A tale of two polymorphic pharmaceuticals: Pyrithyldione and propyphenazone and their 1937 co-crystal patent

Andreas Lemmerer, Joel Bernstein, Ulrich J. Griesser, Volker Kahlenberg, Daniel M. Többens, Saul H. Lapidus, Peter W. Stephens, Catharine Esterhuysen

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


A co-crystal of two polymorphic active pharmaceutical ingredients (APIs), first reported and patented in 1937, has been prepared and thoroughly characterised, including crystal structure analysis. The existence of four crystal forms of one of the APIs, the sedative and hypnotic active pharmaceutical ingredient 3,3-diethyl-2,4(1H,3H)-pyridinedione, pyrithyldione (PYR), and of three crystal forms of the co-crystal-forming second API, the non-steroidal anti-inflammatory drug 1,2-dihydro-1,5-dimethyl-4-(1-methylethyl)- 2-phenyl-3H-pyrazol-3-one, propyphenazone (PROP), has been reported previously, but they have only been partly characterised. For both compounds, none of the metastable forms exist at room temperature. DSC, hot-stage microscopy, X-ray diffraction and powder synchrotron X-ray diffraction were employed to characterise the polymorphic forms and to determine the crystal structures of forms I-III of PYR and forms I and II of PROP. Something old, something novel: Back in 1937, Hoffmann-LaRoche patented a co-crystal of the two active pharmaceutical ingredients pyrithyldione and propyphenazone, shown here prepared by the Kofler contact method. This is an historic example that justifies the current drive to improve physical, chemical or physiological properties by using pharmaceutical co-crystals. In addition, the crystal structures of the polymorphs of the two drug compounds have been determined for the first time by careful manipulation of the stable forms.

Original languageEnglish
Pages (from-to)13445-13460
Number of pages16
JournalChemistry - A European Journal
Issue number48
StatePublished - 25 Nov 2011


  • X-ray diffraction
  • co-crystals
  • hot-stage microscopy
  • pharmaceuticals
  • polymorphism

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry


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