Crystallization: nucleation, polymorphs, hydrates, solvates and amorphous forms MCQs With Answer

Introduction

This focused MCQ set on crystallization — covering nucleation, polymorphs, hydrates, solvates and amorphous forms — is tailored for M.Pharm students preparing for MPC 204T Pharmaceutical Process Chemistry. Questions emphasise fundamental concepts and practical implications: nucleation mechanisms, metastable zone, polymorphic stability (monotropic vs enantiotropic), hydrate/solvate formation and characterization, and differences between crystalline and amorphous solids in terms of solubility, stability and processing. Expect items that test your understanding of thermodynamics, kinetics, analytical techniques (PXRD, DSC, solid-state NMR), and formulation consequences. Use these MCQs for revision, self-assessment and to reinforce decision-making in development of solid dosage forms.

Q1. What is the primary difference between homogeneous and heterogeneous nucleation?

• Homogeneous nucleation occurs uniformly throughout the bulk solution; heterogeneous nucleation occurs at interfaces or foreign surfaces
• Homogeneous nucleation requires higher supersaturation because it involves impurities; heterogeneous occurs only in pure solvents
• Homogeneous nucleation always produces amorphous solids; heterogeneous always produces crystals
• There is no thermodynamic difference; they are kinetically identical

Correct Answer: Homogeneous nucleation occurs uniformly throughout the bulk solution; heterogeneous nucleation occurs at interfaces or foreign surfaces

Q2. Which parameter defines the metastable zone width (MSZW) in crystallization?

• The temperature range between the melting point and the glass transition
• The supersaturation range between solubility and spontaneous nucleation
• The concentration difference between saturated and undersaturated solution
• The pH range where the compound is chemically stable

Correct Answer: The supersaturation range between solubility and spontaneous nucleation

Q3. According to classical nucleation theory, which energy term must be overcome to form a stable nucleus?

• Only the bulk free energy change (volume term)
• Only the surface free energy (interfacial term)
• Both the negative bulk free energy (favourable) and the positive surface free energy (unfavourable)
• Only the entropic contribution from solvent ordering

Correct Answer: Both the negative bulk free energy (favourable) and the positive surface free energy (unfavourable)

Q4. Which experimental technique is most definitive for distinguishing polymorphs of a crystalline drug?

• UV-Visible spectroscopy
• Powder X-ray diffraction (PXRD)
• High-performance liquid chromatography (HPLC)
• Optical rotation measurement

Correct Answer: Powder X-ray diffraction (PXRD)

Q5. What does Ostwald’s Rule of Stages predict about crystallization behavior?

• The most stable polymorph will always form first
• The smallest crystal always grows fastest
• Less stable (metastable) polymorphs often form before the most stable form
• Hydrates form only at high humidity

Correct Answer: Less stable (metastable) polymorphs often form before the most stable form

Q6. Which statement best distinguishes a hydrate from a solvate?

• A hydrate contains water molecules incorporated into the crystal lattice; a solvate contains solvent molecules other than water
• A hydrate is always more stable than the anhydrous form; a solvate is always less stable
• Hydrates form only via steam exposure; solvates form only during solvent evaporation
• There is no structural difference; both are neutral adsorbed layers

Correct Answer: A hydrate contains water molecules incorporated into the crystal lattice; a solvate contains solvent molecules other than water

Q7. What is the principal formulation risk associated with amorphous drug forms?

• They have lower solubility than crystalline forms
• They are chemically inert and cannot be compressed into tablets
• They are thermodynamically unstable and tend to recrystallize, changing performance
• They cannot be characterized by DSC or PXRD

Correct Answer: They are thermodynamically unstable and tend to recrystallize, changing performance

Q8. Which DSC (Differential Scanning Calorimetry) observation indicates a hydrate losing water?

• Endothermic peak below the melting temperature corresponding to dehydration
• Exothermic peak at the melting point
• Glass transition event at high temperature
• Complete absence of thermal events

Correct Answer: Endothermic peak below the melting temperature corresponding to dehydration

Q9. In polymorphism, what is meant by monotropy?

