Enabling direct preferential crystallization in a stable racemic compound system

Lina C. Harfouche; Clément Brandel; Yohann Cartigny; Joop H. Ter Horst; Gérard Coquerel; Samuel Petit

doi:10.1021/acs.molpharmaceut.9b00805

Enabling direct preferential crystallization in a stable racemic compound system

Lina C. Harfouche, Clément Brandel^*, Yohann Cartigny, Joop H. Ter Horst, Gérard Coquerel, Samuel Petit

^*Corresponding author for this work

Strathclyde Institute Of Pharmacy And Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

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Abstract

The preparative resolution by preferential crystallization (PC) of proxyphylline has been achieved despite the existence of a stable racemic compound. This is enabled through the careful selection of a solvent in which both the racemic compound and the metastable conglomerate possess a low nucleation rate. Induction time measurements in isobutyl alcohol show that a highly supersaturated solution (β = 2.3) remains clear for almost 1 h at 20 mL scale, revealing a slow nucleation rate. Seeding the supersaturated solution with the pure enantiomer triggered its crystallization both isothermal and polythermic modes of PC were successfully implemented. Alongside the reported case of diprophylline, this study opens opportunities to broaden the application of PC toward slowly crystallizing racemic compounds.

Original language	English
Pages (from-to)	4670-4676
Number of pages	7
Journal	Molecular Pharmaceutics
Volume	16
Issue number	11
Early online date	23 Sept 2019
DOIs	https://doi.org/10.1021/acs.molpharmaceut.9b00805
Publication status	Published - 4 Nov 2019

Keywords

metastable conglomerate
nucleation inhibition
preferential crystallization
proxyphylline

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Harfouche-etal-MP-2019-Enabling-direct-preferential-crystallization-in-a-stable-racemicAccepted author manuscript, 620 KB

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abstract = "The preparative resolution by preferential crystallization (PC) of proxyphylline has been achieved despite the existence of a stable racemic compound. This is enabled through the careful selection of a solvent in which both the racemic compound and the metastable conglomerate possess a low nucleation rate. Induction time measurements in isobutyl alcohol show that a highly supersaturated solution (β = 2.3) remains clear for almost 1 h at 20 mL scale, revealing a slow nucleation rate. Seeding the supersaturated solution with the pure enantiomer triggered its crystallization both isothermal and polythermic modes of PC were successfully implemented. Alongside the reported case of diprophylline, this study opens opportunities to broaden the application of PC toward slowly crystallizing racemic compounds.",

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AU - Harfouche, Lina C.

AU - Brandel, Clément

AU - Cartigny, Yohann

AU - Ter Horst, Joop H.

AU - Coquerel, Gérard

AU - Petit, Samuel

N1 - This document is the Accepted Manuscript version of a Published Work that appeared in final form in Molecular Pharmaceutics, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work seehttps://doi.org/10.1021/acs.molpharmaceut.9b00805

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N2 - The preparative resolution by preferential crystallization (PC) of proxyphylline has been achieved despite the existence of a stable racemic compound. This is enabled through the careful selection of a solvent in which both the racemic compound and the metastable conglomerate possess a low nucleation rate. Induction time measurements in isobutyl alcohol show that a highly supersaturated solution (β = 2.3) remains clear for almost 1 h at 20 mL scale, revealing a slow nucleation rate. Seeding the supersaturated solution with the pure enantiomer triggered its crystallization both isothermal and polythermic modes of PC were successfully implemented. Alongside the reported case of diprophylline, this study opens opportunities to broaden the application of PC toward slowly crystallizing racemic compounds.

AB - The preparative resolution by preferential crystallization (PC) of proxyphylline has been achieved despite the existence of a stable racemic compound. This is enabled through the careful selection of a solvent in which both the racemic compound and the metastable conglomerate possess a low nucleation rate. Induction time measurements in isobutyl alcohol show that a highly supersaturated solution (β = 2.3) remains clear for almost 1 h at 20 mL scale, revealing a slow nucleation rate. Seeding the supersaturated solution with the pure enantiomer triggered its crystallization both isothermal and polythermic modes of PC were successfully implemented. Alongside the reported case of diprophylline, this study opens opportunities to broaden the application of PC toward slowly crystallizing racemic compounds.

KW - metastable conglomerate

KW - nucleation inhibition

KW - preferential crystallization

KW - proxyphylline

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VL - 16

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JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

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ER -

Enabling direct preferential crystallization in a stable racemic compound system

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Keywords

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