Experimental Electron Density and Neutron Diffraction Studies on the Polymorphs of Sulfathiazole

Area of Science:

• Crystallography and Materials Science
• Solid-state Chemistry
• Molecular Interactions

Background:

• Sulfathiazole exists in multiple crystalline forms (polymorphs).
• Understanding the structural and energetic differences between polymorphs is crucial for drug development and material properties.
• Previous studies have not fully elucidated the conformational stability and energetic landscape of sulfathiazole polymorphs.

Purpose of the Study:

• To investigate the molecular structure, thermal motion, and intermolecular interactions of sulfathiazole polymorphs.
• To analyze the conformational preferences of sulfathiazole in the gas phase.
• To evaluate the lattice energies of different sulfathiazole polymorphs using experimental data.

Main Methods:

• High-resolution X-ray diffraction and neutron diffraction data collection at 100 K.
• Atoms in Molecules (AIM) topological analysis.
• Analysis of anisotropic displacement parameters (adp's) to assess molecular motion.
• Theoretical calculations of gas-phase molecular conformations.
• Computation of lattice energies based on experimental multipole populations.

Main Results:

• All four sulfathiazole forms (I-IV) show similar molecular thermal motion, with significant amplitude for the thiazole sulfur atom perpendicular to the ring.
• A consistent intramolecular S-O···S interaction was identified across all experimental structures, stabilizing the molecular conformation.
• Theoretical analysis revealed two low-energy conformers, one featuring the observed S-O···S interaction and another with an S-O···H-N interaction.
• Minor disorder (1-2%) was observed in forms I and II, without affecting multipole population accuracy.
• Lattice energy calculations were highly sensitive to the refinement model, yielding high uncertainties and preventing definitive determination of polymorph stability order.

Conclusions:

• The intramolecular S-O···S interaction plays a critical role in locking the sulfathiazole molecular conformation.
• While experimental data provides insights into molecular behavior, current computational methods lack the precision to definitively rank the lattice energies and stability of sulfathiazole polymorphs.
• Further refinement of computational approaches is needed for accurate prediction of polymorph stability.