Building up co-crystals: structural motif consistencies across families of co-crystals
AuthorSeaton, Colin C.
Crystal structure prediction
Rights© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons. org/licenses/by/4.0/).
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AbstractThe creation of co-crystals as a route to creating new pharmaceutical phases with modified or defined physicochemical properties is an area of intense research. Much of the current research has focused on creating new phases for numerous active pharmaceutical ingredients (APIs) to alter physical properties such as low solubilities, enhancing processability or stability. Such studies have identified suitable co-formers and common bonding motifs to aid with the design of new co-crystals but understanding how the changes in the molecular structure of the components are reflected in the packing and resulting properties is still lacking. This lack of insight means that the design and growth of new co-crystals is still a largely empirical process with co-formers selected and then attempts to grow the different materials undertaken to evaluate the resulting properties. This work will report on the results of a combination of crystal structure database analysis with computational chemistry studies to identify what structural features are retained across a selection of families of co-crystals with common components. The competition between different potential hydrogen bonding motifs was evaluated using ab initio quantum mechanical calculations and this was related to the commonality in the packing motifs when observed. It is found while the stronger local bonding motifs are often retained within systems, the balance of weaker long-range packing forces gives rise to many subtle shifts in packing leading to greater challenges in the prediction of final crystal structures.
CitationSeaton CC (2021) Building up co-crystals: structural motif consistencies across families of co-crystals. Proceedings. 78(1): 45.
Link to publisher’s versionhttps://doi.org/10.3390/IECP2020-08708
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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.; et al. (2008-05)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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