Intermolecular interactions and disorder in six isostructural celecoxib solvates

Area of Science:

• Crystallography and Materials Science
• Pharmaceutical Chemistry
• Supramolecular Chemistry

Background:

• Celecoxib, a non-steroidal anti-inflammatory drug, exhibits polymorphism, impacting its bioavailability.
• Crystalline solvates, where solvent molecules are incorporated into the crystal lattice, are crucial for controlling drug properties.
• Understanding host-guest interactions in celecoxib solvates is essential for designing stable and effective pharmaceutical forms.

Purpose of the Study:

• To synthesize and characterize six isostructural crystalline solvates of celecoxib with various amide and sulfoxide solvents.
• To investigate the influence of solvent molecules on the crystal structure, unit-cell parameters, and void space of celecoxib.
• To analyze the intermolecular interactions governing the stability and orientation of solvent molecules within the celecoxib framework.

Main Methods:

• Synthesis and single-crystal X-ray diffraction of six celecoxib solvates: dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidin-2-one (NMP), tetramethylurea (TMU), 1,3-dimethyl-3,4,5,6-tetrahydropyrimidin-2(1H)-one (DMPU), and dimethyl sulfoxide (DMSO).
• Analysis of crystal structures, including hydrogen bonding, solvent site symmetry, and orientational disorder.
• Calculation of intermolecular interaction energies using the PIXEL method.

Main Results:

• Six isostructural crystalline solvates of celecoxib were successfully prepared and characterized.
• Celecoxib structures feature 1D channel voids accommodating solvent molecules, which form hydrogen bonds with celecoxib's NH2 groups.
• Significant variations in unit-cell volume and void space were observed, with specific interactions in TMU and DMPU solvates causing enlarged unit cells; intermolecular energies correlated with solvent molecular volume, except for DMSO due to its high polarity.

Conclusions:

• The choice of solvent significantly impacts the crystal packing and void space in celecoxib solvates, despite overall isostructurality.
• Specific solvent-guest interactions, like those involving N-CH3 groups in TMU and DMPU, can lead to unique structural distortions.
• Understanding these structure-property relationships is vital for the rational design of celecoxib crystalline forms with tailored characteristics.