Polymorphism in drug substances MCQs With Answer

Polymorphism in drug substances MCQs With Answer

Polymorphism in drug substances refers to the ability of a single pharmaceutical compound to exist in multiple crystalline forms, each with distinct physical properties. Understanding polymorphism is vital for B. Pharm students because different polymorphs can alter solubility, dissolution rate, stability, melting point, and bioavailability, affecting formulation and performance. Key concepts include stable versus metastable forms, enantiotropic and monotropic relationships, characterization techniques (PXRD, DSC, TGA, IR, SSNMR, single‑crystal XRD), screening and control strategies, and regulatory/patent implications. This collection of targeted MCQs will deepen your grasp of polymorphic behavior and its practical impact on drug development. Now let’s test your knowledge with 30 MCQs on this topic.

Q1. What is the definition of polymorphism in drug substances?

• The formation of co-crystals with other molecules
• Different crystalline forms of the same chemical substance
• Two or more chemical compounds with the same formula
• A change from crystalline to amorphous state

Correct Answer: Different crystalline forms of the same chemical substance

Q2. Which analytical technique is most definitive for determining crystal structure of a polymorph?

• Differential scanning calorimetry (DSC)
• Fourier-transform infrared spectroscopy (FTIR)
• Single-crystal X-ray diffraction
• Thermogravimetric analysis (TGA)

Correct Answer: Single-crystal X-ray diffraction

Q3. Which thermal technique measures heat flow associated with polymorphic transitions and melting?

• Polarized light microscopy
• Differential scanning calorimetry (DSC)
• Powder X-ray diffraction (PXRD)
• Raman spectroscopy

Correct Answer: Differential scanning calorimetry (DSC)

Q4. In an enantiotropic polymorphic system, what is true?

• One form irreversibly converts to another at all temperatures
• Polymorphs have identical melting points
• Polymorph stability reverses at a specific transition temperature
• Metastable form is always less soluble than stable form

Correct Answer: Polymorph stability reverses at a specific transition temperature

Q5. Ostwald’s rule of stages predicts that during crystallization the form that appears first is:

• The most thermodynamically stable
• The least soluble
• The least stable (metastable)
• Always the hydrate form

Correct Answer: The least stable (metastable)

Q6. Which method is primarily used to identify polymorphs by their unique diffraction patterns?

• NMR spectroscopy
• Powder X-ray diffraction (PXRD)
• Mass spectrometry
• UV-visible spectroscopy

Correct Answer: Powder X-ray diffraction (PXRD)

Q7. Which property is most directly influenced by a drug’s polymorphic form?

• Molecular weight
• Chemical structure
• Solubility and dissolution rate
• Theoretical yield of synthesis

Correct Answer: Solubility and dissolution rate

Q8. What does DSC typically show for a polymorphic transition from metastable to stable form?

• A single endotherm equal to melting point only
• An exotherm followed by an endotherm
• No thermal signal
• A continuous baseline shift without peaks

Correct Answer: An exotherm followed by an endotherm

Q9. Which statement best describes monotropic polymorphic systems?

• Polymorphs can reversibly interconvert at a transition temperature
• One form is stable over all temperatures and the other is metastable
• Both forms have identical free energy at a given temperature
• They only occur in chiral compounds

Correct Answer: One form is stable over all temperatures and the other is metastable

Q10. Which technique provides information on molecular conformation and intermolecular interactions in different polymorphs?

• Thermogravimetric analysis (TGA)
• Infrared (IR) and Raman spectroscopy
• Chromatography
• Elemental analysis

Correct Answer: Infrared (IR) and Raman spectroscopy

Q11. Which approach is commonly used in polymorph screening during early drug development?

• Single solvent recrystallization only
• High-throughput crystallization from multiple solvents and conditions
• Only computational prediction without experiments
• Direct compression of API without characterization

Correct Answer: High-throughput crystallization from multiple solvents and conditions

Q12. A hydrate form of a drug contains:

• Covalently bonded water in the molecular structure
• Water molecules incorporated in the crystal lattice
• No water but higher porosity
• Only surface-adsorbed moisture

Correct Answer: Water molecules incorporated in the crystal lattice

Q13. Which experimental observation suggests the presence of more than one polymorph in a sample?

• A single sharp melting point with no other thermal events
• Multiple sets of peaks in a PXRD pattern
• Identical IR spectra to a reference
• No weight loss on TGA

Correct Answer: Multiple sets of peaks in a PXRD pattern

Q14. How does a metastable polymorph typically compare to the stable form in solubility?

• Metastable form is usually less soluble
• Metastable form is usually more soluble
• Both have identical solubility always
• Depends solely on pH, not polymorphism

Correct Answer: Metastable form is usually more soluble

Q15. What is the primary regulatory concern related to polymorphism in marketed drugs?

