Exploring polymorphism and stoichiometric diversity in naproxen/proline cocrystals

Natalia Tumanova, Nikolay Tumanov, Franziska Fischer, Fabrice Morelle, Voraksmy Ban, Koen Robeyns, Yaroslav Filinchuk, Johan Wouters, Franziska Emmerling, Tom Leyssens

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We present naproxen/proline cocrystals discovered when combining enantiopure and racemic naproxen and proline. Using liquid-assisted grinding as the main method to explore the variety of crystal forms in this system, we found 17 cocrystals, of which the structures of only four of them were previously known. The naproxen/proline system exhibited multiple polymorphs of 1 : 1 stoichiometry as well as more rare cocrystals with 1 : 2 and 2 : 3 stoichiometries, two cocrystal hydrates and one cocrystal solvate. In situ ball-milling, used to monitor liquid-assisted grinding reactions, revealed that the solvent dictates the reaction intermediates even if the final reaction product stays the same. Synchrotron X-ray diffraction data collected in situ upon heating allowed us to monitor directly the phase changes upon heating and gave access to pure diffraction patterns of several cocrystals, thus enabling their structure determination from powder X-ray diffraction data; this method also confirmed the formation of a conglomerate in the RS-naproxen/dl-proline system. Proline in cocrystals kept its ability to form charge-assisted head-to-tail N-H...O hydrogen bonds, typical of pure crystalline amino acids, thus increasing the percentage of strong charge-assisted interactions in the structure and consequently providing some of the cocrystals with higher melting points as compared to pure naproxen. The majority of drugs are chiral, and hence, these data are of importance to the pharmaceutical industry as they provide insight into the challenges of chiral cocrystallization.

langue originaleAnglais
Pages (de - à)7308-7321
Nombre de pages14
journalCrystEngComm
Volume20
Numéro de publication45
Les DOIs
étatPublié - 1 janv. 2018

Empreinte digitale

Naproxen
polymorphism
grinding
Polymorphism
Proline
Stoichiometry
stoichiometry
Heating
Reaction intermediates
heating
reaction intermediates
Ball milling
Liquids
liquids
guy wires
Hydrates
Synchrotrons
Reaction products
diffraction
hydrates

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Tumanova, N., Tumanov, N., Fischer, F., Morelle, F., Ban, V., Robeyns, K., ... Leyssens, T. (2018). Exploring polymorphism and stoichiometric diversity in naproxen/proline cocrystals. CrystEngComm, 20(45), 7308-7321. https://doi.org/10.1039/C8CE01338A
Tumanova, Natalia ; Tumanov, Nikolay ; Fischer, Franziska ; Morelle, Fabrice ; Ban, Voraksmy ; Robeyns, Koen ; Filinchuk, Yaroslav ; Wouters, Johan ; Emmerling, Franziska ; Leyssens, Tom. / Exploring polymorphism and stoichiometric diversity in naproxen/proline cocrystals. Dans: CrystEngComm. 2018 ; Vol 20, Numéro 45. p. 7308-7321.
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abstract = "We present naproxen/proline cocrystals discovered when combining enantiopure and racemic naproxen and proline. Using liquid-assisted grinding as the main method to explore the variety of crystal forms in this system, we found 17 cocrystals, of which the structures of only four of them were previously known. The naproxen/proline system exhibited multiple polymorphs of 1 : 1 stoichiometry as well as more rare cocrystals with 1 : 2 and 2 : 3 stoichiometries, two cocrystal hydrates and one cocrystal solvate. In situ ball-milling, used to monitor liquid-assisted grinding reactions, revealed that the solvent dictates the reaction intermediates even if the final reaction product stays the same. Synchrotron X-ray diffraction data collected in situ upon heating allowed us to monitor directly the phase changes upon heating and gave access to pure diffraction patterns of several cocrystals, thus enabling their structure determination from powder X-ray diffraction data; this method also confirmed the formation of a conglomerate in the RS-naproxen/dl-proline system. Proline in cocrystals kept its ability to form charge-assisted head-to-tail N-H...O hydrogen bonds, typical of pure crystalline amino acids, thus increasing the percentage of strong charge-assisted interactions in the structure and consequently providing some of the cocrystals with higher melting points as compared to pure naproxen. The majority of drugs are chiral, and hence, these data are of importance to the pharmaceutical industry as they provide insight into the challenges of chiral cocrystallization.",
author = "Natalia Tumanova and Nikolay Tumanov and Franziska Fischer and Fabrice Morelle and Voraksmy Ban and Koen Robeyns and Yaroslav Filinchuk and Johan Wouters and Franziska Emmerling and Tom Leyssens",
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Tumanova, N, Tumanov, N, Fischer, F, Morelle, F, Ban, V, Robeyns, K, Filinchuk, Y, Wouters, J, Emmerling, F & Leyssens, T 2018, 'Exploring polymorphism and stoichiometric diversity in naproxen/proline cocrystals', CrystEngComm, VOL. 20, Numéro 45, p. 7308-7321. https://doi.org/10.1039/C8CE01338A

