Controlling Crystal Of Nateglinide By Crystallization On Self-assembled Monolayers

The control of polymorphism or pseudopolymorphism is of crucial importance. Inthis paper we studied the role of SAMs in controlling crystal pseudopolymorphism ofnateglinide. Nateglinide molecule possesses several functionalities （carboxyl, ketone,secondary amine, benzene ring）, and these sites have the potential to be used to formnon-covalent interactions with SAMs. Based on the molecule structure we designeddifferent SAMs （SAMs-NH₂、SAMs-Biph、SAMs-PhCF₃、SAMs-PhF₅） which canform hydrogen bonds and π–π stacking interactions with nateglinide molecules. Theobtained crystals were characterized using a combination of analytical techniquesincluding XRPD and polarization microscope analysis. Results showed that Form Dand Form X₂were concomitantly obtained on the surface of SAMs-NH₂. Substratesbearing-Biph,-PhCF₃and-PhF₅selectively nucleated Form D. Crystal precipitatedfrom the solution and gained from the surface of oxidized substrate yielded Form X₂.Besides, we investigated the dynamic process of crystal phase change, melting,recrystallization by employing polarizing microscope with heating and freezing stage.The differences in IR bands between different forms suggest variations inintermolecular forces. In order to accurately explain the effect of SAMs on crystalpseudopolymorphism, the binding energy studies were carried out. First, theinteraction site of nateglinide with the terminal functional groups of SAMs andnateglinide with ethanol molecule was assessed. The binding energy of nateglinidedimer is more negative than that of nateglinide–ethanol, suggesting it is hard to formethanol solvate without SAMs. When nateglinide interacted with SAMs, the bindingenergy values are much more negative compared with that without SAMs. Besides,the binding energy values of nateglinide-ethanol on SAMs-BiPh, SAMs-PhF₅andSAMs-PhCF₃are more negative than that of nateglinide dimer. We postulate that theinteractions between SAMs and the crystallizing molecules cooperated with the stronghydrogen bond between solvent and solute molecules direct the nucleation and growthof Form D.