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 (<b>Hy1_B°</b>) as global energy minimum for 4-aminoquinaldine (<b>4-AQ</b>). We thus performed an interdisciplinary experimental and computational study elucidating the crystal structures, solid form inter-relationships, kinetic and thermodynamic stabilities of the stable anhydrate (<b>AH I°</b>), the kinetic monohydrate (<b>Hy1_A</b> ) and this novel monohydrate polymorph (<b>Hy1_B°</b>) of <b>4-AQ</b>. The crystal structure of <b>Hy1_B°</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 <b>Hy1_B°</b> as the thermodynamically most stable hydrate form. At 25 °C the equilibrium of the <b>4-AQ</b> hydrate/anhydrate system was observed at an <i>a</i>_w (water activity) of 0.14. The finding of <b>Hy1_B°</b> was complicated by the fact that the metastable but kinetically stable <b>Hy1_A</b> shows a higher nucleation and growth rate. The presence of an impurity in an available <b>4-AQ</b> sample facilitated the nucleation of <b>Hy1_B°,</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 <b>4-AQ</b>, are discussed.