Polymorphism of paracetamol: A new understanding of molecular flexibility through local methyl dynamics

Nikolaos Tsapatsaris, Boris A. Kolesov, Jennifer Fischer, Elena V. Boldyreva, Luke Daemen, Juergen Eckert, Heloisa N. Bordallo

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

This study focuses on the interplay of molecular flexibility and hydrogen bonding manifested in the monoclinic (form I) and orthorhombic (form II) polymorphs of paracetamol. By means of incoherent inelastic neutron scattering and density functional theory calculations, the relaxation processes related to the methyl side-group reorientation were analyzed in detail. Our computational study demonstrates the importance of considering quantum effects to explain how methyl reorientations and subtle conformational changes of the molecule are intertwined. Indeed, by analyzing the quasi elastic signal of the neutron data, we were able to show a unique and complex motional flexibility in form II, reflected by a coupling between the methyl and the phenyl reorientation. This is associated with a higher energy barrier of the methyl rotation and a lower Gibbs free energy when compared to form I. We put forward the idea that correlating solubility and molecular flexibility, through the relation between pKa and methyl rotation activation energy, might bring new insights to understanding and predicting drug bioavailability.

Original languageEnglish
Pages (from-to)1032-1041
Number of pages10
JournalMolecular Pharmaceutics
Volume11
Issue number3
DOIs
StatePublished - Mar 3 2014

Keywords

  • DFT calculations
  • hydrogen bonding
  • inelastic neutron scattering
  • methyl rotation
  • molecular drugs
  • polymorphism

Fingerprint Dive into the research topics of 'Polymorphism of paracetamol: A new understanding of molecular flexibility through local methyl dynamics'. Together they form a unique fingerprint.

  • Cite this

    Tsapatsaris, N., Kolesov, B. A., Fischer, J., Boldyreva, E. V., Daemen, L., Eckert, J., & Bordallo, H. N. (2014). Polymorphism of paracetamol: A new understanding of molecular flexibility through local methyl dynamics. Molecular Pharmaceutics, 11(3), 1032-1041. https://doi.org/10.1021/mp400707m