Similar but Not the Same: Difference in the Ability to Form Cocrystals between Nimesulide and the Pyridine Analogues

There have been many studies on the preparation of cocrystals based on the synthon structures, but the synthons cannot completely guarantee the formation of cocrystals. On the basis of the widespread presence of the amino-pyridine synthon, we selected nimesulide (NMS) as the host component and a series of pyridine analogues (pyrazine (PYE), 4,4′-bipyridine (BP), trans-1,2-bis(4-pyridyl)ethylene (BPE), 1,2-bis(4-pyridyl)ethyne (BPY), 1,2-bis(4-pyridyl)ethane (BPA), and 1,3-bis(4-pyridyl)propane (BPP)) as coformers and thoroughly explored the difference in the ability of cocrystal formation. We successfully obtained four new cocrystals of NMS-BP/BPE/BPA/BPY, while cocrystals of NMS and PYE/BPP were not identified. By means of structural analysis and theoretical computation, we believe that PYE, with the weakest H-bond acceptor capacity and insufficient benzene ring, has difficulty in constructing a three-dimensional structure with NMS through effective N–H···N H-bonds and π–π stacking. Molecular flexibility could be a great resistance to form a cocrystal between BPP and NMS. Through quantitative calculation of Ridge and Lasso regression, it is found that the molecular electrostatic potential (MESP), h_ema (sum of hydrogen bond acceptor strengths), Kier flex (molecular flexibility), and the horizontal distance of two N atom projections of coformers have a descending effect on the cocrystal formation.