• Polymorphs change the chemical structure of API
• Polymorphic changes can affect drug performance and reproducibility
• Polymorphs are not patentable
• Regulators do not consider polymorphism

Correct Answer: Polymorphic changes can affect drug performance and reproducibility

Q16. Which technique maps spatial distribution of polymorphs in a tablet?

• Raman mapping or Raman imaging
• Gas chromatography
• Polarimetry
• Size-exclusion chromatography

Correct Answer: Raman mapping or Raman imaging

Q17. What is the significance of lattice energy in polymorphism?

• Higher lattice energy usually correlates with lower melting point
• Higher lattice energy indicates greater thermodynamic stability
• Lattice energy only affects color of crystals
• Lattice energy is irrelevant to polymorphic stability

Correct Answer: Higher lattice energy indicates greater thermodynamic stability

Q18. Which practice can prevent unwanted polymorphic transformation during manufacturing?

• Ignoring environmental controls
• Controlling temperature, humidity and solvent exposure
• Increasing compression force only
• Using any excipient without compatibility testing

Correct Answer: Controlling temperature, humidity and solvent exposure

Q19. Variable-temperature PXRD is useful to:

• Measure chemical purity in solution
• Monitor phase transitions and stability as temperature changes
• Replace DSC completely
• Measure particle size distribution only

Correct Answer: Monitor phase transitions and stability as temperature changes

Q20. Which phenomenon explains solvent-mediated polymorphic transformation during slurry experiments?

• Direct solid-state diffusion without solvent
• Dissolution of one form and recrystallization of another
• Evaporation of solvent only
• Chemical decomposition to a new compound

Correct Answer: Dissolution of one form and recrystallization of another

Q21. Why is the amorphous form often more soluble but less stable than crystalline polymorphs?

• Amorphous has ordered lattice and lower energy
• Amorphous lacks long-range order leading to higher free energy and solubility but lower physical stability
• Amorphous is chemically different from the API
• Amorphous always contains impurities that increase solubility

Correct Answer: Amorphous lacks long-range order leading to higher free energy and solubility but lower physical stability

Q22. Which test helps detect desolvation or hydrate loss on heating?

• Powder X-ray diffraction at room temperature only
• Thermogravimetric analysis (TGA)
• High-performance liquid chromatography (HPLC)
• Optical rotation

Correct Answer: Thermogravimetric analysis (TGA)

Q23. Which factor does NOT typically influence polymorph formation?

• Choice of solvent
• Cooling rate and supersaturation
• pH of solution for neutral APIs
• Atmospheric pressure at sea level only

Correct Answer: Atmospheric pressure at sea level only

Q24. Seeding during crystallization is used to:

• Introduce impurities deliberately
• Promote a desired polymorph and control nucleation
• Prevent any crystallization from occurring
• Change the chemical identity of the API

Correct Answer: Promote a desired polymorph and control nucleation

Q25. Which regulatory document or concept is most related to specification of polymorphic forms?

• ICH Q6A (Specifications)
• ICH Q2 (Analytical validation) only
• ICH Q7 (Good Manufacturing Practice for APIs) only
• No regulatory guidance exists on polymorphism

Correct Answer: ICH Q6A (Specifications)

Q26. Co-crystals differ from polymorphs because co-crystals:

• Are different crystalline forms of the same compound only
• Contain another neutral co-former molecule in the lattice
• Are always hydrates
• Have the same intermolecular interactions as polymorphs

Correct Answer: Contain another neutral co-former molecule in the lattice

Q27. Which statement about polymorphic patents is correct?

• Polymorphs cannot be patented separately
• A novel polymorph with utility can be patentable
• Patents on polymorphs are automatically granted for any crystal
• Patenting polymorphs is irrelevant to drug development

Correct Answer: A novel polymorph with utility can be patentable

Q28. Hot-stage microscopy is useful for polymorph studies because it:

• Provides atomic resolution of the crystal lattice
• Combines visual observation with controlled heating to observe transitions
• Measures solubility directly
• Is identical to PXRD in function

Correct Answer: Combines visual observation with controlled heating to observe transitions

Q29. Which outcome indicates a polymorphic impurity in a batch impacting dissolution?

• Uniform dissolution profile matching specification
• Batch-to-batch variability and slower dissolution than expected
• No change in tablet hardness
• Improved bioavailability in every case

Correct Answer: Batch-to-batch variability and slower dissolution than expected

Q30. Which best practice should be followed when selecting a polymorph for development?

• Choose the most soluble form without stability testing
• Balance thermodynamic stability, solubility, manufacturability and regulatory risk
• Ignore polymorph screening and rely on formulation to fix issues
• Select the form with lowest melting point always

Correct Answer: Balance thermodynamic stability, solubility, manufacturability and regulatory risk

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