Isomorphic Channel-Type Pseudopolymorphs of Azathioprine: From Structural Confirmations to a Rational Polymorph Screening Approach

The ability of the immunosuppressant agent 6-((1-methyl-4-nitro-1H-imidazol-5-yl)­thio)-9H-purine (AZA) to form pseudopolymorphs was investigated by applying conventional solid-state screening methods on 57 solvent systems. Based on the solubility data and physicochemical properties of AZA, a comprehensive polymorph screen was designed using both kinetic and thermodynamic controlled experiments. Moreover, the solubility data output of AZA in N,N-Dimethylacetamide (DMA), N-Methyl-2-pyrrolidone (NMP), N,N-Dimethylformamide (DMF), and Dimethyl sulfoxide (DMSO) caught our attention, indicating values higher than majority of tested solvents and solvent systems. Single-crystal X-ray diffraction revealed four isostructural pseudopolymorphs with DMA, NMP, DMF, and DMSO, as expected. The thermodynamics of reproducible forms were further investigated by TG/DSC analysis, establishing transitions and relations between pseudopolymorphic species. Structural features of novel pseudopolymorphs were compared and presented by Hirshfeld surfaces and associated two-dimensional fingerprint plots, according to their molecular packing in the asymmetric unit-cell.