4-Aminoquinaldine monohydrate polymorphism: prediction and impurity aided discovery of a difficult to access stable form

Abstract

Crystal structure prediction studies indicated the existence of an unknown high density monohydrate structure (Hy1_B°) as the global energy minimum for 4-aminoquinaldine (4-AQ). We thus performed an interdisciplinary experimental and computational study elucidating the crystal structures, solid form inter-relationships, and kinetic and thermodynamic stabilities of the stable anhydrate (AH I°), the kinetic monohydrate (Hy1_A) and this novel monohydrate polymorph (Hy1_B°) of 4-AQ. The crystal structure of Hy1_B° was determined by combining laboratory powder X-ray diffraction data and ab initio calculations. Dehydration studies with differential scanning calorimetry and solubility measurements confirmed the result of the lattice energy calculations, which identified Hy1_B° as the thermodynamically most stable hydrate form. At 25 °C the equilibrium of the 4-AQ hydrate/anhydrate system was observed at an a_w (water activity) of 0.14. The finding of Hy1_B° was complicated by the fact that the metastable but kinetically stable Hy1_A shows a higher nucleation and growth rate. The presence of an impurity in an available 4-AQ sample facilitated the nucleation of Hy1_B°, whose crystallisation is favored under hydrothermal conditions. The value of combining experimental with theoretical studies in hydrate screening and characterisation, as well as the reasons for hydrate formation in 4-AQ, are discussed.