Structural aspects of partial solid solution formation: two crystalline modifications of a chiral derivative of 1,5-dihydro-2<i>H</i>-pyrrol-2-one under consideration

Substituted acetamides (many of which are chiral) are known to be pharmacologically active. 2-Phenylpropionamide (2PPA) is one of the simplest chiral α-substituted acetamides and thus is of interest as a model compound in the growth and design of pharmaceutical crystals. In this study, the crystal structures of racemic and enantiopure forms of 2PPA were determined for the first time using single-crystal X-ray diffraction at 100 K. The relationship between the signs of optical rotation and the absolute configurations is (+)-(S)-2PPA and (−)-(R)-2PPA. Four symmetrically independent molecules with different conformations are observed in crystals of both racemic and enantiopure forms. Remarkably, all forms adopt very similar supramolecular structures, H-bonded corrugated layers, that can be described using a R 2 2(8)R 6 4(16) graph set. The outer surfaces of these layers are built of nonpolar phenyl groups, and their inner structures are composed of H-bonded amide groups. The presence of these layers determines the thin plate shape of 2PPA crystals. Spectroscopically, the racemic and enantiopure forms substantially differ only in the low-frequency Raman region. X-ray diffraction data suggest that the racemic form of 2PPA is a partial solid solution made possible by statistical occupancy of molecular positions by (R)- and (S)-enantiomers.

Section: ■ Results and Discussionmentioning

confidence: 94%

Remarkable Similarity of Molecular Packing in Crystals of Racemic and Enantiopure 2-Phenylpropionamide: Z′ = 4 Structures, Molecular Disorder, and the Formation of a Partial Solid Solution

Castañeda

Lindeman

Krivoshein

et al. 2022

“…At the same time, in the crystal of monoclinic 6c , the main supramolecular associate is a heterochiral chain along the glide plane (Figure d). Among previously studied racemic compounds of pyrrolin-2-one thioethers, − which are usually arranged by 0D centrosymmetric heterochiral H-bonded dimers, crystal 6c is the first repetitive showing a 1D heterochiral chain.…”

Section: Resultsmentioning

confidence: 99%

“…First, for rac-3-chloro-5-hydroxy-1-(4-methylbenzyl)-4-[(4methylphenyl)sulfanyl]-1,5-dihydro-2H-pyrrol-2-one (1), we discovered a pair of synthon polymorphs. 16 The targeted change of crystallization conditions for thioether 1 leads to two different crystal modifications, namely, a racemic compound (P1̅ , Z′ = 1) and racemic compound-based partial solid solution (P2 1 , Z′ = 4). In the first case, a dimeric crystal formative motif is realized, while, in the second case, an Hbonded chain is formed.…”

Section: ■ Introductionmentioning

confidence: 99%

Homochiral versus Heterochiral Crystallization of 3-Pyrrolin-2-one Thioether Results in the Score 2:1 in Favor of Homochirality

Gerasimova

Zakharychev

Saifina

et al. 2022

Self Cite

A rare phase behavior of rac- 1-benzyl-3-bromo-4-[(4chlorophenyl)sulfanyl]-5-hydroxy-1,5-dihydro-2H-pyrrol-2-one, which consists of the formation of two normal monoclinic and hexagonal conglomerates and a monoclinic racemic compound, has been discovered by thermochemical and X-ray diffraction methods. Its monoclinic racemic compound is reproducibly formed as a result of the suspension by stirring the solid phase in hydrocarbons at room temperature, while routine crystallization from a solution leads to the formation of a mixture of the two conglomerates. Thermochemical data suggest that the monoclinic conglomerate is metastable within the entire temperature range, the monoclinic racemic crystal is stable under normal conditions (20 °C) up to 110 °C, and the hexagonal conglomerate is stable at elevated temperatures above 110 °C. The essential structural difference between the homo-and heterochiral crystals lies in the optimal mutual orientation of the donor and acceptor groups of the H-bonds for the former case and the unfavorable mutual orientation for the latter one.

“…In 2000, Coquerel published a review describing in detail the thermodynamic features of the heterogeneous equilibria between condensed phases in enantiomer binary systems . Then, Kaemmerer et al reported the feasibility of the chiral resolution of the polymorphs of malic acid enantiomers and its partial solid solution, and Lodochnikova et al described the structural attributes involved in the formation of a partial SSEs from the racemic 3-chloro-5-hydroxy-1-(4-methylbenzyl)-4-[(4-methylphenyl)sulfanyl]-1,5-dihydro-2 H -pyrrol-2-one . Bredikhin et al.…”

Section: Introductionmentioning

confidence: 99%

“…24 Then, Kaemmerer et al reported the feasibility of the chiral resolution of the polymorphs of malic acid enantiomers and its partial solid solution, 25 and Lodochnikova et al described the structural attributes involved in the formation of a partial SSEs from the racemic 3-chloro-5-hydroxy-1-(4-methylbenzyl)-4-[(4-methylphenyl)sulfanyl]-1,5-dihydro-2H-pyrrol-2-one. 26 Bredikhin et al in their two recent investigations prepared and characterized partial and continuous SSEs. In the first publication, 27 they described the thermochemical properties of chiral API timolol maleate which behaves as a continuous SSEs, while in the second one, 28 his group reported the phase behavior of chiral para-methoxyphenyl glycerol ether and its ability to form continuous and partial solid solutions.…”

Section: Introductionmentioning

confidence: 99%

Racemic Salts and Solid Solutions of Enantiomers of the Antihypertensive Drug Carvedilol

Diniz¹,

Carvalho

Mussel³

et al. 2019

The R and S enantiomers of the antihypertensive drug carvedilol (CVD) can display remarkable miscibility in the crystalline state allowing this active pharmaceutical ingredient (API) to form a solid-solution of enantiomers (SSEs) as well as racemic compounds. Although rare and still little explored, these intriguing systems can also be used to design racemic multicomponent crystal forms toward the improvement of undesirable pharmaceutical properties of APIs. In this study, aiming to understand why there is miscibility between the enantiomers during the supramolecular recognition and crystallization processes of the CVD in the presence of salt formers, two SSEs and one racemic salt were prepared from the reaction of CVD with pharmaceutically acceptable HCl, HBr, and oxalic acids. Two monohydrated isostructural salts, hydrochloride (CVD-HCl-H 2 O) and hydrobromide (CVD-HBr-H 2 O), crystallize as racemic SSEs. These unique systems are formed from the miscibility of the R•••R and S•••S homochiral units that propagate into enantiomerically enriched one-dimensional chains through H-bonds with water molecules along the crystal. The oxalate salt (CVD-OXA), in turn, crystallizes as a standard racemic compound since the oxalate anions, which lie in the inversion center, are directly H-bonded to both R and S CVD enantiomers, forming racemic ionic units that extend along the structure. Complementary to the crystallographic study, conformational and Hirshfeld surface analysis were also performed based on the single-crystal X-ray diffraction data. The salt formations were confirmed from the Fourier transform infrared spectroscopy as well as powder X-ray diffraction patterns, and their thermal behaviors were investigated by a combination of differential scanning calorimetry, thermogravimetric, and hot-stage microscopy techniques.