Exploring polymorphism and stoichiometric diversity in naproxen/proline cocrystals. / Tumanova, Natalia; Tumanov, Nikolay; Fischer, Franziska; Morelle, Fabrice; Ban, Voraksmy; Robeyns, Koen; Filinchuk, Yaroslav; Wouters, Johan; Emmerling, Franziska; Leyssens, Tom.

Dans: CrystEngComm, Vol 20, Numéro 45, 01.01.2018, p. 7308-7321.

Résultats de recherche: Contribution à un journal/une revueArticle

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T1 - Exploring polymorphism and stoichiometric diversity in naproxen/proline cocrystals

AU - Tumanova, Natalia

AU - Tumanov, Nikolay

AU - Fischer, Franziska

AU - Morelle, Fabrice

AU - Ban, Voraksmy

AU - Robeyns, Koen

AU - Filinchuk, Yaroslav

AU - Wouters, Johan

AU - Emmerling, Franziska

AU - Leyssens, Tom

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N2 - We present naproxen/proline cocrystals discovered when combining enantiopure and racemic naproxen and proline. Using liquid-assisted grinding as the main method to explore the variety of crystal forms in this system, we found 17 cocrystals, of which the structures of only four of them were previously known. The naproxen/proline system exhibited multiple polymorphs of 1 : 1 stoichiometry as well as more rare cocrystals with 1 : 2 and 2 : 3 stoichiometries, two cocrystal hydrates and one cocrystal solvate. In situ ball-milling, used to monitor liquid-assisted grinding reactions, revealed that the solvent dictates the reaction intermediates even if the final reaction product stays the same. Synchrotron X-ray diffraction data collected in situ upon heating allowed us to monitor directly the phase changes upon heating and gave access to pure diffraction patterns of several cocrystals, thus enabling their structure determination from powder X-ray diffraction data; this method also confirmed the formation of a conglomerate in the RS-naproxen/dl-proline system. Proline in cocrystals kept its ability to form charge-assisted head-to-tail N-H...O hydrogen bonds, typical of pure crystalline amino acids, thus increasing the percentage of strong charge-assisted interactions in the structure and consequently providing some of the cocrystals with higher melting points as compared to pure naproxen. The majority of drugs are chiral, and hence, these data are of importance to the pharmaceutical industry as they provide insight into the challenges of chiral cocrystallization.

AB - We present naproxen/proline cocrystals discovered when combining enantiopure and racemic naproxen and proline. Using liquid-assisted grinding as the main method to explore the variety of crystal forms in this system, we found 17 cocrystals, of which the structures of only four of them were previously known. The naproxen/proline system exhibited multiple polymorphs of 1 : 1 stoichiometry as well as more rare cocrystals with 1 : 2 and 2 : 3 stoichiometries, two cocrystal hydrates and one cocrystal solvate. In situ ball-milling, used to monitor liquid-assisted grinding reactions, revealed that the solvent dictates the reaction intermediates even if the final reaction product stays the same. Synchrotron X-ray diffraction data collected in situ upon heating allowed us to monitor directly the phase changes upon heating and gave access to pure diffraction patterns of several cocrystals, thus enabling their structure determination from powder X-ray diffraction data; this method also confirmed the formation of a conglomerate in the RS-naproxen/dl-proline system. Proline in cocrystals kept its ability to form charge-assisted head-to-tail N-H...O hydrogen bonds, typical of pure crystalline amino acids, thus increasing the percentage of strong charge-assisted interactions in the structure and consequently providing some of the cocrystals with higher melting points as compared to pure naproxen. The majority of drugs are chiral, and hence, these data are of importance to the pharmaceutical industry as they provide insight into the challenges of chiral cocrystallization.

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Tumanova N, Tumanov N, Fischer F, Morelle F, Ban V, Robeyns K et al. Exploring polymorphism and stoichiometric diversity in naproxen/proline cocrystals. CrystEngComm. 2018 janv. 1;20(45):7308-7321. https://doi.org/10.1039/C8CE01338A