Polymorphism in solids MCQs With Answer

Polymorphism in solids is a crucial topic for B.Pharm students, linking crystal form to drug performance. This concise guide and set of MCQs cover essential concepts such as types of polymorphs, solid-state characterization (PXRD, DSC, FTIR, Raman, solid‑state NMR), thermodynamic behavior (enantiotropic vs monotropic), and practical implications for solubility, stability, and bioavailability of APIs. You’ll also review polymorph screening, control strategies (seeding, solvent selection, crystallization conditions), and regulatory/patent considerations. These questions are designed to strengthen diagnostic, formulation, and quality control skills needed in pharmaceutical development. Now let’s test your knowledge with 50 MCQs on this topic.

Q1. What is the best definition of polymorphism in pharmaceutical solids?

• The ability of a drug to exist in two or more crystalline forms with different arrangements or conformations of molecules
• The formation of salts from weakly acidic drugs
• The conversion of a crystalline drug to its amorphous form only during dissolution
• The degradation of drugs under humidity

Correct Answer: The ability of a drug to exist in two or more crystalline forms with different arrangements or conformations of molecules

Q2. Which analytical technique provides a fingerprint of crystal lattice planes for polymorph identification?

• High-performance liquid chromatography (HPLC)
• Powder X-ray diffraction (PXRD)
• Ultraviolet-visible spectroscopy (UV-Vis)
• Gas chromatography (GC)

Correct Answer: Powder X-ray diffraction (PXRD)

Q3. Which observation from DSC (differential scanning calorimetry) typically indicates two polymorphs with different melting points?

• A single baseline with no peaks
• Two endothermic melting peaks at different temperatures
• A large exothermic peak only
• A broad endotherm that disappears on repeated heating without change

Correct Answer: Two endothermic melting peaks at different temperatures

Q4. What is the main practical impact of polymorphism on oral drug formulations?

• No impact; polymorphs are irrelevant to formulations
• Changes in solubility and dissolution rate affecting bioavailability
• Only affects color of the tablet
• Only influences package labeling

Correct Answer: Changes in solubility and dissolution rate affecting bioavailability

Q5. Which term describes a solid form containing solvent molecules in the crystal lattice?

• Amorphous form
• Hydrate or solvate (pseudopolymorph)
• Polymorph free of solvent
• Co-amorphous system

Correct Answer: Hydrate or solvate (pseudopolymorph)

Q6. Enantiotropic polymorphism is characterized by which feature?

• One form is stable over all temperatures up to melting
• Forms are interconvertible reversibly below the melting point with a transition temperature
• Forms only interconvert upon complete melting and recrystallization
• It refers to formation of salts and co-crystals

Correct Answer: Forms are interconvertible reversibly below the melting point with a transition temperature

Q7. Monotropic polymorphism means:

• One polymorph is always thermodynamically more stable than the other at all temperatures
• Both polymorphs are equally stable at all temperatures
• Polymorphs interchange readily with no preferred stability
• Polymorphs are only formed in the presence of water

Correct Answer: One polymorph is always thermodynamically more stable than the other at all temperatures

Q8. Which method is most useful to detect solvent loss from a solvate or hydrate?

• Nuclear magnetic resonance of solutions
• Thermogravimetric analysis (TGA)
• Optical rotation measurement
• HPLC assay of the solid

Correct Answer: Thermogravimetric analysis (TGA)

Q9. Why is PXRD preferred for routine polymorph screening?

• It gives direct chemical assay of impurities
• It provides characteristic diffraction patterns that distinguish crystal lattices
• It measures solubility directly
• It is the only method that can detect amorphous content

Correct Answer: It provides characteristic diffraction patterns that distinguish crystal lattices

Q10. Which of the following is an example of a real-world regulatory issue caused by polymorphism?

• Color mismatch in packaging
• Ritonavir formulation failure due to unexpected polymorph with lower solubility
• Label font size noncompliance
• Delayed tablet printing

Correct Answer: Ritonavir formulation failure due to unexpected polymorph with lower solubility

Q11. Which technique can map crystal habit and morphology visually during heating?

• Hot-stage microscopy
• Liquid chromatography
• Capillary electrophoresis
• Fourier transform infrared spectroscopy (FTIR) in solution

Correct Answer: Hot-stage microscopy

Q12. Ostwald’s rule of stages predicts which behavior during crystallization?

