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The polymorphism of progesterone: Stabilization of a ‘disappearing’ polymorph by co-crystallization

Authors

  • Robert W. Lancaster,

    1. Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK
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  • Panagiotis G. Karamertzanis,

    1. Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK
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  • Ashley T. Hulme,

    1. Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK
    Current affiliation:
    1. Pharmorphix Ltd., 250 Cambridge Science Park, Milton Road, Cambridge CB4 0WE, UK.
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  • Derek A. Tocher,

    1. Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK
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  • Thomas C. Lewis,

    1. Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK
    Current affiliation:
    1. Pharmaterials (UK) Ltd., The Science and Technology Centre, Earley Gate, Whiteknights Road, Reading RG6 6BZ, UK.
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  • Sarah L. Price

    Corresponding author
    1. Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK
    • Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK, Telephone: +44-20-7679-4622; Fax: +44-20-7679-7463.
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Abstract

Progesterone has been known to be polymorphic for over 70 years, and crystallization conditions for the production of both experimentally characterized polymorphs have been repeatedly reported in the literature up to 1975. Nevertheless, our attempts to produce crystals of the metastable form 2 suitable for single crystal X-ray diffraction failed until the structurally related molecule pregnenolone was introduced as an additive into the crystallization solution. Accurate low temperature crystal structures were obtained for forms 1 and 2, pregnenolone and a newly discovered pregnenolone–progesterone co-crystal, which appeared concomitantly with progesterone forms 1 and 2. Computational work based on the experimental crystal structures and those generated by a search for low energy structures showed that the crystallization of enantiomerically pure progesterone results in a more strained conformation compared with the racemate due to the rotation of the acetyl and 21-methyl groups. The role of impurities or additives in influencing crystallization outcome is discussed. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 3419–3431, 2007

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