Applying hot-stage microscopy to co-crystal screening: A study of nicotinamide with seven active pharmaceutical ingredients.
Berry, David J. Seaton, Colin C. Clegg, W. Harrington, R.W. Coles, S.J. Horton, P.N. Hursthouse, M.B. Storey, Richard Jones, W. Friščić, T.
Berry, David J.
Seaton, Colin C.
Clegg, W.
Harrington, R.W.
Coles, S.J.
Horton, P.N.
Hursthouse, M.B.
Storey, Richard
Jones, W.
Friščić, T.
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2008-05
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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 Kofler 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.
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Berry, D. J., Seaton, C. C., Clegg, W., Harrington, R. W., Coles, S. J., Horton, P. N., Hursthouse, M. B., Storey, R., Jones, W., Friščić, T. and Blagden, N. (2008). Applying hot-stage microscopy to co-crystal screening: A study of nicotinamide with seven active pharmaceutical ingredients. Crystal growth & design, Vol. 8, No. 5, pp. 1697-1712.
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