Single Enantiomer’s Urge to Crystallize in Centrosymmetric Space Groups: Solid Solutions of Phenylpiracetam

Abstract

A detailed thermochemical and structural study of the phenylpiracetam enantiomer system was performed by characterizing the solid solutions, rationalizing the structural driving force for their formation, as well as identifying a common structural origin responsible for the formation of solid solutions of enantiomers. Enantiomerically pure phenylpiracetam forms two enantiotropically related polymorphs (enant–A and enant–B). The transition point (70(7) °C) was determined based on isobaric heat capacity measurements. Structural studies revealed that enant–A and enant–B crystallize in space groups P1 (Z′ = 4) and P212121 (Z′ = 2), respectively. However, pseudoinversion centers were present resulting in apparent centrosymmetric structures. The quasi centrosymmetry was achieved by a large variety of phenylpiracetam conformations in the solid state (six in total). As a result, miscibility of the phenylpiracetam enantiomers in the solid state is present for scalemic and racemic samples, which was confirmed by the melt phase diagram. Racemic phenylpiracetam (rac–A) was determined to crystallize in the P1̅ space group being isostructural to enant–A; furthermore, disorder is present showing that enantiomers are distributed in a random manner. The lack of enantioselectivity in the solid state is explained. Furthermore, structural aspects of phenylpiracetam solid solutions are discussed in the scope of other cases reported in the literature.

Exploring the Crystal Landscape of 3-Methyl-2-phenylbutyramide: Crystallization of Metastable Racemic Forms from the Stable Conglomerate

“…Understanding the interconversion and stability relationships between racemic and conglomerate forms is an important step in the crystallization of an API. − In this context, we have examined the crystallization behavior of 3-methyl-2-phenylbutyramide, 1 , an antimitotic compound that displays racemic and conglomerate forms, Figure . Notably, the solid-state properties of 1 have not been described previously.…”

Crystallization of chiral molecular compounds: what can be learned from the Cambridge Structural Database?

“…Since the release of Enantiomers, Racemates, and Resolutions around 40 years ago, no other reference seems to exist assessing formation of racemic compounds, conglomerates and solid solutions among the chiral compounds in general, other than a number of detailed case studies on individual systems (Lorenz et al, 2011;Wermester et al, 2007;Huang et al, 2006;Brandel et al, 2013;Rekis et al, 2017b;Rekis et al, 2017a).…”

Tuning the Solubility of the Herbicide Bentazon: from Salt to Neutral and to Inclusion Complexes

“…A promising approach for controlling the solid-state features of molecules, in the solid state, comes from crystal engineering, − which aims to modify the solid-state properties through careful control of the interactions that lead to the assembly of components into the final solid. Within this strategy, polymorphism, cocrystallization, and salt formation are the most powerful tools used to generate a range of new bulk properties, including modulation of optical features, − enantioselectivity, , and solubility in water, , among others. For these reasons, the preparation of cocrystals and salts, as well as the screening of different crystal forms of a compound are not only an academic challenge but also an opportunity for innovation.…”