• Two polymorphs are interchangeable reversibly with temperature
• One polymorph is stable over all temperatures and another is metastable at all temperatures
• Polymorphs only differ in solvate content
• Polymorphic transition is rapid and occurs during milling

Correct Answer: One polymorph is stable over all temperatures and another is metastable at all temperatures

Q10. Which factor is least likely to influence the formation of a particular polymorph during crystallization?

• Choice of solvent and its polarity
• Cooling rate or evaporation rate
• The color of the crystallization vessel
• Additives or impurities acting as templates

Correct Answer: The color of the crystallization vessel

Q11. Which analytical signature is characteristic of an amorphous solid compared to its crystalline counterpart?

• Sharp, well-defined PXRD peaks
• Broad halo in PXRD and a glass transition (Tg) in DSC
• Higher melting point than crystalline form
• Distinct, sharp IR bands due to long-range order

Correct Answer: Broad halo in PXRD and a glass transition (Tg) in DSC

Q12. What is a key thermodynamic driver for hydrate formation?

• Decrease in lattice energy upon incorporating water molecules that stabilizes the crystal
• Increase in vapor pressure of the solid
• Hydrates always increase the entropy of the system
• Hydrate formation is driven only by mechanical stress

Correct Answer: Decrease in lattice energy upon incorporating water molecules that stabilizes the crystal

Q13. Which process can produce secondary nucleation during crystallization?

• Seeding with a small crystal population or impingement of crystals causing attrition
• Complete absence of any solid particles in solution
• Reducing stirring rate to zero during growth
• Using a solvent completely miscible with water

Correct Answer: Seeding with a small crystal population or impingement of crystals causing attrition

Q14. Which statement about solvent-mediated polymorphic transformation is correct?

• The less stable polymorph dissolves and the more stable polymorph crystallizes from solution
• Polymorphs are fixed and cannot interconvert through solvent
• Solvent-mediated transformation only occurs at temperatures above melting
• It only happens when the solvent is a non-volatile oil

Correct Answer: The less stable polymorph dissolves and the more stable polymorph crystallizes from solution

Q15. How does seeding influence crystallization outcomes?

• Seeding eliminates the need to control supersaturation
• Seeding can control polymorph and reduce induction time by providing nuclei for growth
• Seeding always leads to amorphous product formation
• Seeding increases the metastable zone width indefinitely

Correct Answer: Seeding can control polymorph and reduce induction time by providing nuclei for growth

Q16. Which of the following best describes conformational polymorphism?

• Polymorphism arising from different packing arrangements of identical molecular conformations only
• Polymorphism resulting from different molecular conformations adopted in the crystal lattice
• Polymorphism exclusive to ionic salts
• Polymorphism caused purely by solvent inclusion

Correct Answer: Polymorphism resulting from different molecular conformations adopted in the crystal lattice

Q17. Which storage condition increases the risk of converting an anhydrous drug to a hydrate?

• Low humidity, low temperature storage
• High humidity and moderate temperature conditions
• Dry inert atmosphere with desiccant
• Storage under refrigerated vacuum

Correct Answer: High humidity and moderate temperature conditions

Q18. Why are solvates important to consider during drug development?

• They do not affect dissolution or stability
• Solvates may alter physical properties such as solubility, stability, and processing behavior and can be regulatory issues
• Solvates are always preferred because they increase melting point
• They always convert to amorphous forms during tableting

Correct Answer: Solvates may alter physical properties such as solubility, stability, and processing behavior and can be regulatory issues

Q19. Which factor most directly increases the nucleation rate for a given compound in solution?

• Decreasing supersaturation
• Increasing interfacial tension between nucleus and solution
• Increasing supersaturation
• Lowering temperature without changing solubility

Correct Answer: Increasing supersaturation

Q20. Which solid-state analytical combination is most useful to fully characterise a suspected new polymorph?

• HPLC and UV-Vis spectroscopy
• PXRD, DSC, and solid-state NMR
• FTIR only
• Optical microscopy alone

Correct Answer: PXRD, DSC, and solid-state NMR

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