Solvates and polymorphic phase transformations of 2-chloro-4-nitrobenzoic acid

Abstract

A previously unknown monohydrate and five solvates of an anti-HIV agent, 2-chloro-4-nitrobenzoic acid (CNBA), were discovered and characterized by various analytical techniques such as powder X-ray diffraction, single-crystal X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. The solvates were readily obtained from the solvents 1,4-dioxane, dimethylsulfoxide, acetophenone, p-xylene and mesitylene. In the crystal structures of three of the solvates (1,4-dioxane, p-xylene and mesitylene solvates) the CNBA molecules form an acid-acid dimer motif and such motifs are stabilized via π⋯π stacking interactions. Slurry experiments confirmed the thermodynamic stability of Form I at room temperature. The results of desolvation experiments and a comparison of the crystal structures of the hydrate/solvates and the pure polymorphs indicate that the desolvation product does not necessarily contain a similar crystal structure to the solvate. Grinding experiments with catalytic amounts of various solvents suggest that Form II converts to Form I in most cases and both forms convert to the hydrate upon grinding with water. Grinding with 1,4-dioxane and mesitylene results in solvates and they transform to the more stable Form I upon extended grinding of 60 min.