• The most stable polymorph always nucleates first
• The kinetically favored, less stable form often appears first and may transform to a more stable form
• Polymorphs cannot transform once formed
• Crystallization always yields amorphous solids

Correct Answer: The kinetically favored, less stable form often appears first and may transform to a more stable form

Q13. Which analytical method best distinguishes polymorphs by molecular-level hydrogen-bonding differences?

• Solution-state 1H NMR
• Infrared (IR) or Raman spectroscopy
• Mass spectrometry
• Gas chromatography

Correct Answer: Infrared (IR) or Raman spectroscopy

Q14. Solid-state NMR is particularly useful in polymorphism studies for what reason?

• It provides direct information on atomic-level chemical environments in the solid
• It is the fastest method for quantitative assay in solution
• It replaces PXRD in all routine analysis
• It only measures moisture content

Correct Answer: It provides direct information on atomic-level chemical environments in the solid

Q15. Which factor commonly influences which polymorph will form during crystallization?

• Solvent type and supersaturation conditions
• Tablet colorants
• Packaging material only
• Time of day the crystallization is carried out

Correct Answer: Solvent type and supersaturation conditions

Q16. What is the main difference between polymorphs and co-crystals?

• Polymorphs differ in crystal packing of the same molecule; co-crystals are crystalline complexes with a different co-former molecule
• Co-crystals are always amorphous
• Polymorphs contain solvent molecules; co-crystals do not
• There is no difference; they are synonyms

Correct Answer: Polymorphs differ in crystal packing of the same molecule; co-crystals are crystalline complexes with a different co-former molecule

Q17. Which experimental approach helps intentionally obtain a desired polymorph during production?

• Seeding with crystals of the desired polymorph
• Ignoring crystallization conditions
• Storing product at random humidity
• Adding unrelated colorants to the melt

Correct Answer: Seeding with crystals of the desired polymorph

Q18. Which solid form usually offers higher dissolution rate and potentially higher bioavailability?

• Highly crystalline stable polymorph always
• Amorphous form due to higher free energy and faster dissolution
• Hydrated form always
• Coated tablets irrespective of solid form

Correct Answer: Amorphous form due to higher free energy and faster dissolution

Q19. What does Rietveld refinement of powder XRD data allow you to do?

• Quantitatively refine crystal structure and estimate phase composition from PXRD patterns
• Measure liquid viscosity
• Analyze only organic impurities in solution
• Estimate tablet hardness non-destructively

Correct Answer: Quantitatively refine crystal structure and estimate phase composition from PXRD patterns

Q20. Which process is a common mechanism for polymorphic transformation in the solid state at room temperature?

• Solution-mediated transformation via dissolution and recrystallization
• Complete combustion
• Direct nuclear fusion
• Sublimation back to original solvent only

Correct Answer: Solution-mediated transformation via dissolution and recrystallization

Q21. What is a pseudopolymorph?

• A polymorph that exists only at extremely high pressure
• A crystalline form where different amounts or types of solvent are included (hydrates/solvates)
• An amorphous impurity
• A co-crystal with another API

Correct Answer: A crystalline form where different amounts or types of solvent are included (hydrates/solvates)

Q22. Which statement about metastable polymorphs is correct?

• Metastable polymorphs have lower free energy than the stable form
• Metastable polymorphs are kinetically favored and may convert to the stable form over time
• Metastable polymorphs cannot be detected by PXRD
• Metastable polymorphs are always preferable for manufacturing

Correct Answer: Metastable polymorphs are kinetically favored and may convert to the stable form over time

Q23. Which technique can quantify amorphous content in a crystalline sample when combined with calibration?

• PXRD with partial least squares or Rietveld-based methods
• Simple optical density measurement
• Thin-layer chromatography (TLC)
• Gas chromatography-mass spectrometry (GC-MS)

Correct Answer: PXRD with partial least squares or Rietveld-based methods

Q24. Which is the most likely cause of a sudden loss of drug performance in a marketed tablet related to polymorphism?

• Unexpected appearance of a less soluble polymorph during manufacturing scale-up
• Changes in font style on label
• Variation in tablet punching speed only
• Minor change in packaging ink composition

Correct Answer: Unexpected appearance of a less soluble polymorph during manufacturing scale-up

Q25. Which computational approach is increasingly used to predict likely polymorphs before experimental work?

