The Use of Co-crystals for the Determination of Absolute Stereochemistry: An Alternative to Salt Formation

Eccles, Kevin S.; Deasy, Rebecca E.; Fábián, László; Maguire, Anita R.; Lawrence, Simon E.

doi:10.1021/jo102148p

Cited by 19 publications

(12 citation statements)

References 28 publications

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“…(À)-cam. Similar cases of structural resemblance in co-crystals derived from enantiopure and racemic forms of chiral substances with achiral co-crystal formers have previously been reported (Lemmerer et al, 2008;Eccles et al, 2011). In another relevant study, (S)-and (R/S)-ibuprofen were found to form almost isostructural co-crystals with nicotinamide; in that case, the (S) and (R/S) co-crystals crystallized in monoclinic (space group P2 1 ) and orthorhombic (space group Pca2 1 ) structures, respectively (Berry et al, 2008).…”

Section: Crystal Structure Of Ccr3:2supporting

confidence: 76%

Binary co-crystals of the active pharmaceutical ingredient 1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene and camphoric acid

Bisht

Patel

Rachuri

et al. 2014

Acta Crystallogr Sect B

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Co-crystals comprising the active pharmaceutical ingredient 1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene, C12H10N4, and the chiral co-formers (+)-, (-)- and (rac)-camphoric acid (cam), C10H16O4, have been synthesized. Two different stoichiometries of the API and co-former are obtained, namely 1:1 and 3:2. Crystallization experiments suggest that the 3:2 co-crystal is kinetically favoured over the 1:1 co-crystal. Single-crystal X-ray diffraction analysis of the co-crystals reveals N-H...O hydrogen bonding as the primary driving force for crystallization of the supramolecular structures. The 1:1 co-crystal contains undulating hydrogen-bonded ribbons, in which the chiral cam molecules impart a helical twist. The 3:2 co-crystal contains discrete Z-shaped motifs comprising three molecules of the API and two molecules of cam. The 3:2 co-crystals with (+)-cam, (-)-cam (space group P21) and (rac)-cam (space group P21/n) are isostructural. The enantiomeric co-crystals contain pseudo-symmetry consistent with space group P21/n, and the co-crystal with (rac)-cam represents a solid solution between the co-crystals containing (+)-cam and (-)-cam.

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Section: Crystal Structure Of Ccr3:2supporting

confidence: 76%

Binary co-crystals of the active pharmaceutical ingredient 1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene and camphoric acid

Bisht

Patel

Rachuri

et al. 2014

Acta Crystallogr Sect B

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“…The interaction between a CCF and ladderane would enable the components to pack more efficiently relative to the pure ladderane. Whereas cocrystallizations are often successfully used to aide the elucidation of the structures biological molecules (22), the application of a cocrystal strategy to determine the relative configuration of a diastereomer had not been reported (23)(24)(25)(26)(27).…”

Section: Resultsmentioning

confidence: 99%

“…To circumvent difficulties to obtain single crystals, we revisited principles of crystal engineering by employing a cocrystallization (Scheme 3). Cocrystallizations are often used to determine structures of biomolecules (e.g., proteins) (22), yet applications to parallel problems involving small molecules have been less explored, with absolute structure determinations of steroids (23,24) and, more recently, separations and structure determinations of natural products (25,26) and a bicyclobutyl being the only examples (27). Here, a cocrystallization of the second isomer with 3,5-dinitrobenzoic acid (3,5-DNBA) readily afforded single crystals that enabled the relative configuration of chiral 1b to be confirmed.…”

mentioning

confidence: 99%

Crystal engineering rescues a solution organic synthesis in a cocrystallization that confirms the configuration of a molecular ladder

Atkinson

Mariappan

Bučar

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Treatment of an achiral molecular ladder of C 2h symmetry composed of five edge-sharing cyclobutane rings, or a [5]-ladderane, with acid results in cis-to trans-isomerization of end pyridyl groups. Solution NMR spectroscopy and quantum chemical calculations support the isomerization to generate two diastereomers. The NMR data, however, could not lead to unambiguous configurational assignments of the two isomers. Single-crystal X-ray diffraction was employed to determine each configuration. One isomer readily crystallized as a pure form and X-ray diffraction revealed the molecule as being achiral based on C i symmetry. The second isomer resisted crystallization under a variety of conditions. Consequently, a strategy based on a cocrystallization was developed to generate single crystals of the second isomer. Cocrystallization of the isomer with a carboxylic acid readily afforded single crystals that confirmed a chiral ladderane based on C 2 symmetry. The chiral ladderane and acid self-assembled to generate a five-component hydrogen-bonded complex that packs to form large solvent-filled homochiral channels of nanometer-scale dimensions. Whereas cocrystallizations are frequently applied to structure determinations of proteins, our study represents the first application of a cocrystallization to confirm the relative configuration of a small-molecule diastereomer generated in a solution-phase organic synthesis. supramolecular synthesis | solid-state reactivity | hydrogen bonding

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“…However, there is no single definition as to what a pharmaceutical co-crystal. Multiple definitions appear in the literature, but a common definition is "a stoichiometric multicomponent system connected by non-covalent interactions where all the components present are solid under ambient conditions" [4][5][6]. As both the API and co-former in a co-crystal must be solid on their own under ambient conditions, solvates and hydrates are not classed as co-crystals.…”

Section: Pharmaceutical Co-crystalsmentioning

confidence: 99%

Formulation And In-Vitro Evaluation Of Cocrystals Of Pantoprazole Sodium For Immediate Release

Jain¹,

Bansal²,

Sharma³

2021

IJPBA

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Pantoprazole is extensively metabolized in the liver and has a total serum clearance of 0.1 l/h/kg, a serum elimination half-life of about 1.1 h, and an apparent volume of distribution of 0.15 L/kg. 98% of pantoprazole is bound to serum proteins. Elimination half-life, clearance, and volume of distribution are independent of the dose. Almost 80% of an oral or intravenous dose is excreted as metabolites in urine; the remainder is found in feces and originates from biliary secretion. The clearance of pantoprazole is only slightly affected by age, with its half-life being approximately 1.25 h in the elderly. Pantoprazole is an acid labile drug that requires protection from degradation in acidic media. Hence, co-crystallization of pantoprazole sodium with appropriate co-formers will inhibit its degradation in acidic medium ensuring fast release in the stomach. The acid-labile drugs for oral administration may also be protected from gastric acidity by inhibiting its degradation upon entering into acidic environment. So, the current approach includes co-crystallization of the provided drug with appropriate co-former which prevents degradation of drug by quick absorption and protects the drug from low pH. Apart from that, the formulations also modulate or control the drug release for an immediate action. Keywords: Pantoprazole sodium, Co-crystal, solvent drop method, Co-former.

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The Use of Co-crystals for the Determination of Absolute Stereochemistry: An Alternative to Salt Formation

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Cited by 19 publications

References 28 publications

Binary co-crystals of the active pharmaceutical ingredient 1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene and camphoric acid

Binary co-crystals of the active pharmaceutical ingredient 1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene and camphoric acid

Crystal engineering rescues a solution organic synthesis in a cocrystallization that confirms the configuration of a molecular ladder

Formulation And In-Vitro Evaluation Of Cocrystals Of Pantoprazole Sodium For Immediate Release

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