Selective Crystal Growth On Self-assembled Monolayer Using Molecular Modeling As An Assistant Method

Polymorphs and co-crystals have recently attracted considerable attention in the pharmaceutical area,as they can exhibit different physical and chemical properties(for instance,stability and solubility).As a kind of ordered 2D functional surface,self-assembled monolayers(SAMs)have broad practical implications in various areas,such as molecular electronics and cell biology.Especially,SAMs can act as templates for the selective nucleation and growth of crystals.Nowadays,with the continuous development of computer technology,molecular modeling has been widely used as an assistant method to understand the selective crystal growth on SAMs.In this work,two types of functional surfaces which are the most widely used,thiol SAMs and siloxane SAMs,were adopted to investigate the effects on polymorphs and co-crystals crystallization.To take full advantage of molecular modeling,this method was carried out to discuss the possible mechanism,and used prior to experiments for the purpose of providing guidance on experimental design as a new approach.Both molecular models and SAMs dynamic models of 3-mercaptopropionic acid(MPA)and 3-chloropropyltrimethoxysilane(CPS)were built,followed by molecular mechanics and molecular dynamics simulation to obtain the structures of SAMs.Through analysis of the radial distribution functions,it can be surmised that the functional groups of monolayers exhibited intermediate-range order.For pharmaceutical polymorphs,three typical pharmaceutical polymorphs,theophylline,L-serine and fumaric acid,were chosen as case studies for basic,zwitterionic and acidic materials.Both surface analyses and binding energy calculations were carried out to study the interactions between each morphologically important face and MPA SAM.The simulation results indicate that MPA SAM may induce the selective crystal growth of theophylline.The following crystallization experiments confirmed the modeling prediction.For pharmaceutical co-crystals,surface analysis and binding energy calculation using molecular modeling software were applied to study the interactions at the SAM/crystal interfaces of theophylline(THE)-saccharin(SAC)cocrystal and SAC,which gave us a further understanding on the selectively crystal growth mechanism of THE-SAC cocrystal on siloxane SAM.