Dynamics and disorder: on the stability of pyrazinamide polymorphs

Area of Science:

• Solid-state chemistry
• Crystallography
• Computational chemistry

Background:

• Pyrazinamide is a crucial anti-tuberculosis drug.
• Understanding polymorph stability is vital for drug formulation and efficacy.
• Polymorphism significantly impacts physicochemical properties.

Purpose of the Study:

• To investigate the structure and relative stability of four pyrazinamide polymorphs.
• To calculate enthalpic and entropic contributions to free energy for each polymorph.
• To predict solid-state phase transition temperatures and stability order.

Main Methods:

• Single crystal X-ray diffraction at low temperatures (10 K and 122 K).
• Periodic ab initio Density Functional Theory (DFT) calculations.
• Normal-mode refinement against X-ray diffraction data.

Main Results:

• Detailed structural data for four pyrazinamide polymorphs at low temperatures.
• Calculated free energies revealing enthalpic and entropic contributions.
• Predicted stability order: α and γ forms are more stable at higher temperatures than β and δ.
• The γ form, due to disorder, becomes the most stable above ~500 K.

Conclusions:

• Vibrational entropy stabilizes the α and γ pyrazinamide polymorphs at higher temperatures.
• The γ polymorph's disorder-driven entropy makes it the most stable form above ~500 K.
• Findings align qualitatively with experimental calorimetry data.