Crystallization of a Desired Metastable Polymorph by Pseudoseeding, Crystal Structure Solution from Its Powder X-ray Diffraction Data, and Confirmation of Polymorphic Transition

Described are the successful, selective crystallization and characterization of one (δ-form) of the
metastable polymorphs of (±)-[2-[4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoyl]ethyl]dimethylsulfonium p-toluenesulfonate (1a), which is assumed to exist as a transient key-intermediate crystalline phase relevant to the
mechanism of Preferential Enrichment, an unusual enantiomeric resolution phenomenon observed upon crystallization of a certain kind of racemates from solvents. By pseudoseeding the supersaturated solution with the δ-form
seed crystals of an anlogous compound, the desired δ-form crystals of (±)-1a could be obtained as a monophasic
powder sample. This selective crystallization can be interpreted in terms of the interplay between an inhibition of
the nucleation or crystal growth process of the undesired stable α-polymorphic form and a heterogeneous nucleation
of the desired metastable δ-form through epitaxy. The physicochemical properties of the δ-form crystal such as
melting point and solubility have been compared with those of the stable α-form one to evaluate the relative stability
of the metastable δ-form. It has also been confirmed that polymorphic transition of the metastable δ-form crystal to
the stable α-form one occurs in contact with a solvent. On the basis of the δ-form crystal structure solved from its
powder X-ray diffraction data measured with a laboratory X-ray source by means of the direct-space approach
employing the Monte Carlo method and the subsequent Rietveld refinement, the origin of the metastability of the
δ-form crystal has been discussed.