Abstract
Six isostructural crystalline solvates of the active pharmaceutical ingredient celecoxib {4-[5-(4-methylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide; C17H14F3N3O2S} are described, containing dimethylformamide (DMF, C3H7NO, 1), dimethylacetamide (DMA, C4H9NO, 2), N-methylpyrrolidin-2-one (NMP, C5H9NO, 3), tetramethylurea (TMU, C5H12N2O, 4), 1,3-dimethyl-3,4,5,6-tetrahydropyrimidin-2(1H)-one (DMPU, C6H12N2O, 5) or dimethyl sulfoxide (DMSO, C2H6OS, 6). The host celecoxib structure contains one-dimensional channel voids accommodating the solvent molecules, which accept hydrogen bonds from the NH2 groups of two celecoxib molecules. The solvent binding sites have local twofold rotation symmetry, which is consistent with the point symmetry of the solvent molecule in 4 and 5, but introduces orientational disorder for the solvent molecules in 1, 2, 3 and 6. Despite the isostructurality of 1-6, the unit-cell volume and solvent-accessible void space show significant variation. In particular, 4 and 5 show an enlarged and skewed unit cell, which can be attributed to a specific interaction between an N-CH3 group in the solvent molecule and the toluene group of celecoxib. Intermolecular interaction energies calculated using the PIXEL method show that the total interaction energy between the celecoxib and solvent molecules is broadly correlated with the molecular volume of the solvent, except in 6, where the increased polarity of the S=O bond leads to greater overall stabilization compared to the similarly-sized DMF molecule in 1. In the structures showing disorder, the most stable orientations of the solvent molecules make C-H...O contacts to the S=O groups of celecoxib.
Highlights
Understanding the structures and properties of crystalline solids can be of significant importance for active pharmaceutical ingredients (APIs) (Sun, 2009)
In the course of this work, we identified a group of six solvates that form an isostructural group, different from any of the multicomponent celecoxib crystal structures in the Cambridge Structural Database (CSD)
We describe the new structure type in this paper and explore aspects of the isostructurality, including variation of the unit-cell parameters, disorder of the solvent molecules, and the intermolecular interactions between the solvent and celecoxib molecules
Summary
Understanding the structures and properties of crystalline solids can be of significant importance for active pharmaceutical ingredients (APIs) (Sun, 2009). Solid-form screening is an integral part of most pre-formulation activities (Morissette et al, 2004), with an aim to establish the range of solid forms that can exist for a given API These generally include both polymorphs and multicomponent forms, which may variously be described as salts, cocrystals, solvates, etc. In the course of this work, we identified a group of six solvates (see Scheme 1) that form an isostructural group, different from any of the multicomponent celecoxib crystal structures in the CSD. We describe the new structure type in this paper and explore aspects of the isostructurality, including variation of the unit-cell parameters, disorder of the solvent molecules, and the intermolecular interactions between the solvent and celecoxib molecules.
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