Polymorphic drugs examined with neutron spectroscopy: Is making more stable forms really that simple?

Research output: Contribution to journalJournal articleResearchpeer-review

Understanding  polymorphism  in  pharmaceutical  ingredients  is  a   long-­  standing  challenge.  A  well-­known  example  is  paracetamol,  C8H9NO2.   The  marketed  stable  form  I  crystallizes  with  corrugated  molecular  layers.   In  contrast,  form  II,  which  is  thermodynamically  favorable  at  high   pressures,  has  relatively  planar  layers  that  can  slip  over  each  other   without  difficulty,    is  metastable  at  ambient  conditions.  By  means  of   inelastic  neutron  scattering  we  demonstrated  that  the  lattice  modes  of   form  II  exhibit  a  sudden  1  meV  energy  shift  at  300  K  under  a  pressure  of   ca  0.4  GPa.  Moreover,  evidence  of  an  increase  of  the  vibrational  energy   in  both  polymorphs  was  found,  which  was  accompanied,  in  form  I,  by  an   unexpectedly  weak  increase  of  the  tunnel  splitting.  These  results   indicate  an  anisotropy  of  the  potential  surface  probed  by  the  methyl   rotor,  and  are  discussed  in  relation  to  the  differences  of  the  strength   of  the  hydrogen  bond  environment  for  each  polymorph.
Original languageEnglish
Article number124-128
JournalChemical Physics
Volume427
ISSN0301-0104
DOIs
Publication statusPublished - 12 Dec 2013

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