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 NH center dot center dot center dot N H-bonds and pi-pi 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.

Automated summary

By utilizing the widespread amino-pyridine synthon, Nimesulide was selected as the host component while a series of pyridine analogues were chosen as coformers, leading to the successful formation of new cocrystals. However, cocrystals between NMS and some pyridine analogues were not identified due to factors such as molecular flexibility and hydrogen bond acceptor strengths. Quantitative calculations revealed that molecular electrostatic potential, hydrogen bond acceptor strengths, molecular flexibility, and the horizontal distance of coformers' N atom projections have a significant impact on the formation of cocrystals.