Introduction to Chiral Crystallization in Pharmaceutical Development and Manufacturing

Tábora, José E.; Brueggemeier, Shawn B.; Sweeney, Jason T.; Lovette, Michael A.

doi:10.1002/9781119600800.ch25

Cited by 2 publications

(3 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The interest in the resolution of racemic “active pharmaceutical ingredients” (APIs) stems from the importance of enantiopure compounds toward the production and processing of safe and efficient pharmaceuticals. − Usually, only one enantiomer in a racemic API is biologically functional, while the other may be inactive or provide side effects. The racemic formulation of thalidomide was a case that clearly demonstrates this concern.…”

Section: Introductionmentioning

confidence: 99%

Spontaneous Resolution of RS-Fluoxetine to a Racemic Conglomerate upon Salt Formation with Oxalic Acid

Carvalho

Diniz

Cardoso

et al. 2022

Crystal Growth & Design

View full text Add to dashboard Cite

Fluoxetine (Flx), an important active pharmaceutical ingredient (API) for the treatment of depression, is commercially available as a racemic hydrochloride salt. Interestingly, the spontaneous resolution of RS-Flx occurred upon salt formation with oxalic acid (H2Oxa). Single crystals of Flx hydrogen-oxalate salt (Flx HOxa) have been obtained by slow evaporation from solution. They have been examined by single-crystal and powder X-ray diffraction, chiral chromatography, thermal analysis, and equilibrium solubility, revealing that Flx HOxa salt crystallizes as a racemic conglomerate. In the salt structure, the Flx+··· HOxa– ionic pairs assemble in 21-helical chains in the Sohncke space group P21 and Z’ = 1, through N+H···O– H-bonds. Additional cationic homochiral chains are formed in the crystals through noncovalent interactions between helicoidal motifs. It was shown that Flx HOxa conglomerates are as thermally stable as the hydrochloride salt of Flx, confirmed by thermal analysis. The identification of Flx HOxa salt conglomerates is a crucial step for the further chiral resolution process for the API and is also a novel multicomponent crystal with promising properties for a new drug formulation.

show abstract

Section: Introductionmentioning

confidence: 99%

Spontaneous Resolution of RS-Fluoxetine to a Racemic Conglomerate upon Salt Formation with Oxalic Acid

Carvalho

Diniz

Cardoso

et al. 2022

Crystal Growth & Design

View full text Add to dashboard Cite

show abstract

“…The crystallization of a molecule in the Sohncke group, which is a space group without mirror or inversion symmetry, is known as chiral crystallization. Chiral crystallization is an attractive topic for scientists engaged in pharmaceutical development and manufacturing, crystal structure prediction, crystal engineering, − and nonlinear optics . The construction of polar crystals that show the chiral property by an assembly of achiral molecules generally occurs infrequently because molecules usually assemble to cancel out their polarity and asymmetric property. , In this context, it is important to understand the circumstances, frequency, and chances of an achiral molecule crystallizing in a homochiral manner .…”

Section: Introductionmentioning

confidence: 99%

“…The construction of polar crystals that show the chiral property by an assembly of achiral molecules generally occurs infrequently because molecules usually assemble to cancel out their polarity and asymmetric property. , In this context, it is important to understand the circumstances, frequency, and chances of an achiral molecule crystallizing in a homochiral manner . While the ability to control chiral crystallization of achiral molecules is intriguing, a rational explanation of this phenomenon has not been reported as yet. ,− Nevertheless, the significance of molecular interactions within the crystal has been acknowledged …”

Section: Introductionmentioning

confidence: 99%

High Proportion of Chiral Crystallization of Achiral Indolyl Sulfonamides: Effect of Intermolecular Interactions

Kikkawa

Maeno

Katagiri³

et al. 2021

Crystal Growth & Design

View full text Add to dashboard Cite

We investigated the effect of indole moieties on chiral crystallization. In this regard, we assessed the influence of intermolecular interactions and contacts on the assembly of these molecules. A systematic analysis of 62 crystal structures of secondary aromatic sulfonamides bearing 4-, 5-, 6-, and 7-aminoindolyl groups revealed that the proportion of indolyl compounds showing chiral crystallization was apparently higher (21%, except for kryptoracemate) than that of nonindolyl sulfonamides (11%). Moreover, 33% (5 out of 15 crystals) and 44% (7 out of 16 crystals) of 4- and 7-indolyl sulfonamide derivatives preferred chiral crystallization, respectively. This suggested a correlation between the type of contact and the chirality of the assembly of adjacent molecules. Specifically, the proportion of achiral indolyl sulfonamides undergoing chiral crystallization was drastically increased by N(indole)H···O interactions, slightly increased by C(sp2)H···π interactions, and decreased owing to π···π interactions. These tendencies were also true for sulfonamides with different substituents, which suggested that the T-shape contact would be more favorable than π···π interactions for chiral crystallization.

show abstract

Introduction to Chiral Crystallization in Pharmaceutical Development and Manufacturing

Cited by 2 publications

References 10 publications

Spontaneous Resolution of RS-Fluoxetine to a Racemic Conglomerate upon Salt Formation with Oxalic Acid

Spontaneous Resolution of RS-Fluoxetine to a Racemic Conglomerate upon Salt Formation with Oxalic Acid

High Proportion of Chiral Crystallization of Achiral Indolyl Sulfonamides: Effect of Intermolecular Interactions

Contact Info

Product

Resources

About