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The polymorphism of progesterone: stabilization of a 'disappearing' polymorph by co-crystallization.

Authors
  • Lancaster, Robert W
  • Karamertzanis, Panagiotis G
  • Hulme, Ashley T
  • Tocher, Derek A
  • Lewis, Thomas C
  • Price, Sarah L
Type
Published Article
Journal
Journal of pharmaceutical sciences
Publication Date
Dec 01, 2007
Volume
96
Issue
12
Pages
3419–3431
Identifiers
PMID: 17621678
Source
Medline
License
Unknown

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.

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