Solvent Effect on Molecular Conformational Evolution and Polymorphic Manipulation of Cimetidine

In the field of pharmaceutical crystallization, the success of polymorphic manipulation is vital to the performance of pharmaceutical formulations, and the choice of solvents might affect polymorphic outcomes directly. To better understand the relationship between molecular structure in solution and in the crystal, the solvent effect on molecular conformational evolution and polymorph control of cimetidine (CIM) was investigated. Three polymorphs (A, B, and D) of cimetidine (CIM) were prepared, and it was found that conformers selected in crystals could significantly affect crystal packing and polymorph stability. Two-dimensional nuclear Overhauser effect spectroscopy and quantum chemical calculation results reveal that conformer A is the dominant molecular conformer, although conformational distribution is strongly solvent-dependent. Furthermore, Fourier transform infrared spectroscopy and solvation free energy calculation results show that the interaction strength of CIM with solvents increases in the order isopropanol ≈ acetonitrile < methanol < ethylene glycol, affecting the difficulty of desolvation. The results imply that the interaction strength of CIM with solvents may affect the difficulty of desolvation, conformational rearrangement, and final polymorphic outcome. In the end, the potential mechanism of conformational evolution and polymorphic manipulation of CIM was presented.