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

Berry, David J., Seaton, Colin C., Clegg, William , Harrington, Ross W., Coles, Simon J., Horton, Peter N., Hursthouse, Michael B., Storey, Richard, Jones, William, Friscic, Tomislav and Blagden, Nicholas (2008) Applying hot-stage microscopy to co-crystal screening: a study of nicotinamide with seven active pharmaceutical ingredients. Crystal Growth and Design, 8 (5). pp. 1697-1712. ISSN 1528-7483

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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.

Keywords:Acetaminophen, Cocrystals, Design, Sulfathiazole, Z'-greater-than-1, Solubility, Polymorphism, Solid-state, Cambridge Structural database, Multiple molecules
Subjects:F Physical Sciences > F131 Crystallography
B Subjects allied to Medicine > B230 Pharmacy
F Physical Sciences > F170 Physical Chemistry
F Physical Sciences > F290 Materials Science not elsewhere classified
Divisions:College of Science > School of Pharmacy
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ID Code:7702
Deposited On:27 Feb 2013 19:53

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