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Anion-switchable supramolecular gels for controlling pharmaceutical crystal growth

Nature Chemistry volume 2, pages 1037–1043 (2010)Cite this article

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Abstract

We describe the use of low-molecular-weight supramolecular gels as media for the growth of molecular crystals. Growth of a range of crystals of organic compounds, including pharmaceuticals, was achieved in bis(urea) gels. Low-molecular-weight supramolecular gelators allow access to an unlimited range of solvent systems, in contrast to conventional aqueous gels such as gelatin and agarose. A detailed study of carbamazepine crystal growth in four different bis(urea) gelators, including a metallogelator, is reported. The crystallization of a range of other drug substances, namely sparfloxacin, piroxicam, theophylline, caffeine, ibuprofen, acetaminophen (paracetamol), sulindac and indomethacin, was also achieved in supramolecular gel media without co-crystal formation. In many cases, crystals can be conveniently recovered from the gels by using supramolecular anion-triggered gel dissolution; however, crystals of substances that themselves bind to anions are dissolved by them. Overall, supramolecular gel-phase crystallization offers an extremely versatile new tool in pharmaceutical polymorph screening.

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Figure 1: SEM images of xerogels of 1 and 3 obtained from drying a 1 wt% gel in toluene.
Figure 2: Stress sweep rheology of gelator 1.
Figure 3: CBZ crystals grown in solutions or gels of 1.
Figure 4: Recovery of a single crystal of CBZ form III by acetate-anion-triggered gel dissolution of a 1:9 CHCl3:toluene gel of gelator 3.
Figure 5: Optical microscopy of CBZ (1 wt%) grown in a metallogel medium together with control experiments showing the effect of the gel.
Figure 6: SEM images of CBZ in metallogels of 4 with CuCl2, showing crystals of carbamazepine grown within the metallogel.

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Acknowledgements

The authors thank the Engineering and Physical Sciences Research Council, GlaxoSmithKline and the Association of the Commonwealth Universities for funding.

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  1. Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK

    Jonathan A. Foster, Marc-Oliver M. Piepenbrock, Gareth O. Lloyd, Nigel Clarke, Judith A. K. Howard & Jonathan W. Steed

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  1. Jonathan A. Foster
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Contributions

J.A.F., M.-O.M.P. and G.O.L. undertook the synthesis of gelators, experimental studies and rheology measurements. N.C. supervised the rheology work, J.A.K.H. supervised the crystallographic work and J.W.S. was responsible for overall project concept, direction and coordination. All authors contributed to writing the manuscript.

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Correspondence to Jonathan W. Steed.

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Foster, J., Piepenbrock, MO., Lloyd, G. et al. Anion-switchable supramolecular gels for controlling pharmaceutical crystal growth. Nature Chem 2, 1037–1043 (2010). https://doi.org/10.1038/nchem.859

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