Opening Pandora’s Box: Chirality, Polymorphism, and Stoichiometric Diversity in Flurbiprofen/Proline Cocrystals

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

Research output: Contribution to journalArticle

Abstract

Proline has been widely used for various cocrystallization applications, including pharmaceutical cocrystals. Combining enantiopure and racemic flurbiprofen and proline, we discovered 18 new crystal structures. Liquid-assisted grinding proved highly efficient to explore all the variety of crystal forms. A unique combination of state-of-the-art characterization techniques, comprising variable temperature in situ X-ray diffraction and in situ ball-milling, along with other physicochemical methods and density functional theory calculations, was indispensable for identifying all the phases. Analyzing the results of in situ ball-milling, we established a stepwise mechanism for the formation of several 1:1 cocrystals via an intermediate 2:1 phase. The nature of the solvent in liquid-assisted grinding was found to significantly affect the reaction rate and, in some cases, the reaction pathway.
Original languageEnglish
Pages (from-to)954-961
Number of pages8
JournalCrystal Growth & Design
Volume18
Issue number2
DOIs
Publication statusPublished - 4 Jan 2018

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Flurbiprofen
Chirality
polymorphism
Ball milling
grinding
Polymorphism
chirality
Proline
boxes
balls
Liquids
liquids
Drug products
Reaction rates
Density functional theory
reaction kinetics
Crystal structure
density functional theory
X ray diffraction
Crystals

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Tumanova, Natalia ; Tumanov, Nikolay ; Robeyns, Koen ; Fischer, Franziska ; Fusaro, Luca ; Morelle, Fabrice ; Ban, Voraksmy ; Hautier, Geoffroy ; Filinchuk, Yaroslav ; Wouters, Johan ; Leyssens, Tom ; Emmerling, Franziska. / Opening Pandora’s Box : Chirality, Polymorphism, and Stoichiometric Diversity in Flurbiprofen/Proline Cocrystals. In: Crystal Growth & Design. 2018 ; Vol. 18, No. 2. pp. 954-961.
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Tumanova, N, Tumanov, N, Robeyns, K, Fischer, F, Fusaro, L, Morelle, F, Ban, V, Hautier, G, Filinchuk, Y, Wouters, J, Leyssens, T & Emmerling, F 2018, 'Opening Pandora’s Box: Chirality, Polymorphism, and Stoichiometric Diversity in Flurbiprofen/Proline Cocrystals', Crystal Growth & Design, vol. 18, no. 2, pp. 954-961. https://doi.org/10.1021/acs.cgd.7b01436

Opening Pandora’s Box : Chirality, Polymorphism, and Stoichiometric Diversity in Flurbiprofen/Proline Cocrystals. / Tumanova, Natalia; Tumanov, Nikolay; Robeyns, Koen; Fischer, Franziska; Fusaro, Luca; Morelle, Fabrice; Ban, Voraksmy; Hautier, Geoffroy; Filinchuk, Yaroslav; Wouters, Johan; Leyssens, Tom; Emmerling, Franziska.

In: Crystal Growth & Design, Vol. 18, No. 2, 04.01.2018, p. 954-961.

Research output: Contribution to journalArticle

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T2 - Chirality, Polymorphism, and Stoichiometric Diversity in Flurbiprofen/Proline Cocrystals

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AU - Tumanov, Nikolay

AU - Robeyns, Koen

AU - Fischer, Franziska

AU - Fusaro, Luca

AU - Morelle, Fabrice

AU - Ban, Voraksmy

AU - Hautier, Geoffroy

AU - Filinchuk, Yaroslav

AU - Wouters, Johan

AU - Leyssens, Tom

AU - Emmerling, Franziska

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