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Applying hot-stage microscopy to co-crystal screening: A study of nicotinamide with seven active pharmaceutical ingredients

Lookup NU author(s): Emeritus Professor Bill Clegg, Dr Ross Harrington

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Abstract

Co-crystal screening is routinely undertaken using high-throughput solution growth. We report a low- to medium-throughput approach, encompassing both a melt and solution crystallization step as a route to the identification of co-crystals. Prior to solution studies, a melt growth step was included utilizing the Koller mixed fusion method. This method allowed elucidation of the thermodynamic landscape within the binary phase diagram and was found to increase overall screening efficiency. The pharmaceutically acceptable adduct nicotinamide was selected and screened against a small set of active pharmaceutical ingredients (APIs) (ibuprofen (both the racemic compound (R/S) and S-enantiomer), fenbufen, flurbiprofen (R/S), ketoprofen (R/S), paracetamol, piracetam, and salicylic acid) as part of a larger systematic study of synthon stability. From the screen, three new co-crystal systems have been identified (ibuprofen (R/S and S) and salicylic acid) and their crystal structures determined. Because of poor crystal growth synchrotron radiation was required for structure solution of the S-ibuprofen nicotinamide co-crystal. Two further potential systems have also been discovered (fenbufen and flurbiprofen), but crystals suitable for structure determination have yet to be obtained. A greater ability to control crystallization kinetics is required to yield phase-pure single-crystalline material for full verification of this crystal engineering strategy.


Publication metadata

Author(s): Berry DJ, Seaton CC, Clegg W, Harrington RW, Coles SJ, Horton PN, Hursthouse MB, Storey R, Jones W, Friscic T, Blagden N

Publication type: Article

Publication status: Published

Journal: Crystal Growth & Design

Year: 2008

Volume: 8

Issue: 5

Pages: 1697-1712

ISSN (print): 1528-7483

ISSN (electronic): 1528-7505

Publisher: American Chemical Society

URL: http://dx.doi.org/10.1021/cg.800035w

DOI: 10.1021/cg.800035w


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