A Newly Discovered Racemic Compound of Pioglitazone Hydrochloride Is More Stable than the Commercial Conglomerate

In the solid state, (±)-3-methyl-2-phenylbutyramide 1 spontaneously resolves into a conglomerate (Form I) that crystallizes in a racemic form (Form II) upon melting followed by vapor crystallization, a rarely reported phenomenon. An additional racemic polymorph, Form III, has been characterized, and the thermodynamic relationship between the three forms established by a variety of computational and experimental methods including grinding, slurry crystallization, and seeding techniques. Both racemic Forms II and III are metastable and readily convert to the more stable conglomerate, Form I. Density functional theory calculations of the different polymorphs of 1 show that the enantiomers of 1 (R & S) are more stable than both racemic forms.

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Khandavilli

Gavin

Maguire

et al. 2018

“…Potentially, polymorphism can be realized for an enantiopure compound, and hence for the corresponding racemic conglomerates. The sustained interest in the peculiarities of “chiral” crystallization, observed recently, − is largely due to the afore-mentioned legal aspects . Another reason is that the coexistence of different crystalline forms complicates the resolution of a chiral substance into enantiomers using preferential crystallization, the use of which opens up tempting industrial prospects. , It is believed that the probability of spontaneous resolution is low and amounts to ∼10%, although there are more optimistic estimates .…”

Section: Introductionmentioning

confidence: 99%

Crystal Landscape of Chiral Drug Chlorphenesin and Its Structural Analogues: Polymorphism of Racemic and Enantiopure Samples, Metastable and Stable Racemic Conglomerates, Diverse in Unity Crystal Motifs

Бредихин

Zakharychev

Губайдуллин

et al. 2021

The phase behavior of chiral API Chlorphenesin 1 and its structural analogues 2 and 3 was investigated by DSC and PXRD methods. For the entire family of compounds 1–3, many crystalline modifications have been found for the first time. It has been shown that both racemic and enantiopure samples 1 form stable and metastable phases; racemic meta-derivative 2, along with stable and metastable racemic compounds, is capable of forming a metastable racemic conglomerate. In the case of the ortho-derivative 3, metastable crystalline racemic compounds were not detected, while both stable and metastable homochiral forms are capable of forming racemic conglomerates. For compounds 1–3, the free energies of metastable forms were estimated experimentally relative to the thermodynamically most stable racemic compounds. All racemic compounds of chloro- and methyl-substituted chlorphenesin analogues, studied by X-ray diffraction analysis, form a common supramolecular motif, while three different crystal organizations have been identified for enantiopure forms. In 7 cases out of the 9 studied, the crystal packing is formed with the participation of two symmetry independent molecules. Apparently, both the unusual diversity of the crystalline landscape and the increased frequency of Z′ > 1 cases in the series under study have a common reason and reflect the variety of ways for intermolecular hydrogen bond formation in the crystals of aryl glycerol ethers.

“…Polymorphism is an evergreen theme for researchers of molecular crystals. , Current interest in this problem is largely supported by the needs of pharmaceutical science and industry. , In recent years, chiral compounds are increasingly becoming objects of the research. − An additional feature of chiral systems that is absent in the case of achiral substances is the possible interconversion of homochiral (scalemic, enantiopure) and heterochiral (mainly racemic) crystalline forms. − In the strict sense of the word, conglomerate homochiral crystals are not polymorphic with respect to any racemic solid. However, like ordinary polymorphs, those and others can be formed from a common feed medium (solution or melt) and can transform into each other both as a result of solid-phase transitions and as a result of contact with the common liquid phase .…”

Section: Introductionmentioning

confidence: 99%

“…However, like ordinary polymorphs, those and others can be formed from a common feed medium (solution or melt) and can transform into each other both as a result of solid-phase transitions and as a result of contact with the common liquid phase . Lack of attention to this feature of a phase behavior of the chiral substance can lead to withdrawal of the dosage form from the market and/or the need for remarketing of the already registered drug …”

Section: Introductionmentioning

confidence: 99%

Spontaneous Resolution of Chiral 3-(2,3-Dimethylphenoxy)propane-1,2-diol under the Circumstances of an Unusual Diversity of Racemic Crystalline Modifications

Бредихин

Zakharychev

Бредихина

et al. 2017

Depending on the conditions of crystallization from solutions, racemic 3-(2,3-dimethylphenoxy)propane-1,2-diol 1 forms three relatively stable crystalline modifications. Each of the crystalline forms, namely, two polymorphic racemic compounds and a racemic conglomerate, has been characterized by single-crystal X-ray diffraction. Two more metastable racemic compounds crystallized from the racemic melt have been found by differential scanning calorimetry method. Additional thermochemical investigations allowed to plot the dependence of the free Gibbs energy on temperature for all the phases found. With the help of slurrying experiments, the nature of the transitions between solid phases has been specified. It has been found that even a slight predominance of one of the enantiomers in almost racemic 1 samples ensures the crystallization of the conglomerate. The revealed features of rac-1 crystallization have been taken into account during the realization of its resolution into individual enantiomers by the entrainment procedure.