Mechanism of a New Type of Solvent-Assisted Solid-to-Solid Polymorphic Transition Causing Preferential Enrichment: Prominent Influence of C(sp²)H···O Interaction on the Control of a Crystal Structure

Abstract

A new mode of the solvent-assisted solid-to-solid transformation of the first-formed and least stable γ-polymorphic form into the most stable ε-polymorphic one occurring during crystallization from the supersaturated EtOH solution of (±)-[2-[4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoyl]ethyl]trimethylammonium benzenesulfonate [(±)-2], which shows an unusual enantiomeric resolution phenomenon called Preferential Enrichment, has been revealed. The crystal structure of the new ε-form, which was obtained as the monophasic powder sample by exhaustive polymorphic transitions via three other metastable polymorphic forms in contact with the solvent, has been solved from the powder X-ray diffraction data by the direct-space approach employing the Monte Carlo method with the subsequent Rietveld refinement. By comparison of the crystal structure of the least stable γ-form with that of the most stable ε-one, the mechanism of this polymorphic transition has been interpreted in terms of a new type of rearrangement of weak intermolecular interactions caused by a slight molecular movement inside the crystal lattice, in which intermolecular C(sp2)H···O interactions prominently control the crystal structure. This new finding complements our recent report on the mechamisn of Preferential Enrichment.