., FaSSIF, FeSSIF) in solubility testing?

• To increase analytical sensitivity of UV detection
• To mimic fasted and fed intestinal conditions and better predict in vivo solubility/dissolution
• To sterilize samples prior to HPLC
• To measure solubility at extreme pH values only

Correct Answer: To mimic fasted and fed intestinal conditions and better predict in vivo solubility/dissolution

Q10. What is meant by “sink conditions” in the context of solubility and dissolution testing?

• Conditions where the dissolution vessel temperature is below 0°C
• A volume and medium choice that keeps dissolved concentration well below saturation (commonly <10–30% of saturation) to prevent back‑pressure on dissolution
• A method ensuring complete precipitation before sampling
• Using surfactants to make the solution cloudy

Correct Answer: A volume and medium choice that keeps dissolved concentration well below saturation (commonly <10–30% of saturation) to prevent back‑pressure on dissolution

Q11. Which technique is commonly used to monitor early precipitation and supersaturation decay in solubility studies?

• Nuclear magnetic resonance imaging of solid particles
• Turbidity or nephelometry combined with HPLC quantification
• Thermogravimetric analysis of the liquid phase
• Conductivity measurement alone

Correct Answer: Turbidity or nephelometry combined with HPLC quantification

Q12. How is the cosolvent method used to estimate aqueous solubility of poorly soluble drugs?

• By measuring solubility in various organic solvents and taking a simple average
• By increasing solubility with cosolvent mixtures and extrapolating to 0% cosolvent using log‑linear (Yalkowsky) relationships
• By dissolving the drug in pure DMSO and assuming identical aqueous behavior
• By measuring only in ethanol and reporting that value as aqueous solubility

Correct Answer: By increasing solubility with cosolvent mixtures and extrapolating to 0% cosolvent using log‑linear (Yalkowsky) relationships

Q13. Which method is standard for measuring the intrinsic dissolution rate (IDR) of a crystalline drug solid?

• Shake‑flask with excess powder
• Rotating disk (constant surface area) method
• Potentiometric titration without stirring
• Static incubation in closed vials at ambient conditions

Correct Answer: Rotating disk (constant surface area) method

Q14. What common artifact can occur when using syringe filters to separate undissolved drug prior to analysis?

• Filters never remove particles smaller than 1 µm
• Significant adsorption of drug to the filter material leading to underestimation of solubility
• Filters increase measured solubility by dissolving drug
• Filters change the pH of the filtrate

Correct Answer: Significant adsorption of drug to the filter material leading to underestimation of solubility

Q15. How do thermodynamic solubility and kinetic solubility fundamentally differ?

• They are identical if measured at room temperature
• Thermodynamic solubility is the equilibrium (true) solubility of the most stable solid form; kinetic solubility is a transient value measured before equilibrium or during rapid dilution
• Kinetic solubility always gives higher values than thermodynamic for any compound
• Thermodynamic solubility is measured only in buffers

Correct Answer: Thermodynamic solubility is the equilibrium (true) solubility of the most stable solid form; kinetic solubility is a transient value measured before equilibrium or during rapid dilution

Q16. What is a main advantage of dialysis‑based separation for solubility or partitioning studies?

• It provides instantaneous separation in seconds
• It separates free and bound drug without rapidly disturbing the equilibrium and allows continuous sampling of the donor/receiver compartments
• Dialysis membranes chemically react with the drug improving solubility
• Dialysis eliminates the need to control temperature

Correct Answer: It separates free and bound drug without rapidly disturbing the equilibrium and allows continuous sampling of the donor/receiver compartments

Q17. How does reducing particle size to the nanometer range affect apparent solubility?

• Particle size reduction has no effect on solubility, only on taste
• Very small particles can show increased apparent solubility due to higher surface free energy, as predicted by the Ostwald‑Freundlich relationship
• Smaller particles always decrease solubility due to aggregation
• Nanoparticles convert any compound into an amorphous form with identical solubility

Correct Answer: Very small particles can show increased apparent solubility due to higher surface free energy, as predicted by the Ostwald‑Freundlich relationship

Q18. Which of the following is NOT typically required to be reported in a formal solubility study report?

• Temperature and equilibration time used
• pH of the medium and analytical method validation
• Solid form/characterization (e.g., polymorph, amorphous content)
• Color description of the drug powder without relation to analysis

Correct Answer: Color description of the drug powder without relation to analysis

Q19. For an ionizable drug, what experimental approach best determines how solubility changes with pH?

• Measure solubility at pH 7 only
• Construct a pH‑solubility profile by measuring solubility across a range of pH values and relate to pKa
• Use only organic cosolvents and ignore pH effects
• Estimate pH effect from melting point alone

Correct Answer: Construct a pH‑solubility profile by measuring solubility across a range of pH values and relate to pKa

Q20. What is a frequent experimental mistake that leads to inaccurate solubility values?

• Ensuring multiple timepoint sampling until equilibrium
• Using insufficient equilibration time and reporting a single early timepoint as “solubility”
• Validating the analytical method with standards
• Recording temperature and pH for each sample

Correct Answer: Using insufficient equilibration time and reporting a single early timepoint as “solubility”

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