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

Abstract

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.

Chiral Symmetry Breaking Phenomenon Caused by a Phase Transition

“…Thus far, we have found four types of solvent-assisted solid-to-solid transformations of a kinetically formed metastable γ-form crystalline phase into a thermodynamically more stable one (α-, α 1 -, δ-, or ε-form) [5,6,[20][21][22][23][24][25][33][34][35][36][37][38][39][40][41][42][43][44][45], which are relevant to the occurrence of preferential enrichment, in a process of crystal growth.…”

“…Among them, the δ-form and α 1 -form crystals are most commonly found for the compounds showing preferential enrichment [20][21][22][23][24][25][33][34][35][36][37][38][39][40][41][42][43][44][45], while only one case is observed for each of the α-and ε-forms [5,6,21,22,39]. In this section, the crystal structures of the δ-and α 1 -forms are described in detail, because this crystal structure provides a crucial information on the mechanism of the polymorphic transition causing preferential enrichment.…”

Induction and Inhibition of Preferential Enrichment by Controlling the Mode of the Polymorphic Transition with Seed Crystals

“…[3,9,19,20] Compound (AE )-1 c was found to be a new type (k form) consisting of a heterochiral 2D sheet structure, which is quite different from the d form essential for preferential enrichment to occur ( Figure 7 and Table 2). [5,7] This kform crystal structure is characterized by a heterochiral 1D chain along the c axis, which is formed by 1) two kinds of intermolecular hydrogen bonds between the hydroxy group and the nearest amide NH (O···N distance: 3.156 ) and between the same hydroxy group and an oxygen atom of the nearest sulfonate group (O···O distance: 2.524 ) and 2) the O···Br contact (O···Br distance: 3.475 ) arising from the Coulombic donor-acceptor interaction between the methoxy oxygen atom and the nearest bromine atom.…”

“…[3][4][5][6][7][8] Mechanistically, it has been revealed that preferential enrichment is a secondary, dynamic enantiomeric-resolution phenomenon caused by the solvent-assisted solid-to-solid transformation of a metastable g-polymorphic form into a thermodynamically stable d form (or e form in a specific case) during crystallization from the supersaturated solution of a certain kind of racemic mixed crystals (i.e., solid solutions or pseudoracemates) composed of the two enantiomers (Figure 1). [3,7,8,9] Accordingly, a certain mode of polymorphic transition has turned out to be crucial to the occurrence of preferential enrichment. Therefore, on the basis of the elucidated mechanism of this unique polymorphic transition observed for a series of racemic samples that can show preferential enrichment, it may become possible to induce preferential enrichment for their structurally analogous racemic samples, which cannot exhibit this phenomenon, by controlling the mode of the polymorphic transition.…”

“…[9,12,14,15] Such control of polymorphism by seeding is usually accounted for by the heterogeneous nucleation and the subsequent epitaxial growth on the crystalline surface. If the molecular packing mode in the incipient crystal grown on the crystalline surface is thermodynamically unstable, the subsequent polymorphic transition should occur on the surface too.…”