Structural Insights into the Highly Solvating System of Axitinib via Binary and Ternary Solvates

Axitinib is a well-known model in crystal engineering, exhibiting a high tendency to form various solvates, and more than 70 kinds of solvates have been reported. Therefore, it is a challenge to elucidate the effect of solvents on the crystallization of Axitinib and develop the polymorph or solvate landscape of Axitinib. Here, we illustrate an uncommon and complicated solvation behavior of Axitinib from the structural analysis and theoretical characterization. The structures of two new ternary solvates and five binary solvates are reported for the first time. Experimental and theoretical calculation and studies on phase transition are performed to rationalize and understand the formation of solvates and the transformation of polymorphisms. Crystal structure analysis and molecular properties reveal that shape, size, the hydrogen bond donor of the solvents, and the chance to lower crystal free energy are the main factors to drive solvates. Three sets of isostructural binary solvate are distinguished and calculated quantitatively to prove that the intermolecular interactions, strong hydrogen bond donor, CH−π, and orientation force control the classification results of binary solvates. Stability of solvates is found to be associated with the intermolecular interaction energies of solvent molecules with surrounding molecules. The polymorphic behavior of the desolventized product is attributed to the two-dimensional isostructurality between form IV and solvate.