• Crystal structure prediction using molecular modeling and lattice energy calculations
• Empirical solubility prediction only
• Simple logP calculations in water
• Spectrophotometric scanning of tablets

Correct Answer: Crystal structure prediction using molecular modeling and lattice energy calculations

Q26. How does humidity influence polymorphic forms for hygroscopic drugs?

• It has no influence on solid form
• High humidity can promote hydrate formation or solid-state transformations
• Humidity only affects color
• Humidity always reduces solubility

Correct Answer: High humidity can promote hydrate formation or solid-state transformations

Q27. Which of the following best describes a salt form relative to polymorphs?

• A salt is a molecular packing variant of the same neutral molecule
• A salt is formed by ionization and pairing of counterions, producing a different chemical species
• Salt formation is identical to co-crystal formation
• Salts are always amorphous

Correct Answer: A salt is formed by ionization and pairing of counterions, producing a different chemical species

Q28. Which experimental design is used for high-throughput polymorph screening in early development?

• Large-scale manufacturing runs only
• Parallel small-volume crystallizations varying solvent, temperature, and additives
• Single-condition recrystallization repeated dozens of times
• Only computational prediction without experiments

Correct Answer: Parallel small-volume crystallizations varying solvent, temperature, and additives

Q29. What role do impurities often play in polymorph formation?

• Impurities have no effect on crystallization
• They can act as templates, inhibit or promote nucleation of particular polymorphs
• They always convert crystals to amorphous solids
• They only affect tablet coating adhesion

Correct Answer: They can act as templates, inhibit or promote nucleation of particular polymorphs

Q30. Which statement about melting point and polymorph stability is generally correct?

• The polymorph with the higher melting point is always the most stable at all temperatures
• Melting point alone does not fully define polymorph stability; thermodynamic data across temperatures are needed
• Lower melting point always means better stability
• Melting point is irrelevant to polymorphism studies

Correct Answer: Melting point alone does not fully define polymorph stability; thermodynamic data across temperatures are needed

Q31. Which experimental evidence indicates a solid-solid polymorphic transition without melting?

• A PXRD pattern change at a certain temperature observed in hot-stage PXRD while no endotherm indicating melting is seen
• A change in tablet hardness without structural analysis
• Only a single melting peak on DSC
• No change in any analytical method

Correct Answer: A PXRD pattern change at a certain temperature observed in hot-stage PXRD while no endotherm indicating melting is seen

Q32. Which of the following is NOT a common technique for polymorph characterization?

• Powder X-ray diffraction (PXRD)
• Differential scanning calorimetry (DSC)
• Ultrahigh-performance liquid chromatography for enantiomers only (UHPLC)
• Raman spectroscopy

Correct Answer: Ultrahigh-performance liquid chromatography for enantiomers only (UHPLC)

Q33. What is the significance of the transition temperature between enantiotropic forms?

• It indicates the temperature below which both forms are identical
• It is the temperature at which the relative thermodynamic stability of two polymorphs changes
• It is always equal to the melting point of the lower-melting form
• It only applies to amorphous solids

Correct Answer: It is the temperature at which the relative thermodynamic stability of two polymorphs changes

Q34. Which process is an example of mechanochemistry relevant to polymorphism?

• Ball milling that induces polymorphic transformations or amorphization
• Heating in a microwave oven for color change only
• Simple dilution in water
• Vacuum filtration without stress

Correct Answer: Ball milling that induces polymorphic transformations or amorphization

Q35. In formulation, why might one prefer the thermodynamically stable polymorph?

• It guarantees better long-term physical stability and reproducibility
• It always gives the highest dissolution rate
• It is always cheaper to synthesize
• It never requires analytical testing

Correct Answer: It guarantees better long-term physical stability and reproducibility

Q36. Which observation suggests a solvate or hydrate rather than a true polymorph?

• Mass loss in TGA corresponding to discrete amounts of solvent combined with changes in PXRD
• No change in TGA but different PXRD
• Only a color change without mass loss
• Only HPLC shows different impurities

Correct Answer: Mass loss in TGA corresponding to discrete amounts of solvent combined with changes in PXRD

Q37. Which term best describes the practice of exploring many crystallization conditions to find all possible solid forms?

• Polymorph hiding
• Polymorph screening
• Polymorph destruction
• Polymorph silencing

Correct Answer: Polymorph screening

Q38. Why is reproducible control of polymorphic form critical in scale-up?

