Study of crystal properties and polymorphism MCQs With Answer

Introduction: Study of crystal properties and polymorphism is a crucial area in product development and technology transfer for M.Pharm students. Understanding how a drug substance can exist in different crystalline forms affects solubility, dissolution, stability, manufacturability, and bioavailability. This blog-style MCQ set focuses on core concepts such as crystal lattices, packing, polymorphic transitions, thermodynamic relationships, analytical techniques (PXRD, DSC, IR, Raman), and practical implications for formulation, scale-up and regulatory control. These questions are designed to deepen comprehension, encourage critical thinking about solid-state problems encountered during development, and prepare students for real-world decision-making in pharmaceutical development and intellectual property considerations.

Q1. Which characterization technique provides direct information about the long-range order and unit cell parameters of a crystalline drug substance?

• Differential scanning calorimetry (DSC)
• Powder X-ray diffraction (PXRD)
• Infrared spectroscopy (IR)
• Thermogravimetric analysis (TGA)

Correct Answer: Powder X-ray diffraction (PXRD)

Q2. What term describes two or more crystalline forms of the same chemical substance with different arrangements or conformations in the crystal lattice?

• Isotropy
• Polymorphism
• Hydration
• Amorphism

Correct Answer: Polymorphism

Q3. Which of the following best indicates a monotropic relationship between two polymorphs?

• The forms convert reversibly at an equilibrium transition temperature
• One form is always more stable than the other at all temperatures below melting
• Both forms coexist at the transition temperature
• They show identical melting points

Correct Answer: One form is always more stable than the other at all temperatures below melting

Q4. Ostwald’s Rule of Stages predicts that during crystallization the first-formed solid is usually:

• The thermodynamically most stable polymorph
• An amorphous glassy phase
• The kinetically favored, less stable polymorph
• A stoichiometric solvate only

Correct Answer: The kinetically favored, less stable polymorph

Q5. Which solid-state technique measures heat flow associated with transitions such as melting, crystallization, and solid-solid transformations?

• Dynamic vapor sorption (DVS)
• Thermogravimetric analysis (TGA)
• Differential scanning calorimetry (DSC)
• Solid-state NMR

Correct Answer: Differential scanning calorimetry (DSC)

Q6. Which phenomenon directly impacts solubility and dissolution rate among polymorphs?

• Difference in optical rotation
• Difference in lattice energy and surface free energy
• Difference in molecular weight
• Difference in vapor pressure

Correct Answer: Difference in lattice energy and surface free energy

Q7. What is a cocrystal in the context of pharmaceutical solids?

• A crystal containing solvent molecules in the lattice
• A multicomponent crystal formed from an API and a coformer in a definite stoichiometric ratio
• A polymorph that forms only at high pressure
• A solid solution where API is amorphous

Correct Answer: A multicomponent crystal formed from an API and a coformer in a definite stoichiometric ratio

Q8. Which analytical method is most sensitive to detecting hydrate/solvate stoichiometry and loss of solvent on heating?

• Powder X-ray diffraction (PXRD)
• Thermogravimetric analysis (TGA)
• Polarized light microscopy
• Ultraviolet-visible spectroscopy (UV-Vis)

Correct Answer: Thermogravimetric analysis (TGA)

Q9. In solid-state screening for polymorphs, which parameter is commonly varied to discover new forms?

• Optical density of the sample
• Crystallization solvent, temperature, and rate of cooling
• Molecular weight of the API
• Ambient magnetic field

Correct Answer: Crystallization solvent, temperature, and rate of cooling

Q10. What does a shift in melting endotherm to a lower temperature in DSC typically suggest when comparing two polymorphs?

• The sample has become more crystalline
• The polymorph with lower melting is likely less thermodynamically stable
• Higher lattice energy for the lower-melting form
• That impurity-free material is present

Correct Answer: The polymorph with lower melting is likely less thermodynamically stable

Q11. Which term describes a crystal habit modification used to improve downstream processing such as flow and compressibility?

• Polymorph conversion
• Particle engineering or habit modification
• Co-crystallization
• Hydrate formation

Correct Answer: Particle engineering or habit modification

Q12. Which solid-state technique can provide information about molecular conformation and hydrogen bonding in crystals?

• Single crystal X-ray diffraction
• Optical microscopy without polarization
• High-performance liquid chromatography (HPLC)
• Milligram calorimetry

Correct Answer: Single crystal X-ray diffraction

Q13. Why is polymorph control critical for regulatory submissions and patent strategy?

• Polymorphs are irrelevant to drug safety
• Different polymorphs can lead to different bioavailability, stability, and may be separately patentable
• All polymorphs are treated equivalently by regulators
• Polymorphism only affects color of the final product

Correct Answer: Different polymorphs can lead to different bioavailability, stability, and may be separately patentable

Q14. Which of the following is a practical method to induce polymorphic transformation on a kilogram scale?

• Changing molecular formula by substitution
• Seeding with crystals of the desired polymorph during crystallization
• Increasing atmospheric pressure by 10 bar
• Running HPLC at different pH

Correct Answer: Seeding with crystals of the desired polymorph during crystallization

Q15. In a reversible enantiotropic polymorphic system, what happens at the transition temperature?

• The higher temperature form sublimates and disappears
• Both polymorphs have equal free energy and convert reversibly
• The more stable low-temperature form degrades chemically
• No thermal event is observed

Correct Answer: Both polymorphs have equal free energy and convert reversibly

Q16. Which phenomenon explains why mechanical milling can produce amorphous material or new polymorphs?

• Increase in lattice energy
• Induction of high defect density, increased surface energy and localized heating
• Reduction of molecular weight
• Selective solvent incorporation

Correct Answer: Induction of high defect density, increased surface energy and localized heating

Q17. What is the primary regulatory concern when an API converts to a less soluble polymorph during storage?

• Change in tablet color only
• Potential loss of bioavailability and altered therapeutic performance
• Improved manufacturability
• Increase in melting point without consequence

Correct Answer: Potential loss of bioavailability and altered therapeutic performance

Q18. Which approach is used to distinguish polymorphs that have very similar PXRD patterns due to peak overlap?

• Use of only visual color comparison
• Complementary techniques like solid-state NMR, Raman spectroscopy, and DSC
• Relying solely on melting point
• Measuring optical rotation

Correct Answer: Complementary techniques like solid-state NMR, Raman spectroscopy, and DSC

Q19. What is a solid solution in the context of crystalline pharmaceuticals?

• A physical mixture of two crystalline powders
• A homogeneous crystalline phase where minor components substitute into the host lattice
• A non-stoichiometric amorphous blend
• A crystal containing only solvent molecules

Correct Answer: A homogeneous crystalline phase where minor components substitute into the host lattice

Q20. During technology transfer, why must polymorph screening and control strategies be documented in the transfer dossier?

• To provide recipes for excipient procurement only
• To ensure reproducible manufacture, maintain product quality, and meet regulatory expectations about solid-state form
• Because polymorphism is not relevant post-approval
• To avoid any crystallization during formulation

Correct Answer: To ensure reproducible manufacture, maintain product quality, and meet regulatory expectations about solid-state form

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