Insight into the Structure and Property Diversity of Four Nicorandil Oxalate Salt Polymorphs Based on Experiments and Quantum Chemistry Study

This contribution presents a novel and comparative study on the relationship between the crystal structure and the property diversity of a complex polymorph system of nicorandil oxalate (NIC-OA) salts. Single-crystal structures of four salt polymorphs with 1:1 stoichiometry were prepared, and crystal structure analysis revealed the difference of configuration and tautomer structure among those polymorphs. Bulk samples of three polymorphs (S1, S3 and S4) were successfully isolated from ethanol/water solution, while the metastable form S2 could not be obtained. Detailed property studies including solvent-mediated polymorph transformation, physical-chemical stability, and intrinsic dissolution of those polymorphs were conducted. Phase transformation from S3 to S4 in high-humidity conditions and accelerated conditions was driven by lowering of lattice energy. High hygroscopicity would accelerate the process. All polymorphs showed better chemical stability and greater dissolution rate compared to NIC. The binding energy between NIC and oxalate acid and crystal-solvent interaction were studied to investigate the correlation between polymorph packing and bulk property. The chemical stability of NIC was affected by the diversity in cation–anion binding modes, while the dissolution process of the polymorphs was influenced by the crystal face differences and the interaction between the crystal and solvent. It is the first time that four crystalline forms of NIC-OA are reported, and the structure and property diversity among these salt polymorphs are revealed with experiments and the quantum chemistry method, which provided new insights into the NIC-OA polymorphs in the crystal engineering field and might contribute to the property research of the complex pharmaceutical polymorphism system.