Molecular Dynamic Simulation of D-Mannitol Polymorphs in Solid State and in Solution Relating With Spontaneous Nucleation

Abstract

In this article, the polymorphic nucleation of D-mannitol was studied in depth by molecular simulating the solid state of different forms and the aqueous solution both in unsaturated and supersaturated conditions. In our previous work, it was found that different polymorphs of D-mannitol could nucleate in various supersaturations. Here in this work, we try to use molecular dynamic simulation as a tool to explore the system to microscopically understand the phenomenon. First, the molecular structure of the 3 D-mannitol polymorphs in the solid unit cell is studied, and it is found that the molecular conformation directly affects the stability of the polymorphs. Then, the properties of D-mannitol molecules in unsaturated and supersaturated aqueous solutions are investigated. The results reveal that D-mannitol molecules are mostly monomers in unsaturated aqueous solution, while dimers start to show as the increase of concentration and also in the supersaturated aqueous solutions. Moreover, the form of the dimer varies with the degree of supersaturation, which might be the reason why the final crystal forms are different under different supersaturations. It seems that the I-dimers in supersaturated aqueous solutions is beneficial to the formation of the delta form of D-mannitol, and the T-dimers might be likely to form alpha crystal form, while the H-type dimers should be more favorable for to nucleate the beta form.