• Because different polymorphs can alter processability, tabletability, and product performance
• Because it changes the brand color only
• Polymorphs have no effect in large batches
• Scale-up eliminates polymorphism automatically

Correct Answer: Because different polymorphs can alter processability, tabletability, and product performance

Q39. Which of the following is a classical example of an API known to show multiple polymorphs used in teaching?

• Ibuprofen with a single solid form only
• Carbamazepine showing several polymorphs and solvates
• Glucose as only amorphous
• Water as a non-crystalline drug

Correct Answer: Carbamazepine showing several polymorphs and solvates

Q40. Which parameter is most directly related to lattice stability among polymorphs?

• Lattice energy and Gibbs free energy differences
• Only moisture content
• Tablet coating thickness
• UV absorbance at 260 nm

Correct Answer: Lattice energy and Gibbs free energy differences

Q41. Which experimental evidence would indicate a metastable polymorph has converted to a more stable form during storage?

• PXRD pattern changes showing disappearance of peaks of the original form and appearance of peaks of another form
• Unchanged PXRD with color loss only
• Only small changes in HPLC retention time unrelated to solid form
• No observable changes in any solid-state method

Correct Answer: PXRD pattern changes showing disappearance of peaks of the original form and appearance of peaks of another form

Q42. Which law or guideline requires characterization of solid-state forms during pharmaceutical development?

• ICH guidelines on pharmaceutical development and impurity reporting emphasize solid-state characterization
• Only local advertising laws
• There are no guidelines for solid form characterization
• Food labeling regulations only

Correct Answer: ICH guidelines on pharmaceutical development and impurity reporting emphasize solid-state characterization

Q43. Which of the following best describes a co-amorphous formulation in relation to polymorphism?

• Two components forming a single crystalline lattice
• Two small molecules mixed in an amorphous state to stabilize each other and improve properties
• A hydrated crystalline form
• A polymer-coated crystal

Correct Answer: Two small molecules mixed in an amorphous state to stabilize each other and improve properties

Q44. What is the typical effect of increasing crystal perfection on dissolution rate?

• More perfect crystals typically dissolve more slowly due to lower surface free energy
• More perfect crystals always dissolve faster
• Crystal perfection has no effect on dissolution
• Dissolution is independent of crystal properties

Correct Answer: More perfect crystals typically dissolve more slowly due to lower surface free energy

Q45. Which approach can reduce risk of late-stage discovery of an undesired polymorph?

• Comprehensive early polymorph screening and robust control strategy
• Skipping preclinical solid-state studies
• Relying solely on a single crystallization method
• Ignoring regulatory requirements

Correct Answer: Comprehensive early polymorph screening and robust control strategy

Q46. Which observation in Raman spectroscopy suggests a different polymorph?

• Shifts or intensity changes in characteristic vibrational bands compared to a reference
• No change in spectral baseline only
• Only slight temperature fluctuations in instrument room
• Changes in optical density of a liquid sample

Correct Answer: Shifts or intensity changes in characteristic vibrational bands compared to a reference

Q47. Which factor is least likely to affect polymorph nucleation?

• Color of the lab coat worn by the scientist
• Supersaturation level
• Presence of impurities or additives
• Temperature and solvent choice

Correct Answer: Color of the lab coat worn by the scientist

Q48. Which is a typical regulatory expectation for a marketed drug regarding polymorphs?

• Full characterization of clinically relevant solid forms and controls to ensure consistent quality
• No information about solid forms is needed
• Only information about tablet color is required
• Only packaging conditions are considered in polymorph regulation

Correct Answer: Full characterization of clinically relevant solid forms and controls to ensure consistent quality

Q49. Which transformation pathway often requires solvent and leads to more complete conversion between polymorphs?

• Solution-mediated transformation via dissolution and recrystallization
• Direct vapor decomposition only
• Simple mechanical shaking without solvent
• Photochemical cleavage only

Correct Answer: Solution-mediated transformation via dissolution and recrystallization

Q50. Which control strategy is useful to maintain the desired polymorph during manufacturing?

• Careful control of crystallization parameters, use of seeding, and monitoring by PXRD/DSC
• No monitoring and random crystallization
• Only visual inspection of crystals
• Relying on ambient uncontrolled humidity

Correct Answer: Careful control of crystallization parameters, use of seeding, and monitoring by PXRD/DSC

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